Wnt Signaling Deregulation in the Aging and Alzheimer’s Brain

Growing evidence suggests that synaptic signaling is compromised in the aging brain and in Alzheimer’s disease (AD), contributing to synaptic decline. Wnt signaling is a prominent pathway at the synapse and is required for synaptic plasticity and maintenance in the adult brain. In this review, we summarize the current knowledge on deregulation of Wnt signaling in the context of aging and AD. Emerging studies suggest that enhancing Wnt signaling could boost synaptic function during aging, and ameliorate synaptic pathology in AD. Although further research is needed to determine the precise contribution of deficient Wnt signaling to AD pathogenesis, targeting Wnt signaling components may provide novel therapeutic avenues for synapse protection or restoration in the brain.

[1]  G. Terstappen,et al.  Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1 , 2006, Neurobiology of Disease.

[2]  S. Lovestone,et al.  Dishevelled Regulates the Metabolism of Amyloid Precursor Protein via Protein Kinase C/Mitogen-Activated Protein Kinase and c-Jun Terminal Kinase , 2001, The Journal of Neuroscience.

[3]  H. Eldar-Finkelman,et al.  Inhibition of Glycogen Synthase Kinase-3 Ameliorates β-Amyloid Pathology and Restores Lysosomal Acidification and Mammalian Target of Rapamycin Activity in the Alzheimer Disease Mouse Model , 2012, The Journal of Biological Chemistry.

[4]  Jaakko Kopra,et al.  Deficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice , 2014, Nature Communications.

[5]  J. Güell-Bosch,et al.  Mouse Models of Alzheimer's Disease. , 2017, Journal of Alzheimer's disease : JAD.

[6]  A. Marzo,et al.  Wnt Signaling Mediates LTP-Dependent Spine Plasticity and AMPAR Localization through Frizzled-7 Receptors , 2018, Cell reports.

[7]  E. Aronica,et al.  Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Associated with Neuronal Degeneration in Alzheimer's Brain , 2004, The Journal of Neuroscience.

[8]  J. Rogers,et al.  Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer’s Disease , 2014, Neuron.

[9]  M. Boutros,et al.  Wnt signaling in cancer , 2016, Oncogene.

[10]  M. Varella‐Garcia,et al.  Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation , 2008, Nature.

[11]  B. Pakkenberg,et al.  Impaired Wnt Signaling in the Prefrontal Cortex of Alzheimer’s Disease , 2018, Molecular Neurobiology.

[12]  G. Terstappen,et al.  Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells , 2006, Journal of neurochemistry.

[13]  M. Mlodzik,et al.  Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility , 2007, Nature Reviews Genetics.

[14]  David A. Bennett,et al.  REST and Stress Resistance in Aging and Alzheimer’s Disease , 2014, Nature.

[15]  N. Inestrosa,et al.  Regulation of NMDA-Receptor Synaptic Transmission by Wnt Signaling , 2011, The Journal of Neuroscience.

[16]  N. Inestrosa,et al.  Frizzled‐1 is involved in the neuroprotective effect of Wnt3a against Aβ oligomers , 2008, Journal of cellular physiology.

[17]  C. Niehrs,et al.  Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline. , 2013, Cell stem cell.

[18]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[19]  N. Inestrosa,et al.  Wnt-5a occludes Aβ oligomer-induced depression of glutamatergic transmission in hippocampal neurons , 2010, Molecular Neurodegeneration.

[20]  M. Asashima,et al.  Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  S. Humphreys,et al.  Grassroots creativity and community in new media environments: Yarn Harlot and the 4000 knitting Olympians , 2008 .

[22]  L. Apostolova.  Alzheimer Disease , 2016, Continuum.

[23]  G. Terstappen,et al.  Increased Dickkopf‐1 expression in transgenic mouse models of neurodegenerative disease , 2010, Journal of neurochemistry.

[24]  A. Myers,et al.  Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease , 2007, Proceedings of the National Academy of Sciences.

[25]  Nazanin Mirzaei,et al.  Activation of the Wnt/β‐catenin pathway represses the transcription of the β‐amyloid precursor protein cleaving enzyme (BACE1) via binding of T‐cell factor‐4 to BACE1 promoter , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  F. LaFerla,et al.  Synaptic Impairment in Alzheimer’s Disease: A Dysregulated Symphony , 2017, Trends in Neurosciences.

[27]  The effects of aging on the expression of Wnt pathway genes in mouse tissues , 2014, AGE.

[28]  N. Inestrosa,et al.  Inhibition of Wnt signaling induces amyloidogenic processing of amyloid precursor protein and the production and aggregation of Amyloid‐β (Aβ)42 peptides , 2016, Journal of neurochemistry.

[29]  S. Shibamoto,et al.  Inhibitory effect of a presenilin 1 mutation on the Wnt signalling pathway by enhancement of beta-catenin phosphorylation. , 2001, European journal of biochemistry.

[30]  H. Marie,et al.  Hippocampal synaptic plasticity in Alzheimer's disease: what have we learned so far from transgenic models? , 2011, Alzheimer's & Dementia.

[31]  Antara De,et al.  Wnt/Ca2+ signaling pathway: a brief overview. , 2011, Acta biochimica et biophysica Sinica.

[32]  Nick C Fox,et al.  Letter abstract - Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's Disease , 2009 .

[33]  N. Inestrosa,et al.  Wnt-3a overcomes β-amyloid toxicity in rat hippocampal neurons , 2004 .

[34]  H. Braak,et al.  Distribution of Active Glycogen Synthase Kinase 3β (GSK-3β) in Brains Staged for Alzheimer Disease Neurofibrillary Changes , 1999 .

[35]  P. Salinas,et al.  Wnts in action: from synapse formation to synaptic maintenance , 2013, Front. Cell. Neurosci..

[36]  Hélène Marie,et al.  Hippocampal synaptic plasticity in Alzheimer's disease: what have we learned so far from transgenic models? , 2011, Alzheimer's & Dementia.

[37]  Dong-Sun Han,et al.  Long-term estrogen deprivation leads to elevation of Dickkopf-1 and dysregulation of Wnt/β-Catenin signaling in hippocampal CA1 neurons , 2013, Steroids.

[38]  M. Pallàs,et al.  Downregulation of canonical Wnt signaling in hippocampus of SAMP8 mice , 2015, Neurobiology of Aging.

[39]  A. Chien,et al.  Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers. , 2012, Gastroenterology.

[40]  N. Inestrosa,et al.  Wnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons. , 2004, Experimental cell research.

[41]  M. Eisenstein,et al.  A unique type of GSK-3 inhibitor brings new opportunities to the clinic , 2016, Science Signaling.

[42]  M. Onufriev,et al.  Lentiviral Modulation of Wnt/β-Catenin Signaling Affects In Vivo LTP , 2017, Cellular and Molecular Neurobiology.

[43]  T. O’Halloran,et al.  Molecular Pathways: Revisiting Glycogen Synthase Kinase-3β as a Target for the Treatment of Cancer , 2017, Clinical Cancer Research.

[44]  H. Varmus,et al.  Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice , 1988, Cell.

[45]  M. Mattson,et al.  Communication breakdown: The impact of ageing on synapse structure , 2014, Ageing Research Reviews.

[46]  P. Bosco,et al.  Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease , 2009, Nature Genetics.

[47]  B. Yankner,et al.  Neural mechanisms of ageing and cognitive decline , 2010, Nature.

[48]  J. Lucas,et al.  Spatial learning deficit in transgenic mice that conditionally over‐express GSK‐3β in the brain but do not form tau filaments , 2002, Journal of neurochemistry.

[49]  H. Braak,et al.  Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. , 1999, Journal of neuropathology and experimental neurology.

[50]  Hans Clevers,et al.  Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis , 1998, Nature.

[51]  V. Budnik,et al.  Wnt signaling during synaptic development and plasticity , 2011, Current Opinion in Neurobiology.

[52]  Huaxi Xu,et al.  TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway , 2017, The Journal of Neuroscience.

[53]  J. Morrison,et al.  The ageing cortical synapse: hallmarks and implications for cognitive decline , 2012, Nature Reviews Neuroscience.

[54]  C. Arias,et al.  Susceptibility to GSK3β-induced tau phosphorylation differs between the young and aged hippocampus after Wnt signaling inhibition. , 2014, Journal of Alzheimer's disease : JAD.

[55]  S. Lovestone,et al.  Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil , 2018, Alzheimer's & Dementia.

[56]  N. Inestrosa,et al.  Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by β-amyloid fibrils , 2003, Molecular Psychiatry.

[57]  A. I. Rojo,et al.  A role for APP in Wnt signalling links synapse loss with β-amyloid production , 2018, Translational Psychiatry.

[58]  F. Cacucci,et al.  Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus , 2016, Current Biology.

[59]  G. Breen,et al.  Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt–PCP–JNK pathway , 2012, Molecular Psychiatry.

[60]  C. Scavone,et al.  Age-related neuroinflammation and changes in AKT-GSK-3β and WNT/ β-CATENIN signaling in rat hippocampus , 2015, Aging.

[61]  L. Kiemeney,et al.  Corrigendum: Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer , 2009, Nature Genetics.

[62]  P. Salinas,et al.  Wnt proteins as modulators of synaptic plasticity , 2018, Current Opinion in Neurobiology.

[63]  F. Edwards,et al.  A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. , 2015, Cell reports.

[64]  R. Nusse,et al.  Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities , 2017, Cell.

[65]  C. Arias,et al.  The emerging role of Wnt signaling dysregulation in the understanding and modification of age-associated diseases , 2017, Ageing Research Reviews.

[66]  Jonathan R Pollack,et al.  A transcriptional response to Wnt protein in human embryonic carcinoma cells , 2002, BMC Developmental Biology.

[67]  P. Salinas,et al.  The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss , 2012, The Journal of Neuroscience.