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Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

Lin Jia, Juan Piña-Crespo, Yonghe Li

Molecular Brain · 2019 · Review · CC BY

doi:10.1186/s13041-019-0525-5

Abstract

Alzheimer’s disease (AD) is an aging-related neurological disorder characterized by synaptic loss and dementia. Wnt/β-catenin signaling is an essential signal transduction pathway that regulates numerous cellular processes including cell survival. In brain, Wnt/β-catenin signaling is not only crucial for neuronal survival and neurogenesis, but it plays important roles in regulating synaptic plasticity and blood-brain barrier integrity and function. Moreover, activation of Wnt/β-catenin signaling inhibits amyloid-β production and tau protein hyperphosphorylation in the brain. Critically, Wnt/β-catenin signaling is greatly suppressed in AD brain via multiple pathogenic mechanisms. As such, restoring Wnt/β-catenin signaling represents a unique opportunity for the rational design of novel AD therapies.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Alzheimer’s disease (AD) is the most common form of dementia accompanied by detrimental cognitive deficits and pathological accumulation of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles. As one of the most important medical and social problems, there is an urgent need for effective therapies. The amyloid hypothesis is based on neuropathological evidence showing Aβ aggregates (amyloid plaques) in AD brain and on the identification of over 200 mutations in the amyloid precursor protein (APP) and presenilin (PSEN) genes that cause familial AD (FAD). The amyloid hypothesis has been the main driver of drug discovery efforts in the past 25 years; however, all clinical trials using anti-Aβ drugs as a treatment for AD have ended in failure. Therefore, current paradigms in AD drug discovery have shifted to the development of drugs that target the multiple disease processes that support the progression of AD pathology, and novel targeted therapies are urgently needed to prevent and treat AD.

The Wnt/β-catenin signaling pathway is a significant pathway regulating cell proliferation, migration and differentiation, and Wnt proteins are key drivers of adult stem cells in mammals. Studies have shown that dysregulated Wnt/β-catenin signaling plays an important role in the pathogenesis of AD. In this review, we summarize our current understanding of regulation and function of the Wnt/β-catenin signaling pathway in AD brain and provide evidence indicating that the Wnt/β-catenin signaling pathway represents a new attractive therapeutic target for drug discovery in AD.

Roles of Wnt/β-catenin signaling in physiological and pathophysiological processes in the brain

Wnt proteins are secreted glycoproteins that bind to the extracellular cysteine-rich domain of the Frizzled (Fzd) receptor family and Wnt co-receptor low density lipoprotein receptor-related protein 5 (LRP5) or LRP6 to activate the canonical Wnt/β-catenin signaling pathway. Binding of Wnt to the Fzd/LRP5/6 receptor complex results in inhibition of glycogen synthase kinase 3β (GSK3β) and stabilization of cytosolic β-catenin. Stabilized β-catenin then translocates into the nucleus, interacts with T-cell factor/lymphoid enhancing factor (TCF/LEF), and induces the expression of specific target genes (Fig. 1). Wnt/β-catenin signaling is tightly regulated at the cell surface by various secreted proteins and receptors. While Zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43) promote LRP5/6 degradation, the extracellular molecule R-spondin (Rspo) together with its receptors leucine rich repeat containing G protein-coupled receptor 4/5/6 (LGR4/5/6) induces ZNRF3/RNF43 turnover, making LRP5/6 available on the cell surface for activation of the Wnt/β-catenin signaling pathway (Fig. 1). Moreover, Dickkopf (DKK) and soluble Frizzled-related protein (sFRP) bind to LRP5/6 and Fzd, respectively, and prevent LRP-Wnt-Fz complex formation in response to Wnts (Fig. 1 b).

In the rest of this section, we summarize our current understanding of the roles of Wnt/β-catenin signaling on multiple physiological and pathophysiological processes in AD brain (Fig. 2).

Wnt/β-catenin signaling promotes neuronal survival and neurogenesis

The neurodegenerative process in AD is initially characterized by synaptic damage followed by neuronal loss. The Wnt/β-catenin signaling pathway is a key pathway controlling cell death and survival. Indeed, loss of Wnt/β-catenin signaling renders neuron more susceptible to Aβ-induced apoptosis, and activation of Wnt/β-catenin signaling rescues Aβ-induced neuronal death and behavioral deficits.

While there is a debate of the presence of neurogenesis in human adult brain, emerging evidence suggests that human hippocampus neurogenesis persists in aged adult brain and declines dramatically in AD brain. Importantly, numerous studies have demonstrated that Wnt/β-catenin signaling is a key regulator of adult hippocampal neurogenesis. Wnt7a plays a critical role in multiple steps of neurogenesis by activating Wnt/β-catenin signaling and specific downstream target genes involved in cell cycle control and neuronal differentiation. Moreover, astrocyte-secreted Wnt proteins are decreased in aged mice, leading to suppression of Wnt/β-catenin signaling, down-regulation of survivin levels in neural progenitor cells (NPCs) and impaired adult neurogenesis during aging. Interestingly, neurogenesis induced by anti-aggregant tau mutant is associated with the activation of Wnt/β-catenin signaling. Mechanistically, transcriptional activation of the mitotic regulator survivin, the basic helix-loop-helix transcription factor NeuroD1 and prospero-related homeodomain transcription factor Prox1, which all are essential for the generation of granule cells in the hippocampus, is dependent on activation of the Wnt/β-catenin signaling pathway.

Wnt/β-catenin signaling enhances synaptic plasticity

Synaptic plasticity is associated with higher brain functions such as learning and memory. Synapse loss, which occurs prior to neuronal death at early stages in AD brain, is a major correlate of cognitive impairment in AD brain. Recent studies have found that Wnt/β-catenin signaling is essential for synaptic plasticity. Wnt proteins are not only required for synapse formation, but they can modulate neurotransmission by acting both pre- and post-synaptically. Long-term potentiation (LTP) is considered a cellular correlate of learning, and studies have demonstrated that Wnt proteins can promote LTP. Significantly, neuronal activity can induce the release of several Wnt proteins such as Wnt1, Wnt2, Wnt3A and Wnt7a/b and decrease the expression of Wnt antagonist sFRP3; while LTP is severely impaired by functional blockade of endogenous Wnt proteins with Wnt antagonists DKK1 and SFRPs.

LRP6 is an essential Wnt co-receptor for activation of Wnt/β-catenin signaling on the cell surface. LRP6 is selectively localized to excitatory synapses, and is required for excitatory synapse development in vitro and in vivo. Moreover, neuronal deficiency of LRP6 results in synaptic and cognitive abnormalities in aged mice. All together, these studies indicate that neuronal LRP6-mediated Wnt/β-catenin signaling plays an important role in synaptic function and cognition.

DKK1 binds to LRP6 and blocks Wnt/β-catenin signaling on the cell surface. Mice with a dorsal hippocampal infusion of DKK1 exhibited impaired hippocampal-dependent novel object recognition memory with rapidly decreasing levels of key Wnt/β-catenin signaling proteins, including β-catenin, Cyclin D1, c-myc, Wnt7a, and PSD95. Induction of DKK1 expression in the hippocampus triggers synapse loss, synaptic dysfunction and memory impairment, all of which can be fully restored by reactivation of Wnt/β-catenin signaling after cessation of DKK1 expression in the hippocampus. Collectively, these findings further demonstrate the critical role of LRP6-mediated Wnt/β-catenin signaling in synaptic plasticity.

Wnt/β-catenin signaling is essential for the integrity and function of the blood-brain barrier (BBB)

The BBB protects the brain from exposure to neurotoxic blood-derived debris, cells and microbial pathogens. Therefore, BBB disruption allows influx of harmful substances into the brain, induces inflammatory and immune responses, and may subsequently initiate multiple pathways of neurodegeneration. BBB breakdown is an early biomarker of human cognitive impairment in AD. It is observed before dementia, neurodegeneration and/or brain atrophy occur. BBB disruption is a key pathogenic feature of AD, which includes increased BBB permeability, microbleeding, diminished glucose transport, impaired Pgp-1 function (Aβ clearance), perivascular accumulation of neurotoxic blood-derived products, and cellular infiltration and degeneration of pericytes and endothelial cells. Therefore, developing novel approaches that target BBB repair is a promising strategy for AD therapy.

In the past decade, studies have established that the Wnt/β-catenin pathway is a key pathway required not only for BBB formation but also for BBB integrity and function. By binding to Wnt receptor Fzd4 and Wnt co-receptor LRP5/6, Wnt ligands Wnt7a and Wnt7b, which are mainly produced by neurons and astrocytes in brain, activate Wnt/β-catenin signaling in BBB endothelial cells (ECs), and activation of Wnt/β-catenin signaling is a key driver of BBB formation and function. In addition, Reck, a GPI-anchored membrane protein, and Gpr124, an orphan GPCR, are essential cofactors on the cell surface for Wnt7a/Wnt7b-specific signaling in mammalian CNS angiogenesis, BBB integrity and function.

Brain ECs are held together by tight junctions, in which claudins are the main constituent. In addition, glucose transporter 1 (GLUT1), which is specifically expressed in BBB ECs, is responsible for the transport of glucose from the blood into the brain; and p-glycoprotein (Pgp-1) is an active efflux transporter highly expressed on the luminal surface of BBB endothelial cells. Mechanically, claudin-1, − 3 and − 5, the three major claudins expressed in brain ECs, are the transcriptional targets of Wnt/β-catenin signaling in BBB ECs. Moreover, Wnt/β-catenin signaling drives the expression of the BBB-specific glucose transporter GLUT1 and efflux transporter Pgp-1 in BBB ECs.

Wnt/β-catenin signaling inhibits BACE1 expression and suppresses Aβ production/aggregation

One of the two major hallmarks of AD is the accumulation of amyloid plaques between neurons in the brain. Recent studies have found that Wnt/β-catenin signaling is able to inhibit amyloidogenic processing of APP by suppressing the transcription of the β-site APP cleaving enzyme (BACE1). While activation of Wnt/β-catenin signaling reduces Aβ42 production and aggregation, Wnt inhibition induces opposite effects on APP processing and Aβ42 production/aggregation in a cellular model. Moreover, loss of Wnt/β-catenin signaling induces AD-like neuropathological hallmarks in wild-type mice, and accelerates the development of AD-like pathology in an AD mouse model overexpressed human APP with two FAD mutations.

Wnt/β-catenin signaling suppresses tau phosphorylation

Another major hallmark of AD is the presence of intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated forms of the microtubule-associated protein tau (MAPT) in neurons. GSK3β is an important kinase associated with hyperphosphorylation of tau protein (p-tau) at AD-relevant phosphorylation sites. Activation of Wnt/β-catenin signaling results in the inhibition of GSK3β activity and subsequent suppression of tau phosphorylation. Indeed, the Wnt antagonist DKK1 is able to inhibit Wnt/β-catenin signaling and induce both tau hyperphosphorylation and neuronal death. In contrast, activation of Wnt/β-catenin signaling can inhibit Aβ-induced tau hyperphosphorylation and neuronal death.

Wnt/β-catenin signaling in microglia activity and neuroinflammation

Glia-mediated neuroinflammation is another pathological hallmark of AD. Genetic factors such as rare variants of TREM2 (triggering receptor expressed on myeloid cells-2) strongly increase the risk of developing AD, confirming a role of neuroinflammation as a driving force in AD. Interestingly, TREM2, which is exclusively expressed by microglia in brain, can promote microglial survival by activating Wnt/β-catenin signaling through posttranslational regulation of β-catenin. On the other hand, Wnt antagonist sFRP1 and sFRP2 act as negative modulators of the disintegrin and metalloproteinase domain 10 protein (ADAM10), which is an α-secretase responsible for shedding of the TREM2 ectodomain to produce soluble TREM2 (sTREM2); and recent studies indicate that sTREM2 displays a protective role in AD brain. Moreover, activation of Wnt/β-catenin signaling with Wnt3a protein, LiCl, or TDZD-8 rescued microglia survival and microgliosis in Trem2−/− microglia and Trem2−/− mouse brain. In addition, postnatal neuronal deletion of Wnt co-receptor LRP6 leads to microglial activation and neuroinflammation. However, there are conflicting results regarding the roles of Wnt/β-catenin signaling on microglial activation and neuroinflammation. Wnt/β-catenin signaling is active in microglia during neuroinflammation, raising the question as to whether enhanced Wnt/β-catenin signaling in microglia is harmful in AD brain, and further experimental work will be required to resolve this controversy.

Wnt/β-catenin signaling is diminished in AD brain

While the Wnt/β-catenin signaling pathway is essential for brain function, this pathway is greatly suppressed via multiple pathogenic mechanisms in AD brain.

Wnt/β-catenin signaling is down-regulated in the aging brain

It is well established that increasing age is the greatest risk factor for AD. Mounting evidence indicates a down-regulation of Wnt/β-catenin signaling in the aging brain, which may contribute to reduced neurogenesis and cognitive impairment. In the aging brain, expression of Wnt proteins (such as Wnt 2, 3, 4, Wnt7b and Wnt10b) and disheveled (Dvl) proteins (such as Dvl2 and Dvl3) is down-regulated, while expression of Wnt antagonist DKK1 is up-regulated; leading to the suppression of Wnt/β-catenin signaling. Importantly, the age-associated reduction in astrocytic levels of Wnt proteins impairs adult neurogenesis, and rescue of secreted Wnt protein levels by exercise promotes adult neurogenesis.

Dysregulation and malfunction of Wnt co-receptor LRP6 in AD brain

A growing body of evidence shows dysregulation and loss of function of Wnt co-receptor LRP6 contributes to down-regulation of Wnt/β-catenin signaling in AD. Firstly, two LRP6 SNPs and an alternatively splice variant that display impaired Wnt/β-catenin signaling activity, are associated with increased risk of developing AD. Secondly, expression of LRP6 is downregulated in AD brain, and deficiency in LRP6-mediated Wnt/β-catenin signaling contributes to synaptic dysfunction and amyloid pathology in AD. Thirdly, apolipoprotein E4 (ApoE4), the most important risk factor for late-onset AD, can inhibit Wnt/β-catenin signaling in neuronal LRP6-expressing PC-12 cells. Finally, LRP6 physically interacts with APP and suppresses Aβ production, while the Swedish familial AD variant of APP (APPSwe) displays reduced activation of Wnt/β-catenin signaling.

Up-regulation of DKK1 expression results in suppression of Wnt/β-catenin signaling in AD brain

Aβ peptides can induce DKK1 expression and inhibit Wnt/β-catenin signaling in primary cortical neurons, and DKK1 expression in the adult hippocampus can induce synapse degeneration. Moreover, Aβ-induced synaptic loss can be attenuated by DKK1-neutralizing antibodies in mouse brain slices. DKK1 is upregulated in postmortem AD brain, where it colocalizes with neurofibrillary tangles and distrophic neurites. The upregulation DKK1 in AD brain and its colocalization with hyperphosphorylated tau have been also demonstrated in transgenic AD-like mouse models. Critically, there is a pathogenic-positive feedback loop with Aβ stimulating DKK1 expression, thereby promoting synapse loss and driving further Aβ production.

Activation of GSK3β in AD brain

The binding of Wnt protein to Fzd/LRP results in inhibition of GSK3β and consequent activation of Wnt/β-catenin signaling. GSK3β is one of two major kinases responsible for β-catenin phosphorylation, and activation of GSK3β induces β-catenin phosphorylation and degradation. The increased activity of GSK3β has been found in the brain of AD patients, which could be resulted from the up-regulation of DKK1 and down-regulation of LRP6 in the AD brain. A recent study shows that a significant decrease in β-catenin protein levels is inversely associated with increased activation of GSK3β in the prefrontal cortical lobe structures of human AD brains, further strengthening the notion that GSK3β activity is associated with Wnt/β-catenin signaling in AD brain. Notably, GSK3β is a key kinase for tau phosphorylation, and overactivation of GSK3β is intimately linked to tau hyperphosphorylation, Aβ deposition, plaque-associated microglial-mediated inflammatory responses and memory impairment.

AD-associated APP mutants suppress Wnt/β-catenin signaling in AD brain

APP mutations can cause early-onset FAD. While studies using wild-type APP produced conflicting results regarding the activity of Wnt/β-catenin signaling, studies with FAD-associated APP mutants consistently revealed that Wnt/β-catenin signaling is inhibited by FAD-associated APP mutants. Studies in APP transgenic and knockout animal models and human AD brains demonstrated that APP and β-catenin co-localize and form a physical complex that is not present in healthy controls, and that β-catenin expression is greatly increased in hippocampal CA1 pyramidal cells from APP knockout mice. Studies in primary neurons showed that overexpression of APP and its mutants promoted β-catenin degradation, while APP knockdown produced opposite effects.

Regulation of Wnt/β-catenin signaling by PSEN1 and its AD-associated mutants in AD brain

Mutations in PSEN1 are among the major causes of early-onset FAD. In the hippocampus, PSEN1 and PSEN2 play an important role in the regulation of synaptic plasticity, Aβ production and intracellular Ca2+ homeostasis. Many studies support the notion that PSEN1 and its mutants associated with FAD are negative regulators of Wnt/β-catenin signaling, although inconsistent results with respect to the effects of FAD-associated PSEN1 mutants on Wnt/β-catenin signaling have been reported. In a genetic modifier screening, Drosophila PSEN was identified as a suppressor of wingless/Wnt signaling. PSEN deficiency enhances Wnt/β-catenin signaling through relocalization of GSK3 to the late-endosomal compartment, and facilitates the stepwise phosphorylation of β-catenin independently of the Wnt-controlled Axin complex. Moreover, the expression of β-catenin is reduced in AD patients carrying PSEN1 mutations, and PSEN1 mutations associated with AD cause a perturbation in the intracellular trafficking of β-catenin, decrease the stability and/or enhance the degradation of β-catenin. However, some FAD-associated PSEN1 mutants such as FAD-PSEN1L286V and -PSEN1M146L fail to induce β-catenin degradation. Instead, FAD-PSEN1L286V can upregulate a subset of TCF/β-catenin transcription by enhancing the level of cAMP-response element-binding protein (CREB)-binding protein (CBP).

Targeting Wnt/β-catenin signaling in AD therapy

Giving that the Wnt/β-catenin pathway is greatly suppressed in the brain of AD patients, restoring Wnt/β-catenin signaling represents a unique opportunity for rational AD therapy (Fig. 2).

The active lifestyle-induced cognitive improvement is associated with activation of Wnt/β-catenin signaling

A physically active lifestyle in adults and the elderly can improve brain health and reduce cognitive impairment associated with aging. It has been reported that the enhancement of cognitive function by lifelong exercise is associated with induction of Wnt gene expression in the hippocampus. Particularly, long-term moderate exercise and environmental enrichment can stimulate Wnt/β-catenin signaling by reducing DKK1 protein levels and increasing LRP6 and Wnt3a protein levels in hippocampus of adult animals. These findings suggest that activation of Wnt/β-catenin signaling is a potential mechanism underlying the cognitive improvement associated with an active lifestyle.

Estrogen-induced neuroprotection is associated with inhibition of DKK1 expression

Estrogens can exert numerous protective actions in the adult brain, and reduced estrogen levels in adulthood are associated with increased risk of AD in women. In female rats, long-term estrogen deprivation leads to elevation of basal DKK1 expression and suppression of Wnt/β-catenin signaling in the CA1 hippocampal region. Moreover, estrogen-induced neuroprotection and attenuation of tau phosphorylation are associated with DKK1 inhibition and subsequent activation of Wnt/β-catenin signaling. Together, these findings suggest that inhibition of DKK1 is a potential mechanism for estrogen-induced neuroprotection.

GSK3β inhibitors

The activity of GSK3β is negatively regulated by Wnt/β-catenin signaling. Given the key role of GSK3 activity on the pathogenesis of AD, various GSK3β inhibitors have been shown to inhibit tau hyperphosphorylation and reduce Aβ levels in both neuronal and nonneuronal cells, and rescue cognitive deficits in several murine models of AD. However, due to the wide range of GSK3β substrates and physiological actions, the use of GSK3β inhibitors in clinical studies in AD patients has been disappointing. Therefore, novel GSK3β inhibitors that selectively regulate the activity of this kinase in Wnt/β-catenin signaling in brain are highly desirable.

DKK1 inhibitors

Suppression of Wnt/β-catenin signaling by Aβ-induced up-regulation of DKK1 expression in AD brain suggests DKK1 inhibition is a potential therapeutic strategy for restoring Wnt/β-catenin signaling in AD. Indeed, it has been found that DKK1 anti-sense oligonucleotides (ASO) attenuate neuronal apoptosis and prevent tau hyperphosphorylation in Aβ-treated neurons, and that DKK1-neutralizing antibodies attenuate synapse loss induced by Aβ in mouse brain slices.

A virtual screen of the National Cancer Institute database for chemical compounds identified a small molecule, IIIC3 (NCI8642, gallocyanine), as a DKK1 inhibitor. IIIC3 can inhibit DKK1 binding to LRP6 with an IC50 of 3 μM, and revert DKK1-mediated inhibition of Wnt/β-catenin signalling. Moreover, IIIC3 can reduce basal blood-glucose concentrations and improve glucose tolerance in mice. Interestingly, IIIC3 and its derivatives can decrease DKK1-induced Tau phosphorylation. However, it is unclear whether these gallocyanine inhibitors of DKK1 can cross the BBB.

Other activators of Wnt/β-catenin signaling

WASP-1 is a small molecule Wnt activator with an EC50 of about 250 nM in the Wnt reporter assays. Although the exact mechanism of action of this compound is unclear, activation of Wnt/β-catenin signaling by bilateral intra-hippocampal infusion of WASP-1 rescues memory loss and improves synaptic dysfunction in murine models of AD.

Curcumin, a natural compound found in the plant turmeric (Curcuma longa), displays protective effects in various animal models of AD. Studies have shown that curcumin can potentially promote Wnt/β-catenin signaling by increasing the expression of Wnt proteins and Wnt co-receptor LRP5/6 and suppressing the expression of Wnt antagonist DKK1. However, because of its poor brain bioavailability, curcumin is of limited use in human AD patients, and there is currently lack of clinical evidence to support its therapeutic use in AD patients. Recently, it has been reported that curcumin nanoparticles, which exhibit increased brain bioavailability, potently stimulate adult neurogenesis and mitigate cognitive impairment in the AD model via activation of the Wnt/β-catenin pathway.

Statins are a class of drugs typically used to lower blood levels of cholesterol by reducing the production of cholesterol by the liver, and many studies suggest that statin use might protect against AD pathology. Several studies have shown that statins are activators of Wnt/β-catenin signaling. Mechanistically, statins enhance Wnt/β-catenin signaling through regulation of isoprenoid synthesis, which is not associated with cholesterol levels. Interestingly, it has been demonstrated that lovastatin protects neuronal cells from Aβ-induced apoptosis via activation of Wnt/β-catenin signaling, and that simvastatin suppresses neural cell apoptosis and enhances locomotor recovery by stimulating Wnt/β-catenin signaling after spinal cord injury. Moreover, simvastatin can promote Wnt/β-catenin signaling in the hippocampus of adult mice, and enhance neurogenesis both in cultured adult neural stem cells and the mouse hippocampus. All together, these findings suggest that activation of Wnt/β-catenin signaling is one of the mechanisms by which statins are beneficial in AD and other neurological disorders.

Conclusion and perspectives

Compared to a large number of Wnt inhibitors as potential agents for cancer prevention and treatment, there are only a few Wnt activators reported in the literature. Particularly, there are no specific BBB-permeant Wnt activators that can be used as potential candidates for the treatment of AD or other neurological disorders. While Wnt/β-catenin signaling is critical for synaptic plasticity, neuronal survival, neurogenesis and many other brain functions, it is greatly diminished in the brain of AD patients. Therefore, small molecule Wnt activators that restore Wnt/β-catenin signaling in brain, particularly those targeting Wnt antagonist DKK1, Wnt receptor LRP6 and tau regulator GSK3β, could represent novel therapeutic tools for the treatment for AD. In addition, emerging evidence indicates that Wnt/β-catenin signaling is also disrupted in other neurodegenerative disorders such as Parkinson’s disease. Thus, Wnt activators hold a great therapeutic potential for other neurological disorders.

It is well established that Wnt/β-catenin signaling plays a key role in the regulation of bone mineral density, and that the Wnt/β-catenin signaling pathway is an attractive target for therapeutic intervention to restore bone strength in patients with osteoporosis disorders. Interestingly, AD patients have a much greater risk of suffering osteoporosis. In addition, low bone mineral density phenotypes are manifested in AD mouse models. Particularly, a recent study demonstrated that Wnt/β-catenin signaling is disrupted both in brain and bone of the htau mouse model of tauopathy, which has an early low bone mineral density phenotype. Therefore, osteoporosis and AD could share a key mechanism of pathogenesis, and Wnt activators might not only reduce cognitive impairment but also prevent bone loss in the AD patients.

There is always a concern that overstimulation of Wnt/β-catenin signaling can promote cancer because aberrant activation of Wnt/β-catenin signaling can lead to tumor formation. However, there are no reports of increased incidence of cancer in families carrying LRP5 gain-of-function mutations, and Sost- or Dkk1-deficient animals do not have an increased risk of tumor developments. Nevertheless, the therapeutic application of Wnt activators should be given precisely to restore, but not overactivate, the Wnt/β-catenin signaling pathway in AD patients.

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    Zhu Y, Demidov ON, Goh AM, Virshup DM, Lane DP, Bulavin DV. Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging. J Clin Invest. 2014;124:3263-3273.

    Not in our library10.1172/jci73015

  31. 31.

    Qiu CW, Liu ZY, Hou K, Liu SY, Hu YX, Zhang L, et al. Wip1 knockout inhibits neurogenesis by affecting the Wnt/beta-catenin signaling pathway in focal cerebral ischemia in mice. Exp Neurol. 2018;309:44-53.

    Not in our library10.1016/j.expneurol.2018.07.011

  32. 32.

    Qu Q, Sun G, Murai K, Ye P, Li W, Asuelime G, et al. Wnt7a regulates multiple steps of neurogenesis. Mol Cell Biol. 2013;33:2551-2559.

    Not in our library10.1128/mcb.00325-13

  33. 33.

    Miranda CJ, Braun L, Jiang Y, Hester ME, Zhang L, Riolo M, et al. Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling. Aging Cell. 2012;11:542-552.

    Not in our library10.1111/j.1474-9726.2012.00816.x

  34. 34.
    Anti-aggregant tau mutant promotes neurogenesis · 2017
    Not checked
  35. 35.

    Schneider R, Koop B, Schroter F, Cline J, Ingwersen J, Berndt C, et al. Activation of Wnt signaling promotes hippocampal neurogenesis in experimental autoimmune encephalomyelitis. Mol Neurodegener. 2016;11:53.

    Not in our library10.1186/s13024-016-0117-0

  36. 36.

    DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990;27:457-464.

    Not in our library10.1002/ana.410270502

  37. 37.

    Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572-580.

    Not in our library10.1002/ana.410300410

  38. 38.

    McLeod F, Salinas PC. Wnt proteins as modulators of synaptic plasticity. Curr Opin Neurobiol. 2018;53:90-95.

    Not in our library10.1016/j.conb.2018.06.003

  39. 39.

    Buechler J, Salinas PC. Deficient Wnt signaling and synaptic vulnerability in Alzheimer's disease: emerging roles for the LRP6 receptor. Front Synaptic Neurosci. 2018;10:38.

    Not in our library10.3389/fnsyn.2018.00038

  40. 40.

    Titley HK, Brunel N, Hansel C. Toward a Neurocentric view of learning. Neuron. 2017;95:19-32.

    Not in our library10.1016/j.neuron.2017.05.021

  41. 41.

    Chen J, Park CS, Tang SJ. Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation. J Biol Chem. 2006;281:11910-11916.

    Not in our library10.1074/jbc.m511920200

  42. 42.

    Cerpa W, Gambrill A, Inestrosa NC, Barria A. Regulation of NMDA-receptor synaptic transmission by Wnt signaling. J Neurosci. 2011;31:9466-9471.

    Not in our library10.1523/jneurosci.6311-10.2011

  43. 43.
    Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus · 2016
    No notice
  44. 44.

    McLeod F, Bossio A, Marzo A, Ciani L, Sibilla S, Hannan S, et al. Wnt signaling mediates LTP-dependent spine plasticity and AMPAR localization through Frizzled-7 receptors. Cell Rep. 2018;23:1060-1071.

    Not in our library10.1016/j.celrep.2018.03.119

  45. 45.

    Ataman B, Ashley J, Gorczyca M, Ramachandran P, Fouquet W, Sigrist SJ, et al. Rapid activity-dependent modifications in synaptic structure and function require bidirectional Wnt signaling. Neuron. 2008;57:705-718.

    Not in our library10.1016/j.neuron.2008.01.026

  46. 46.

    Wayman GA, Impey S, Marks D, Saneyoshi T, Grant WF, Derkach V, et al. Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron. 2006;50:897-909.

    Not in our library10.1016/j.neuron.2006.05.008

  47. 47.

    Ciani L, Marzo A, Boyle K, Stamatakou E, Lopes DM, Anane D, et al. Wnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1. Nat Commun. 2015;6:8302.

    Not in our library10.1038/ncomms9302

  48. 48.

    Sharma K, Choi SY, Zhang Y, Nieland TJ, Long S, Li M, et al. High-throughput genetic screen for synaptogenic factors: identification of LRP6 as critical for excitatory synapse development. Cell Rep. 2013;5:1330-1341.

    Not in our library10.1016/j.celrep.2013.11.008

  49. 49.

    Liu CC, Tsai CW, Deak F, Rogers J, Penuliar M, Sung YM, et al. Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer's disease. Neuron. 2014;84:63-77.

    Not in our library10.1016/j.neuron.2014.08.048

  50. 50.

    Fortress AM, Schram SL, Tuscher JJ, Frick KM. Canonical Wnt signaling is necessary for object recognition memory consolidation. J Neurosci. 2013;33:12619-12626.

    Not in our library10.1523/jneurosci.0659-13.2013

  51. 51.

    Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133-150.

    Not in our library10.1038/nrneurol.2017.188

  52. 52.

    Sweeney MD, Kisler K, Montagne A, Toga AW, Zlokovic BV. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci. 2018;21:1318-1331.

    Not in our library10.1038/s41593-018-0234-x

  53. 53.
    Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism · 2018
    Corrected
  54. 54.

    Montagne A, Zhao Z, Zlokovic BV. Alzheimer's disease: a matter of blood-brain barrier dysfunction? J Exp Med. 2017;214:3151-3169.

    Not in our library10.1084/jem.20171406

  55. 55.

    Nation DA, Sweeney MD, Montagne A, Sagare AP, LM D’O, Pachicano M, et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019.

    Not in our library10.1038/s41591-018-0297-y

  56. 56.
    Blood–brain-barriers in aging and in Alzheimer’s disease · 2013
    No notice
  57. 57.
    Novel insights into the development and maintenance of the blood–brain barrier · 2014
    No notice
  58. 58.
    Functional morphology of the blood–brain barrier in health and disease · 2018
    No notice
  59. 59.

    Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929-11947.

    Not in our library10.1523/jneurosci.1860-14.2014

  60. 60.

    Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, et al. Wnt/beta-catenin signaling controls development of the blood-brain barrier. J Cell Biol. 2008;183:409-417.

    Not in our library10.1083/jcb.200806024

  61. 61.

    Daneman R, Agalliu D, Zhou L, Kuhnert F, Kuo CJ, Barres BA. Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc Natl Acad Sci U S A. 2009;106:641-646.

    Not in our library10.1073/pnas.0805165106

  62. 62.

    Stenman JM, Rajagopal J, Carroll TJ, Ishibashi M, McMahon J, McMahon AP. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Sci. 2008;322:1247-1250.

    Not in our library10.1126/science.1164594

  63. 63.

    Zhou Y, Nathans J. Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling. Dev Cell. 2014;31:248-256.

    Not in our library10.1016/j.devcel.2014.08.018

  64. 64.

    Cho C, Smallwood PM, Nathans J. Reck and Gpr124 are essential receptor cofactors for Wnt7a/Wnt7b-specific signaling in mammalian CNS angiogenesis and blood-brain barrier regulation. Neuron. 2017;95:1221-1225.

    Not in our library10.1016/j.neuron.2017.08.032

  65. 65.

    Chang J, Mancuso MR, Maier C, Liang X, Yuki K, Yang L, et al. Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Nat Med. 2017;23:450-460.

    Not in our library10.1038/nm.4309

  66. 66.

    Vallon M, Yuki K, Nguyen TD, Chang J, Yuan J, Siepe D, et al. A RECK-WNT7 receptor-ligand interaction enables isoform-specific regulation of Wnt bioavailability. Cell Rep. 2018;25:339-349.

    Not in our library10.1016/j.celrep.2018.09.045

  67. 67.

    Tran KA, Zhang X, Predescu D, Huang X, Machado RF, Gothert JR, et al. Endothelial beta-catenin signaling is required for maintaining adult blood-brain barrier integrity and central nervous system homeostasis. Circ. 2016;133:177-186.

    Not in our library10.1161/circulationaha.115.015982

  68. 68.
    Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis · 2015
    No notice
  69. 69.
    Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury · 2018
    No notice
  70. 70.

    Zhou Y, Wang Y, Tischfield M, Williams J, Smallwood PM, Rattner A, et al. Canonical WNT signaling components in vascular development and barrier formation. J Clin Invest. 2014;124:3825-3846.

    Not in our library10.1172/jci76431

  71. 71.

    Lim JC, Kania KD, Wijesuriya H, Chawla S, Sethi JK, Pulaski L, et al. Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells. J Neurochem. 2008;106:1855-1865.

    Not in our library10.1111/j.1471-4159.2008.05537.x

  72. 72.

    Bloom GS. Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014;71:505-508.

    Not in our library10.1001/jamaneurol.2013.5847

  73. 73.

    Li H, Liu CC, Zheng H, Huang TY. Amyloid, tau, pathogen infection and antimicrobial protection in Alzheimer's disease -conformist, nonconformist, and realistic prospects for AD pathogenesis. Transl Neurodegener. 2018;7:34.

    Not in our library10.1186/s40035-018-0139-3

  74. 74.

    Parr C, Mirzaei N, Christian M, Sastre M. Activation of the Wnt/beta-catenin pathway represses the transcription of the beta-amyloid precursor protein cleaving enzyme (BACE1) via binding of T-cell factor-4 to BACE1 promoter. FASEB J. 2015;29:623-635.

    Not in our library10.1096/fj.14-253211

  75. 75.

    Tapia-Rojas C, Burgos PV, Inestrosa NC. Inhibition of Wnt signaling induces amyloidogenic processing of amyloid precursor protein and the production and aggregation of amyloid-beta (Abeta)42 peptides. J Neurochem. 2016;139:1175-1191.

    Not in our library10.1111/jnc.13873

  76. 76.

    Tapia-Rojas C, Inestrosa NC. Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer's disease in J20-APP transgenic and wild-type mice. J Neurochem. 2018;144:443-465.

    Not in our library10.1111/jnc.14278

  77. 77.

    Wu XL, Pina-Crespo J, Zhang YW, Chen XC, Xu HX. Tau-mediated Neurodegeneration and Potential Implications in Diagnosis and Treatment of Alzheimer's Disease. Chin Med J (Engl). 2017;130:2978-2990.

    Not in our library10.4103/0366-6999.220313

  78. 78.

    Hernandez F, Lucas JJ, Avila J. GSK3 and tau: two convergence points in Alzheimer's disease. J Alzheimers Dis. 2013;33(Suppl 1):S141-S144.

    Not in our library10.3233/jad-2012-129025

  79. 79.

    Scali C, Caraci F, Gianfriddo M, Diodato E, Roncarati R, Pollio G, et al. Inhibition of Wnt signaling, modulation of tau phosphorylation and induction of neuronal cell death by DKK1. Neurobiol Dis. 2006;24:254-265.

    Not in our library10.1016/j.nbd.2006.06.016

  80. 80.

    Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, et al. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci. 2004;24:6021-6027.

    Not in our library10.1523/jneurosci.1381-04.2004

  81. 81.

    Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015;14:388-405.

    Not in our library10.1016/s1474-4422(15)70016-5

  82. 82.
    Glial contributions to neurodegeneration in tauopathies · 2017
    No notice
  83. 83.
    Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease · 2018
    No notice
  84. 84.
    Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk · 2017
    No notice
  85. 85.
    New insights into the role of TREM2 in Alzheimer’s disease · 2018
    No notice
  86. 86.
    TREM2 in Neurodegenerative Diseases · 2017
    No notice
  87. 87.
    TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy · 2017
    No notice
  88. 88.

    Zhao Y, Wu X, Li X, Jiang LL, Gui X, Liu Y, et al. TREM2 is a receptor for beta-amyloid that mediates microglial function. Neuron. 2018;97:1023-1031.

    Not in our library10.1016/j.neuron.2018.01.031

  89. 89.

    Zheng H, Jia L, Liu CC, Rong Z, Zhong L, Yang L, et al. TREM2 promotes microglial survival by activating Wnt/beta-catenin pathway. J Neurosci. 2017;37:1772-1784.

    Not in our library10.1523/jneurosci.2459-16.2017

  90. 90.

    Esteve P, Sandonis A, Cardozo M, Malapeira J, Ibanez C, Crespo I, et al. SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis. Nat Neurosci. 2011;14:562-U43.

    Not in our library10.1038/nn.2794

  91. 91.
    Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model · 2019
    Corrected
  92. 92.

    Ewers Michael, Franzmeier Nicolai, Suárez-Calvet Marc, Morenas-Rodriguez Estrella, Caballero Miguel Angel Araque, Kleinberger Gernot, Piccio Laura, Cruchaga Carlos, Deming Yuetiva, Dichgans Martin, Trojanowski John Q., Shaw Leslie M., Weiner Michael W., Haass Christian. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Science Translational Medicine. 2019;11(507):eaav6221.

    Not in our library10.1126/scitranslmed.aav6221

  93. 93.

    Deming Yuetiva, Filipello Fabia, Cignarella Francesca, Cantoni Claudia, Hsu Simon, Mikesell Robert, Li Zeran, Del-Aguila Jorge L, Dube Umber, Farias Fabiana Geraldo, Bradley Joseph, Budde John, Ibanez Laura, Fernandez Maria Victoria, Blennow Kaj, Zetterberg Henrik, Heslegrave Amanda, Johansson Per M, Svensson Johan, Nellgård Bengt, Lleo Alberto, Alcolea Daniel, Clarimon Jordi, Rami Lorena, Molinuevo José Luis, Suárez-Calvet Marc, Morenas-Rodríguez Estrella, Kleinberger Gernot, Ewers Michael, Harari Oscar, Haass Christian, Brett Thomas J, Benitez Bruno A., Karch Celeste M., Piccio Laura, Cruchaga Carlos. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk. Science Translational Medicine. 2019;11(505):eaau2291.

    Not in our library10.1126/scitranslmed.aau2291

  94. 94.

    Halleskog C, Mulder J, Dahlstrom J, Mackie K, Hortobagyi T, Tanila H, et al. WNT signaling in activated microglia is proinflammatory. Glia. 2011;59:119-131.

    Not in our library10.1002/glia.21081

  95. 95.

    Herrup K. Reimagining Alzheimer's disease--an age-based hypothesis. J Neurosci. 2010;30:16755-16762.

    Not in our library10.1523/jneurosci.4521-10.2010

  96. 96.
    The age factor in Alzheimer’s disease · 2015
    No notice
  97. 97.

    Garcia-Velazquez L, Arias C. The emerging role of Wnt signaling dysregulation in the understanding and modification of age-associated diseases. Ageing Res Rev. 2017;37:135-145.

    Not in our library10.1016/j.arr.2017.06.001

  98. 98.

    Hofmann JW, McBryan T, Adams PD, Sedivy JM. The effects of aging on the expression of Wnt pathway genes in mouse tissues. Age (Dordr). 2014:36–9618.

    Not in our library10.1007/s11357-014-9618-3

  99. 99.

    Orellana AM, Vasconcelos AR, Leite JA, de Sa LL, Andreotti DZ, Munhoz CD, et al. Age-related neuroinflammation and changes in AKT-GSK-3beta and WNT/ beta-CATENIN signaling in rat hippocampus. Aging (Albany NY). 2015;7:1094-1111.

    Not in our library10.18632/aging.100853

  100. 100.

    Bayod S, Felice P, Andres P, Rosa P, Camins A, Pallas M, et al. Downregulation of canonical Wnt signaling in hippocampus of SAMP8 mice. Neurobiol Aging. 2015;36:720-729.

    Not in our library10.1016/j.neurobiolaging.2014.09.017

  101. 101.

    De Ferrari GV, Papassotiropoulos A, Biechele T, Wavrant De-Vrieze F, Avila ME, Major MB, et al. Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease. Proc Natl Acad Sci U S A. 2007;104:9434-9439.

    Not in our library10.1073/pnas.0603523104

  102. 102.

    Alarcon MA, Medina MA, Hu Q, Avila ME, Bustos BI, Perez-Palma E, et al. A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease. Neurobiol Aging. 1709;2013(34):e9-18.

    Not in our library10.1016/j.neurobiolaging.2012.11.004

  103. 103.
    Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease · 2019
    No notice
  104. 104.

    Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019.

    Not in our library10.1038/s41582-019-0228-7

  105. 105.

    Caruso A, Motolese M, Iacovelli L, Caraci F, Copani A, Nicoletti F, et al. Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells. J Neurochem. 2006;98:364-371.

    Not in our library10.1111/j.1471-4159.2006.03867.x

  106. 106.

    Elliott C, Rojo AI, Ribe E, Broadstock M, Xia W, Morin P, et al. A role for APP in Wnt signalling links synapse loss with beta-amyloid production. Transl Psychiatry. 2018;8:179.

    Not in our library10.1038/s41398-018-0231-6

  107. 107.

    Purro SA, Dickins EM, Salinas PC. The secreted Wnt antagonist Dickkopf-1 is required for amyloid beta-mediated synaptic loss. J Neurosci. 2012;32:3492-3498.

    Not in our library10.1523/jneurosci.4562-11.2012

  108. 108.

    Rosi MC, Luccarini I, Grossi C, Fiorentini A, Spillantini MG, Prisco A, et al. Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease. J Neurochem. 2010;112:1539-1551.

    Not in our library10.1111/j.1471-4159.2009.06566.x

  109. 109.

    Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012;13:767-779.

    Not in our library10.1038/nrm3470

  110. 110.

    Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108:837-847.

    Not in our library10.1016/s0092-8674(02)00685-2

  111. 111.
    The GSK3 hypothesis of Alzheimer’s disease · 2007
    No notice
  112. 112.
    GSK-3β, a pivotal kinase in Alzheimer disease · 2014
    No notice
  113. 113.

    Folke J, Pakkenberg B, Brudek T. Impaired Wnt signaling in the prefrontal cortex of Alzheimer's disease. Mol Neurobiol. 2019;56:873-891.

    Not in our library10.1007/s12035-018-1103-z

  114. 114.

    Zhu H, Zhang W, Zhao Y, Shu X, Wang W, Wang D, et al. GSK3beta-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions. Mol Neurodegener. 2018;13:62.

    Not in our library10.1186/s13024-018-0295-z

  115. 115.

    Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nat. 1991;349:704-706.

    Not in our library10.1038/349704a0

  116. 116.

    Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996;2:864-870.

    Not in our library10.1038/nm0896-864

  117. 117.

    Chen Y, Bodles AM. Amyloid precursor protein modulates beta-catenin degradation. J Neuroinflammation. 2007;4:29.

    Not in our library10.1186/1742-2094-4-29

  118. 118.

    Zhang N, Parr CJC, Birch AM, Goldfinger MH, Sastre M. The amyloid precursor protein binds to beta-catenin and modulates its cellular distribution. Neurosci Lett. 2018;685:190-195.

    Not in our library10.1016/j.neulet.2018.08.044

  119. 119.

    Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nat. 1995;375:754-760.

    Not in our library10.1038/375754a0

  120. 120.

    Lee SH, Lutz D, Mossalam M, Bolshakov VY, Frotscher M, Shen J. Presenilins regulate synaptic plasticity and mitochondrial calcium homeostasis in the hippocampal mossy fiber pathway. Mol Neurodegener. 2017;12:48.

    Not in our library10.1186/s13024-017-0189-5

  121. 121.

    Zoltowska KM, Maesako M, Lushnikova I, Takeda S, Keller LJ, Skibo G, et al. Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid beta production. Mol Neurodegener. 2017;12:15.

    Not in our library10.1186/s13024-017-0159-y

  122. 122.

    Nishimura M, Yu G, Levesque G, Zhang DM, Ruel L, Chen F, et al. Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of beta-catenin, a component of the presenilin protein complex. Nat Med. 1999;5:164-169.

    Not in our library10.1038/5526

  123. 123.

    Weihl CC, Miller RJ, Roos RP. The role of beta-catenin stability in mutant PS1-associated apoptosis. Neuroreport. 1999;10:2527-2532.

    Not in our library10.1097/00001756-199908200-00017

  124. 124.

    Weihl CC, Ghadge GD, Kennedy SG, Hay N, Miller RJ, Roos RP. Mutant presenilin-1 induces apoptosis and downregulates Akt/PKB. J Neurosci. 1999;19:5360-5369.

    Not in our library10.1523/jneurosci.19-13-05360.1999

  125. 125.

    Cox RT, McEwen DG, Myster DL, Duronio RJ, Loureiro J, Peifer M. A screen for mutations that suppress the phenotype of Drosophila armadillo, the beta-catenin homolog. Genet. 2000;155:1725-1740.

    Not in our library10.1093/genetics/155.4.1725

  126. 126.

    Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, et al. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell. 2002;110:751-762.

    Not in our library10.1016/s0092-8674(02)00970-4

  127. 127.

    Noll E, Medina M, Hartley D, Zhou J, Perrimon N, Kosik KS. Presenilin affects arm/beta-catenin localization and function in Drosophila. Dev Biol. 2000;227:450-464.

    Not in our library10.1006/dbio.2000.9925

  128. 128.

    Soriano S, Kang DE, Fu M, Pestell R, Chevallier N, Zheng H, et al. Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing. J Cell Biol. 2001;152:785-794.

    Not in our library10.1083/jcb.152.4.785

  129. 129.

    Boonen RA, van Tijn P, Zivkovic D. Wnt signaling in Alzheimer's disease: up or down, that is the question. Ageing Res Rev. 2009;8:71-82.

    Not in our library10.1016/j.arr.2008.11.003

  130. 130.
    Presenilin Deficiency or Lysosomal Inhibition Enhances Wnt Signaling through Relocalization of GSK3 to the Late-Endosomal Compartment · 2012
    Not checked
  131. 131.

    Teo JL, Ma H, Nguyen C, Lam C, Kahn M. Specific inhibition of CBP/beta-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation. Proc Natl Acad Sci U S A. 2005;102:12171-12176.

    Not in our library10.1073/pnas.0504600102

  132. 132.

    Kang DE, Soriano S, Frosch MP, Collins T, Naruse S, Sisodia SS, et al. Presenilin 1 facilitates the constitutive turnover of beta-catenin: differential activity of Alzheimer's disease-linked PS1 mutants in the beta-catenin-signaling pathway. J Neurosci. 1999;19:4229-4237.

    Not in our library10.1523/jneurosci.19-11-04229.1999

  133. 133.

    Kirk-Sanchez NJ, McGough EL. Physical exercise and cognitive performance in the elderly: current perspectives. Clin Interv Aging. 2014;9:51-62.

    Not in our library10.2147/cia.s39506

  134. 134.

    Stranahan AM, Lee K, Becker KG, Zhang Y, Maudsley S, Martin B, et al. Hippocampal gene expression patterns underlying the enhancement of memory by running in aged mice. Neurobiol Aging. 2010;31:1937-1949.

    Not in our library10.1016/j.neurobiolaging.2008.10.016

  135. 135.

    Bayod S, Mennella I, Sanchez-Roige S, Lalanza JF, Escorihuela RM, Camins A, et al. Wnt pathway regulation by long-term moderate exercise in rat hippocampus. Brain Res. 2014;1543:38-48.

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    Pike CJ. Sex and the development of Alzheimer's disease. J Neurosci Res. 2017;95:671-680.

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    Merlo S, Spampinato SF, Sortino MA. Estrogen and Alzheimer's disease: still an attractive topic despite disappointment from early clinical results. Eur J Pharmacol. 2017;817:51-58.

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    Scott EL, Zhang QG, Han D, Desai BN, Brann DW. Long-term estrogen deprivation leads to elevation of Dickkopf-1 and dysregulation of Wnt/beta-catenin signaling in hippocampal CA1 neurons. Steroids. 2013;78:624-632.

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    Zhang QG, Wang R, Khan M, Mahesh V, Brann DW. Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. J Neurosci. 2008;28:8430-8441.

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    Maqbool M, Mobashir M, Hoda N. Pivotal role of glycogen synthase kinase-3: a therapeutic target for Alzheimer's disease. Eur J Med Chem. 2016;107:63-81.

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    Godyn J, Jonczyk J, Panek D, Malawska B. Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacol Rep. 2016;68:127-138.

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    Ren C, Gu X, Li H, Lei S, Wang Z, Wang J, et al. The role of DKK1 in Alzheimer's disease: a potential intervention point of brain damage prevention? Pharmacol Res. 2019;144:331-335.

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    Li X, Shan J, Chang W, Kim I, Bao J, Lee HJ, et al. Chemical and genetic evidence for the involvement of Wnt antagonist Dickkopf2 in regulation of glucose metabolism. Proc Natl Acad Sci U S A. 2012;109:11402-11407.

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    Iozzi S, Remelli R, Lelli B, Diamanti D, Pileri S, Bracci L, et al. Functional characterization of a small-molecule inhibitor of the DKK1-LRP6 interaction. ISRN Mol Biol. 2012;2012:823875.

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    Mpousis S, Thysiadis S, Avramidis N, Katsamakas S, Efthimiopoulos S, Sarli V. Synthesis and evaluation of gallocyanine dyes as potential agents for the treatment of Alzheimer's disease and related neurodegenerative tauopathies. Eur J Med Chem. 2016;108:28-38.

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    Thysiadis S, Katsamakas S, Mpousis S, Avramidis N, Efthimiopoulos S, Sarli V. Design and synthesis of gallocyanine inhibitors of DKK1/LRP6 interactions for treatment of Alzheimer's disease. Bioorg Chem. 2018;80:230-244.

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    Beaumont V, Thompson SA, Choudhry F, Nuthall H, Glantschnig H, Lipfert L, et al. Evidence for an enhancement of excitatory transmission in adult CNS by Wnt signaling pathway modulation. Mol Cell Neurosci. 2007;35:513-524.

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    Vargas JY, Fuenzalida M, Inestrosa NC. In vivo activation of Wnt signaling pathway enhances cognitive function of adult mice and reverses cognitive deficits in an Alzheimer's disease model. J Neurosci. 2014;34:2191-2202.

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    Vargas JY, Ahumada J, Arrazola MS, Fuenzalida M, Inestrosa NC. WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Abeta oligomers. Exp Neurol. 2015;264:14-25.

    Not in our library10.1016/j.expneurol.2014.11.005

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    Farkhondeh T, Samarghandian S, Pourbagher-Shahri AM, Sedaghat M. The impact of curcumin and its modified formulations on Alzheimer's disease. J Cell Physiol. 2019;234:16953-16965.

    Not in our library10.1002/jcp.28411

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    Sanei M, Saberi-Demneh A. Effect of curcumin on memory impairment: a systematic review. Phytomedicine. 2019;52:98-106.

    Not in our library10.1016/j.phymed.2018.06.016

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    Zhang X, Yin WK, Shi XD, Li Y. Curcumin activates Wnt/beta-catenin signaling pathway through inhibiting the activity of GSK-3beta in APPswe transfected SY5Y cells. Eur J Pharm Sci. 2011;42:540-546.

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    Tiwari SK, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, et al. Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer's disease model via canonical Wnt/beta-catenin pathway. ACS Nano. 2014;8:76-103.

    Not in our library10.1021/nn405077y

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    Cramer C, Haan MN, Galea S, Langa KM, Kalbfleisch JD. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurol. 2008;71:344-350.

    Not in our library10.1212/01.wnl.0000319647.15752.7b

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    Bettermann K, Arnold AM, Williamson J, Rapp S, Sink K, Toole JF, et al. Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study. J Stroke Cerebrovasc Dis. 2012;21:436-444.

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    Smith KB, Kang P, Sabbagh MN. Alzheimer's Disease Neuroimaging I. The Effect of Statins on Rate of Cognitive Decline in Mild Cognitive Impairment. Alzheimers Dement (N Y). 2017;3:149-156.

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    Steenland K, Zhao L, Goldstein FC, Levey AI. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment. J Am Geriatr Soc. 2013;61:1449-1455.

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    Heymann AD, Ravona-Springer R, Moshier EL, Godbold J, Beeri MS. Statin use is associated with better cognitive function in elderly with type 2 diabetes. J Alzheimers Dis. 2015;47:55-59.

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    Salins P, Shawesh S, He Y, Dibrov A, Kashour T, Arthur G, et al. Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling. Neurosci Lett. 2007;412:211-216.

    Not in our library10.1016/j.neulet.2006.07.045

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    Lin CL, Cheng H, Tung CW, Huang WJ, Chang PJ, Yang JT, et al. Simvastatin reverses high glucose-induced apoptosis of mesangial cells via modulation of Wnt signaling pathway. Am J Nephrol. 2008;28:290-297.

    Not in our library10.1159/000111142

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    Biechele TL, Camp ND, Fass DM, Kulikauskas RM, Robin NC, White BD, et al. Chemical-genetic screen identifies riluzole as an enhancer of Wnt/beta-catenin signaling in melanoma. Chem Biol. 2010;17:1177-1182.

    Not in our library10.1016/j.chembiol.2010.08.012

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    Qiao LJ, Kang KL, Heo JS. Simvastatin promotes osteogenic differentiation of mouse embryonic stem cells via canonical Wnt/beta-catenin signaling. Mol Cells. 2011;32:437-444.

    Not in our library10.1007/s10059-011-0107-6

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    Robin NC, Agoston Z, Biechele TL, James RG, Berndt JD, Moon RT. Simvastatin promotes adult hippocampal neurogenesis by enhancing Wnt/beta-catenin signaling. Stem Cell Rep. 2014;2:9-17.

    Not in our library10.1016/j.stemcr.2013.11.002

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    Gao K, Shen Z, Yuan Y, Han D, Song C, Guo Y, et al. Simvastatin inhibits neural cell apoptosis and promotes locomotor recovery via activation of Wnt/beta-catenin signaling pathway after spinal cord injury. J Neurochem. 2016;138:139-149.

    Not in our library10.1111/jnc.13382

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    Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13:513-532.

    Not in our library10.1038/nrd4233

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    Inestrosa NC, Arenas E. Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci. 2010;11:77-86.

    Not in our library10.1038/nrn2755

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    Arenas E. Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson's disease. J Mol Cell Biol. 2014;6:42-53.

    Not in our library10.1093/jmcb/mju001

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    Cantuti-Castelvetri I, Keller-McGandy C, Bouzou B, Asteris G, Clark TW, Frosch MP, et al. Effects of gender on nigral gene expression and parkinson disease. Neurobiol Dis. 2007;26:606-614.

    Not in our library10.1016/j.nbd.2007.02.009

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    Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease · 2011
    Not checked
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    Berwick DC, Javaheri B, Wetzel A, Hopkinson M, Nixon-Abell J, Granno S, et al. Pathogenic LRRK2 variants are gain-of-function mutations that enhance LRRK2-mediated repression of beta-catenin signaling. Mol Neurodegener. 2017;12:9.

    Not in our library10.1186/s13024-017-0153-4

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    Salasova A, Yokota C, Potesil D, Zdrahal Z, Bryja V, Arenas E. A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway. Mol Neurodegener. 2017;12:54.

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    Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19:179-192.

    Not in our library10.1038/nm.3074

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    Amjadi-Moheb F, Akhavan-Niaki H. Wnt signaling pathway in osteoporosis: epigenetic regulation, interaction with other signaling pathways, and therapeutic promises. J Cell Physiol. 2019.

    Not in our library10.1002/jcp.28207

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    Melton LJ, Beard CM, Kokmen E, Atkinson EJ, O'Fallon WM. Fracture risk in patients with Alzheimer's disease. J Am Geriatr Soc. 1994;42:614-619.

    Not in our library10.1111/j.1532-5415.1994.tb06859.x

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    Johansson C, Skoog I. A population-based study on the association between dementia and hip fractures in 85-year olds. Aging (Milano). 1996;8:189-196.

    Not in our library10.1007/bf03339676

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    Looker AC, Borrud LG, Dawson-Hughes B, Shepherd JA, Wright NC. Osteoporosis or low bone mass at the femur neck or lumbar spine in older adults: United States, 2005-2008. NCHS Data Brief. 2012:1–8.

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    Amouzougan A, Lafaie L, Marotte H, Denarie D, Collet P, Pallot-Prades B, et al. High prevalence of dementia in women with osteoporosis. Joint Bone Spine. 2017;84:611-614.

    Not in our library10.1016/j.jbspin.2016.08.002

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    Dengler-Crish CM, Smith MA, Wilson GN. Early evidence of Low bone density and decreased serotonergic synthesis in the dorsal raphe of a Tauopathy model of Alzheimer's disease. J Alzheimers Dis. 2017;55:1605-1619.

    Not in our library10.3233/jad-160658

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    Dengler-Crish CM, Ball HC, Lin L, Novak KM, Cooper LN. Evidence of Wnt/beta-catenin alterations in brain and bone of a tauopathy mouse model of Alzheimer's disease. Neurobiol Aging. 2018;67:148-158.

    Not in our library10.1016/j.neurobiolaging.2018.03.021

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    Yang MW, Wang TH, Yan PP, Chu LW, Yu J, Gao ZD, et al. Curcumin improves bone microarchitecture and enhances mineral density in APP/PS1 transgenic mice. Phytomedicine. 2011;18:205-213.

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    Cui S, Xiong F, Hong Y, Jung JU, Li XS, Liu JZ, et al. APPswe/Abeta regulation of osteoclast activation and RAGE expression in an age-dependent manner. J Bone Miner Res. 2011;26:1084-1098.

    Not in our library10.1002/jbmr.299

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    Dengler-Crish CM, Elefteriou F. Shared mechanisms: osteoporosis and Alzheimer's disease? Aging-Us. 2019;11:1317-1318.

    Not in our library10.18632/aging.101828

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    Monroe DG, McGee-Lawrence ME, Oursler MJ, Westendorf JJ. Update on Wnt signaling in bone cell biology and bone disease. Gene. 2012;492:1-18.

    Not in our library10.1016/j.gene.2011.10.044

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