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.

Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer’s Disease

“…Importantly, we demonstrated that LRP6 levels and Wnt signaling are significantly reduced in postmortem brains from late-onset AD patients. Consistent with our findings, altered expression of several Wnt signaling components has been implicated in the pathogenesis of AD (Caricasole et al, 2004; He and Shen, 2009; Wan et al, 2014). In addition, the levels of β-catenin are significantly reduced in AD individuals bearing presenilin-1 mutations (Nishimura et al, 1999).…”

Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease

“…These functional categories are in agreement with published reports of aging and AD-specific pathways. For example, immunity is known to be involved in the pathology of AD 26 , and the Wnt signaling pathway, required for synaptic transmission and plasticity, is downregulated by β-amyloid in AD 27,28 . Also, the Aβ42 oligomers have been shown to enhance the Ras–ERK signaling pathways, inducing tau hyperphosphorylation in AD 29,30 .…”

Autophagy in Alzheimer’s disease

“…These ubiquitous trans-membrane proteins have diverse biological roles in wnt signaling pathway, calcium channel regulation, cell adhesion, apoptosis, neurite outgrowth and synaptic plasticity [51, 52] (reviewed in [53]). There is now evidence that PSs may also play a role in mediating autophagy.…”