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Wnt Signaling: A Boon or Bane for Alzheimer’s Disease Volume 51- Issue 1

Satadeepa Kal1 and Suborno Jati2*

  • 1Department of Pediatrics, University of California, San Diego, La Jolla, CA, United States
  • 2Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, United States

Received: June 07, 2023;   Published: June 14, 2023

*Corresponding author: Suborno Jati, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, United States

DOI: 10.26717/BJSTR.2023.51.008045

Abstract PDF


Alzheimer’s disease (AD) is the most abundant form of dementia worldwide and elderly people are prone to this disease. Until now, no such therapeutic intervention has been identified to curb it. Wnt signaling being a major regulator of systemic homeostasis, plays a significant role in the disease response. Wnt signaling pathway is intrinsically associated with the regulation of synaptic plasticity, microglial activation and maintenance of blood brain barrier (BBB). In spite of these all-round executions, there is a lack of detailed study to present an opinion about the importance of this signaling cascade in AD. In this review we will uphold the major queries related to the disease which can be elucidated by Wnt signaling pathway.

Keywords: Wnt; Alzheimer’s Disease; Neuron; Astrocyte; Microglia

Abbreviations: CNS: Central Nervous System; NSC: Neuronal Stem Cells; PCP: Planar Cell Polarity; ETC: Electron Transport Chain; DAM: Disease Associated Microglia


Alzheimer’s disease is one of the most prevalent neurodegenerative diseases in the world which mostly appears with aging [1,2]. Neuronal death, followed by cognitive decline and memory loss serve as an important outcome of the disease [3]. The Central Nervous System (CNS) comprises different cell types, mainly neurons and glia (Astrocytes, Microglia, Oligodendrocytes). Glial cells provide appropriate metabolic support to the neurons for their proper functioning and helps to maintain a stable bioenergetics for proper neuronal transmission [4,5]. Nonetheless, different neuronal type in different region of the brain also regulate the function of the glial cells in a spatio-temporal manner [6]. This crosstalk between neuron and glia is regulated by a multitude of signaling processes. Wnt signaling regulate the proliferation and differentiation of neuronal stem cells (NSC) and is an integral part of neurogenesis and neuronal function [7,8]. Wnt ligands also serve as important factors for the activation of the glial cells, which plays a crucial role in neuronal apoptosis during neurodegeneration [9,10]. Here, we discuss how the balance of different wnt ligands can affect the homeostasis of neuron-glia cross-talk, the anomaly of which is a major driving force of neurodegeneration.

WNT Signaling in Synaptic Transmission and Cognitive Decline

Wnt family of protein ligand comprises of 19 different secreted glycoproteins which are conserved across different mammalian species [11,12]. Although they are majorly classified in two classes canonical and non-canonical, the overlap of the signaling intermediates and outcome is quite often [13,14]. Several studies have reported the importance of this signaling in dendritic development, synaptic transmission, synaptogenesis and in different disorders [15-18]. Cognition, memory and motor movements are among several behavioral parameters which is compromised in different neurodegenerative diseases including AD [19]. Wnt7a/b is known to play a vital role in the assembly of synaptosomes and thereby contributes to the synaptic plasticity [20,21]. As reduced synaptic transmission is one of the early markers of AD [22], the variation in the level of Wnt7a/b signaling cascade in neurons and the glial cells can be highlighted as an important area of future research. Since, Wnt signaling is known to affect the calcium uptake [23,24], an important contributor of action potential, there is scope of exploration in the role of Wnt7a/b in calcium uptake deregulation during neurodegeneration. Whether Wnt7a/b contributes in microglial activation and astrocytic metabolic disbalance is not known. Since ROR1, a well-known receptor for different ligands is also a genetic risk factor for AD, It will be intriguing to look at the interaction of different Wnt ligands (Wnt7a/b, Wnt5a, Wnt3a) with ROR1 in cellspecific context in the diseased brain.

Wnt Signaling in Disease Associated Microglia

Microglia are the immune cells residing in CNS and equipped with metabolic versatility to patrol in different regions of the brain [25,26]. During host-pathogen interaction, Wnt5a is known to regulate the uptake and autophagy mediated containment of the pathogens through alteration of cytoskeletal dynamics in macrophages [27-30]. Since impaired autophagy in neurons and microglia in diseased brain is very well characterized [31,32], further insight into the status of Wnt signaling intermediates in different brain cell types can provide deeper knowledge about the impact of this pathway in AD. Canonical Wnt3a/β-catenin signaling is known to transcriptionally regulate the expression of STUB1 [33], an E3 ubiquitin ligase intrinsically associated with the deposition of misfolded protein aggregates in AD brain [34,35]. Altogether, Wnt ligands vividly regulate the degradation machinery of misfolded proteins and cellular components in the system. Wnt ligands can also regulate the inflammatory state of the microglia [9]. Dysregulation of these above signaling parameters may activate the microglia and contribute in their M1 to M2 transition in CNS. Several lines of evidence suggest that complex Wnt signaling cascades are closely associated with deposition of cholesterol in macrophages resulting in aberrantly functioned fatty macrophages at atherosclerotic lesions [36-38]. On the other hand, cholesterol is also known to activate different modes of Wnt signaling in a concentration dependent manner [39]. In AD brains, cholesterol deposition and excessive lipid droplet formation in microglia has also been recently reported [40-42]. Taken together, dysfunctional autophagy mediated degradation machinery and deposition of cholesterol may give rise to a different class of microglia known as Disease Associated Microglia (DAM) in the AD brain with distinct transcriptional signatures [43]. It will be interesting to explore whether Wnt ligands play similar functions and steers the transformation of microglia from homeostatic state to proinflammatory DAM state in CNS. WNT/Planar Cell Polarity (PCP) pathway not only regulates the calcium balance but also contributes to cytoskeletal alteration and polarity of the cells [44]. As microglia can migrate in different regions of the brain, it will be fascinating to explore the role of WNT/PCP pathway in microglial polarization and their metabolic versatility in disease condition.

WNT Signaling in Astrocytes

Astrocytes are known to be the most important metabolic lifeline for neurons [45,46]. Astrocytic Wnt signaling is crucial for maintenance of BBB and protect the neurons [47]. Neurons generate tons of free fatty acids and different metabolic byproducts during synaptic transmission but they are not equipped with efficient cellular machinery to reduce that metabolic stress. Interestingly, mitochondria in astrocytes are fortified to reduce the Fatty Acid and lipid stress for neurons due to their efficient ETC (Electron Transport Chain) complex I assembly and function [48]. Astrocytic activation and dysfunction are one of the very early manifests of the disease [49], failing of which leads to neuronal apoptosis. Wnt signaling has not yet been studied extensively in astrocytic activation. Astrocyte-neuron lactate shuttle is one of the well-established metabolic pipelines between neurons and astrocytes. Wnt ligands, being a regulator of vesicle transport inside the cells presumably play a major role in maintenance of the shuttle.


Alzheimer’s Disease comprises the most abundant form of dementia. Tau aggregates and Aβ- plaques are the early manifests of the disease which results in neuronal death and successive neurodegeneration [50]. In CNS different cell types are intrinsically wired to maintain proper synaptic plasticity resulting in cognition and memory function. In AD brain, activated microglia are the major bearer of tau spreading and neuroinflammation [51]. The inflammatory cytokines released by activated microglia are serious threat for the neurons [52]. On the other hand, aberrantly activated astrocytes in the diseased condition are uncooperative to take the metabolic burden from neurons and this in turn can activate the microglia to come close together and phagocytose the dying neurons. Wnt signaling, being a central regulator of development and neurogenesis [53] supposedly play a significant role in this crosstalk which has not been investigated till now. GSK3β, one of the intermediates of canonical Wnt signaling has been showed to regulate Tau hyperphosphorylation and aggregation [54]. However, GSK3β can also be regulated by Insulin signaling cascade through AKT [55]. So, only pin-pointing GSK3β makes the role of Wnt signaling inconclusive in the disease. Although, few reports mentioned about the variation of specific Wnts in different cell types at mRNA level, the mechanistic details are still missing [56]. Few reports suggest Wnt signaling as beneficial but there are studies showing the detrimental role of this signaling [57,58]. To address this question, Wnt signaling cascade needs to be dissected in a cell-specific manner. With identification of Wnt receptor ROR1 as a genetic risk factor [59], there is an urgency to study the importance of this signaling in the disease. LRP1, a coreceptor for many Wnt ligands also known to interact with Tau and promotes Tau seeding in neurons [60]. Apoβ4, the strongest genetic risk factor of AD is known to regulate Wnt signaling pathway in neuroendocrine cells [61]. All these discrete studies are bringing Wnt signaling into limelight for AD and demands more comprehensive insight for the role of Wnt signaling and its intermediates in the disease. Different modes of activation or inactivation of this signaling may unlock some novel therapeutic interventions for the disease.


Right now there are more than 55 million Alzheimer’s Disease patients worldwide and the number is expected to reach around 139 million by 2050 [62]. These increasing numbers expose the failure of a successful therapeutic intervention for the disease. Wnt signaling pathway has already been targeted in cancer and in some cases the inhibitors are successful in restraining the disease [63-65]. In AD, there is a lack of mechanistic insight about the role of Wnt signaling in disease progression. Considering the significance of Wnt signaling in neurogenesis, synaptic development and neuroinflammation, a comprehensive study of this signaling pathway in AD may guide the discovery of a successful treatment alternative.

Conflict of Interest

The authors declare no conflict of interest.

Author Contribution

S.J conceived the idea and wrote the manuscript. S.K did the literature search and helped in writing.


S.J is supported by AFTD Holloway Postdoctoral fellowship (Award #2020-02).


  1. Holtzman DM, John CM, Goate A (2011) Alzheimer’s Disease: The Challenge of the Second Century. Sci Transl Med 3(77): 77sr1.
  2. DeTure MA, Dickson DW (2019) The neuropathological diagnosis of Alzheimer’s disease. Molecular Neurodegeneration 14: 32.
  3. Goel P, Chakrabarti S, Goel K, Bhutani K, Chopra T, et al. (2022) Neuronal cell death mechanisms in Alzheimer’s disease: An insight. Frontiers in Molecular Neuroscience 15: 937133.
  4. Lee KH, Cha M, Lee BH (2021) Crosstalk between Neuron and Glial Cells in Oxidative Injury and Neuroprotection. International Journal of Molecular Sciences 22(24): 13315.
  5. Jha MK, Morrison BM (2018) Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters. Exp Neurol 309: 23­-31.
  6. Mizutani R, Saiga R, Yamamoto Y, Uesugi M, Takeuchi A, et al. (2021) Structural diverseness of neurons between brain areas and between cases. Transl Psychiatry 11(1): 1-9.
  7. Wexler EM, Paucer A, Kornblum HI, Palmer TD, Geschwind DH (2009) Endogenous Wnt Signaling Maintains Neural Progenitor Cell Potency. Stem Cells 27(5): 1130-1141.
  8. Kalani MYS, Cheshier SH, Cord BJ, Bababeygy SR, Vogel H, et al. (2008) Wnt-mediated self-renewal of neural stem/progenitor cells. Proceedings of the National Academy of Sciences 105(44): 16970-16975.
  9. Halleskog C, Mulder J, Dahlström J, Mackie K, Hortobágyi T, et al. (2011) WNT signaling in activated microglia is pro-inflammatory. Glia 59(1): 119-131.
  10. Shimizu T, Smits R, Ikenaka K (2016) Microglia-Induced Activation of Noncanonical Wnt Signaling Aggravates Neurodegeneration in Demyelinating Disorders. Molecular and Cellular Biology 36(21): 2728-2741.
  11. Nusse R, Varmus H (2012) Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J 31(12): 2670-2684.
  12. Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3): 469-480.
  13. Qi J, Lee H-J, Saquet A, Cheng X-N, Shao M, et al. (2017) Autoinhibition of Dishevelled protein regulated by its extreme C terminus plays a distinct role in Wnt/β-catenin and Wnt/planar cell polarity (PCP) signaling pathways. J Biol Chem 292(14): 5898-5908.
  14. Lee H-J, Shi D-L, Zheng JJ (2015) Conformational change of Dishevelled plays a key regulatory role in the Wnt signaling pathways. Elife 4: e08142.
  15. He C-W, Liao C-P, Pan C-L (2018) Wnt signalling in the development of axon, dendrites and synapses. Open Biol 8(10): 180116.
  16. Bodmer D, Levine-Wilkinson S, Richmond A, Hirsh S, Kuruvilla R (2009) Wnt5a mediates nerve growth factor-dependent axonal branching and growth in developing sympathetic neurons. J Neurosci 29(23): 7569-7581.
  17. Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC (2005) Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat Neurosci 8(1): 34-42.
  18. Chen C-M, Orefice LL, Chiu S-L, LeGates TA, Hattar S, et al. (2017) Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice. Proc Natl Acad Sci U S A 114(4): E619-E628.
  19. Corey-Bloom J (2002) The ABC of Alzheimer’s disease: cognitive changes and their management in Alzheimer’s disease and related dementias. Int Psychogeriatr 14(Suppl 1): 51-75.
  20. Hall AC, Lucas FR, Salinas PC (2000) Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell 100(5): 525-535.
  21. Qu Q, Sun G, Murai K, Ye P, Li W, et al. (2013) Wnt7a Regulates Multiple Steps of Neurogenesis. Molecular and Cellular Biology 33(13): 2551-2559.
  22. Chen Y, Fu AKY, Ip NY (2019) Synaptic dysfunction in Alzheimer’s disease: Mechanisms and therapeutic strategies. Pharmacol Ther 195: 186-198.
  23. McQuate A, Latorre-Esteves E, Barria A (2017) A Wnt/Calcium Signaling Cascade Regulates Neuronal Excitability and Trafficking of NMDARs. Cell 21(1): 60-69.
  24. Spinsanti P, De Vita T, Caruso A, Melchiorri D, Misasi R, et al. (2008) Differential activation of the calcium/protein kinase C and the canonical beta-catenin pathway by Wnt1 and Wnt7a produces opposite effects on cell proliferation in PC12 cells. J Neurochem 104(6): 1588-1598.
  25. Lenz KM, Nelson LH (2018) Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function. Front Immunol 9: 698.
  26. Bernier L-P, York EM, Kamyabi A, Choi HB, Weilinger NL, et al. (2020) Microglial metabolic flexibility supports immune surveillance of the brain parenchyma. Nat Commun 11(1): 1559.
  27. Jati S, Kundu S, Chakraborty A, Mahata SK, Nizet V, et al. (2018) Wnt5A Signaling Promotes Defense Against Bacterial Pathogens by Activating a Host Autophagy Circuit. Frontiers in Immunology 9: 679.
  28. Jati S, Sengupta S, Sen M (2021) Wnt5A-Mediated Actin Organization Regulates Host Response to Bacterial Pathogens and Non-Pathogens. Front Immunol 11: 628191.
  29. Jati S, Sarraf TR, Naskar D, Sen M (2019) Wnt Signaling: Pathogen Incursion and Immune Defense. Frontiers in Immunology 10: 2551.
  30. Jati S, Sen M, Jati S, Sen M (2019) “Wnt Signaling Regulates Macrophage Mediated Immune Response to Pathogens.,” Macrophage Activation - Biology and Disease. IntechOpen.
  31. Lee J-H, Yang D-S, Goulbourne CN, Im E, Stavrides P, et al. (2022) Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci 25: 688-701.
  32. Orr ME, Oddo S (2013) Autophagic/lysosomal dysfunction in Alzheimer’s disease. Alzheimer’s Research & Therapy 5(5): 53.
  33. Kal S, Chakraborty S, Karmakar S, Ghosh MK (2022) Wnt/β-catenin signaling and p68 conjointly regulate CHIP in colorectal carcinoma. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1869(3): 119185.
  34. Zhang S, Hu Z, Mao C, Shi C, Xu Y (2020) CHIP as a therapeutic target for neurological diseases. Cell Death Dis 11(9): 727.
  35. Tsvetkov P, Adamovich Y, Elliott E, Shaul Y (2011) E3 Ligase STUB1/CHIP Regulates NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Accumulation in Aged Brain, a Process Impaired in Certain Alzheimer Disease Patients. J Biol Chem 286(11): 8839-8845.
  36. Xian X, Ding Y, Dieckmann M, Zhou L, Plattner F, et al. (2017) LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis. eLife 6: e29292.
  37. Awan S, Lambert M, Imtiaz A, Alpy F, Tomasetto C, et al. (2022) Wnt5a Promotes Lysosomal Cholesterol Egress and Protects Against Atherosclerosis. Circulation Research 130(2): 184-199.
  38. Wang F, Liu Z, Park S-H, Gwag T, Lu W, et al. (2018) Myeloid β-Catenin Deficiency Exacerbates Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice. Arterioscler Thromb Vasc Biol 38(7): 1468-1478.
  39. Sheng R, Kim H, Lee H, Xin Y, Chen Y, et al. (2014) Cholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling. Nat Commun 5: 4393.
  40. Nugent AA, Lin K, van Lengerich B, Lianoglou S, Przybyla L, et al. (2020) TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge. Neuron 105(5): 837-854.e9.
  41. Zhao F, Wang C, Zhu X (2020) Isoform-specific roles of AMPK catalytic α subunits in Alzheimer’s disease. J Clin Invest 130(7): 3403-3405.
  42. Chang TY, Chang CCY, Harned TC, De La Torre AL, Lee J, et al. (2021) Blocking cholesterol storage to treat Alzheimer’s disease. Explor Neuroprotective Ther 1(3): 173-184.
  43. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, et al. (2018) Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration. Cell 173(5): 1073-1081.
  44. Yang Y, Mlodzik M (2015) Wnt-Frizzled/Planar Cell Polarity Signaling: Cellular Orientation by Facing the Wind (Wnt). Annu Rev Cell Dev Biol 31: 623-646.
  45. Zhang H, Zheng Q, Guo T, Zhang S, Zheng S, et al. (2022) Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability. Mol Psychiatry, p. 1-14.
  46. Beard E, Lengacher S, Dias S, Magistretti PJ, Finsterwald C (2022) Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives. Front Physiol 12: 825816.
  47. Song S, Huang H, Guan X, Fiesler V, Chattopadhyay A, et al. (2021) Activation of endothelial Wnt/β-catenin signaling by protective astrocytes repairs BBB damage in ischemic stroke. Prog Neurobiol 199: 101963.
  48. Lopez-Fabuel I, Le Douce J, Logan A, James AM, Bonvento G, et al. (2016) Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes. Proceedings of the National Academy of Sciences 113(46): 13063-13068.
  49. Smit T, Deshayes NAC, Borchelt DR, Kamphuis W, Middeldorp J, et al. (2021) Reactive astrocytes as treatment targets in Alzheimer’s disease—Systematic review of studies using the APPswePS1dE9 mouse model. Glia 69(8): 1852-1881.
  50. Bloom GS (2014) Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71(4): 505-508.
  51. Muzio L, Viotti A, Martino G (2021) Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy. Frontiers in Neuroscience 15: 742065.
  52. Brown GC, Vilalta A (2015) How microglia kill neurons. Brain Res 1628: 288-297.
  53. Lie D-C, Colamarino SA, Song H-J, Désiré L, Mira H, et al. (2005) Wnt signalling regulates adult hippocampal neurogenesis. Nature 437: 1370-1375.
  54. Rankin CA, Sun Q, Gamblin TC (2007) Tau phosphorylation by GSK-3β promotes tangle-like filament morphology. Molecular Neurodegeneration 2: 12.
  55. Leng S, Zhang W, Zheng Y, Liberman Z, Rhodes CJ, et al. (2010) Glycogen synthase kinase 3β mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. J Endocrinol 206(2): 171-181.
  56. Palomer E, Buechler J, Salinas PC (2019) Wnt Signaling Deregulation in the Aging and Alzheimer’s Brain. Front Cell Neurosci 13: 227.
  57. Jia L, Piña-Crespo J, Li Y (2019) Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease. Molecular Brain 12(1): 104.
  58. Aghaizu ND, Jin H, Whiting PJ (2020) Dysregulated Wnt Signalling in the Alzheimer’s Brain. Brain Sciences 10(12): 902.
  59. Lagisetty Y, Bourquard T, Al-Ramahi I, Mangleburg CG, Mota S, et al. (2022) Identification of risk genes for Alzheimer’s disease by gene embedding. Cell Genom 2(9): 100162.
  60. Rauch JN, Luna G, Guzman E, Audouard M, Challis C, et al. (2020) LRP1 is a master regulator of tau uptake and spread. Nature 580: 381-385.
  61. Caruso A, Motolese M, Iacovelli L, Caraci F, Copani A, et al. (2006) Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells. J Neurochem 98(2): 364-371.
  62. 2023 Dementia.
  63. DeVito NC, Sturdivant M, Thievanthiran B, Xiao C, Plebanek MP, et al. Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy. Cell Rep (2021) 35(5): 109071.
  64. (2023) Novartis Pharmaceuticals. A Phase I, Open-label, Dose Escalation Study of Oral LGK974 in Patients With Malignancies Dependent on Wnt Ligands.
  65. Neiheisel A, Kaur M, Ma N, Havard P, Shenoy AK (2022) Wnt pathway modulators in cancer therapeutics: An update on completed and ongoing clinical trials. Int J Cancer 150(5): 727-740.