The seminar will discuss the role of Wnt signaling in the pathogenesis of Alzheimer's disease. Wnt signaling is involved in critical developmental processes and adult tissue homeostasis. In the brain, Wnt signaling maintains synaptic structure and function and plays a role in long term potentiation. Exposure to beta-amyloid, a pathological feature of Alzheimer's, disrupts Wnt signaling proteins like frizzled, disheveled, and GSK-3beta, leading to neurodegeneration. Emerging evidence suggests activating Wnt signaling through Wnt ligands or related pathways could serve as a potential therapeutic approach for Alzheimer's disease.

1. Department of Pharmacology
Pharmacology and Neuroscience Graduate Program
Seminar
ROLE OF WNT SIGNALING IN ALZHEIMER’S DISEASE
PATHOGENESIS
Presented by:
Nisha Rizvi
Tuesday, April 20, 2010 – 3:00 p.m.
Med-Micro SCLF II Conference Room
825 North Rutledge
Springfield, Illinois
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by
abnormal deposition of extracellular β-amyloid plaques and intracellular hyperphosphorylated tau
tangles. Many theories related to the pathogenesis of AD have been proposed and are being studied
extensively. One of them suggests that a dysfunctional Wnt signaling pathway, at least in part, may be
associated with altered transcriptional regulation of target genes leading to metabolic defects and
activation of apoptotic signals for progressive and selective death of specific neuronal cell
populations.
Wnt pathway is a critical mediator of intercellular signaling events through highly conserved
family of secreted proteins involved in multiple developmental events during embryogenesis and
adult tissue homeostasis. It is extensively being studied for its involvement in the pathogenesis of a
number of diseases like diabetes, cancer, schizophrenia and Alzheimer’s disease. In the mature
nervous system, expression of Wnt signaling suggests its role in maintenance of synaptic structure,
function and plasticity. It modulates both pre- and postsynaptic protein clustering important for
neurite growth and establishment of new functional synapses which may contribute to long term
potentiation (LTP). Neuronal exposure to Aβ induces alteration in expression and/or activity of
various canonical and non-canonical Wnt proteins such as the frizzled (Fz)/ low density lipoprotein
receptor-related protein (LRP) complex, disheveled (Dsh), glycogen synthase kinase-3β (GSK-3β), and
β-catenin ultimately leading to neurodegeneration. Also, recent studies report that Wnt signaling
interacts with peroxisome proliferator-activated receptor γ (PPARγ) and muscarinic acetylcholine
receptor (mAChR) pathways together eliciting neuroprotection. Thus, there is growing evidence that
Wnt signaling is a putative target for Aβ-dependent synaptotoxicity and its activation by Wnt ligands,
PPARγ or M1 mAChR agonists could serve as a potential therapeutic strategy in Alzheimer’s disease.