Impaired Wnt Signaling in the Prefrontal Cortex of Alzheimer's Disease

Wnt pathway is involved in synaptic plasticity and neuronal survival, and alterations in Wnt signaling have previously been reported both in aging and neurodegenerative diseases, including Alzheimer's disease (AD). This study sought to evaluate Wnt signaling pathway interplay integrity across prefrontal lobe structures in AD patients compared to normal aging. Using the open-access BrainCloud™ database, 84 gene expression profiles and clustering effect were analyzed in the dorsomedial prefrontal cortex (PFC) across a time span of 21-78 years of age. Next, expression levels of the selected genes were investigated in post-mortem brain tissue from 30 AD patients and 30 age-matched controls in three interdependent brain areas of the PFC. Results were assessed in relation to Braak stage and cognitive impairment of the patients. We found a general age-related factor in Wnt pathway genes with a group of genes being closely interrelated in their expression across the time span investigated in healthy individuals. This interrelation was altered in the AD brains studied, as several genes presented aberrant transcription, even though not always being altered at protein levels. Noteworthy, beta(β)-catenin and glycogen synthase kinase 3-beta (GSK3β) showed a dynamic switch in protein levels and activity, especially in the orbitofrontal cortex and the medial frontal gyrus. A significant decrease in β-catenin protein levels were inversely associated with increased GSK3β tyrosine activating phosphorylation, in addition to downstream effects associated with disease progression and cognitive decline. This study is the first that comprehensively evaluates Wnt signaling pathway in the prefrontal cortical lobe structures of AD brains, in relation to age-related coordinated Wnt signaling changes. Our findings further support that increased kinase activity of GSK3β is associated with AD pathology in the PFC.