The role of Wnt signaling in the development of Alzheimer's disease: a potential therapeutic target?

Abstract

Accumulating evidence supports a key role for Wnt signaling in the development of the central nervous system (CNS) during embryonic development and in the regulation of the structure and function of the adult brain. Alzheimer's disease (AD) is the most common form of senile dementia, which is characterized by β-amyloid (Aβ) deposition in specific brain regions. However, the molecular mechanism underlying AD pathology remains elusive. Dysfunctional Wnt signaling is associated with several diseases such as epilepsy, cancer, metabolic disease, and AD. Increasing evidence suggests that downregulation of Wnt signaling, induced by Aβ, is associated with disease progression of AD. More importantly, persistent activation of Wnt signaling through Wnt ligands, or inhibition of negative regulators of Wnt signaling, such as Dickkopf-1 (DKK-1) and glycogen synthase kinase-3β (GSK-3β) that are hyperactive in the disease state, is able to protect against Aβ toxicity and ameliorate cognitive performance in AD. Together, these data suggest that Wnt signaling might be a potential therapeutic target of AD. Here, we review recent studies related to the progression of AD where Wnt signaling might be relevant and participate in the development of the disease. Then, we focus on the potential relevance of manipulating the Wnt signaling pathway for the treatment of AD.