Dysregulated Wnt Signalling in the Alzheimer’s Brain

Abstract

The Wnt signalling system is essential for both the developing and adult central nervous system. It regulates numerous cellular functions ranging from neurogenesis to blood brain barrier biology. Dysregulated Wnt signalling can thus have significant consequences for normal brain function, which is becoming increasingly clear in Alzheimer’s disease (AD), an age-related neurodegenerative disorder that is the most prevalent form of dementia. AD exhibits a range of pathophysiological manifestations including aberrant amyloid precursor protein processing, tau pathology, synapse loss, neuroinflammation and blood brain barrier breakdown, which have been associated to a greater or lesser degree with abnormal Wnt signalling. Here we provide a comprehensive overview of the role of Wnt signalling in the CNS, and the research that implicates dysregulated Wnt signalling in the ageing brain and in AD pathogenesis. We also discuss the opportunities for therapeutic intervention in AD via modulation of the Wnt signalling pathway, and highlight some of the challenges and the gaps in our current understanding that need to be met to enable that goal.

On the Common Journey of Neural Cells through Ischemic Brain Injury and Alzheimer’s Disease

“…Importantly, ApoE, a major genetic risk factor for AD, promotes the degeneration of endothelial cells and hampers the clearance of Aβ exerted by pericytes. Moreover, brain endothelial cells connected by tight junctions and their main constituents, claudins, are Wnt/β-catenin target genes [ 241 ]. In line with this, Wnt7a and β-catenin knockouts in adult mice decreased the expression of claudins, which was accompanied by inflammation, insults to the CNS vasculature, and the dysregulated BBB maintenance.…”

From Channels to Canonical Wnt Signaling: A Pathological Perspective

“…(ii) tau protein hyper-phosphorylation process that involves GSK3β and Dikkopf 1 (DKK1), and generates neurofibrillary tangles within neurons; (iii) hippocampal-dependent cognitive impairment [73][74][75].…”

“…In AD, Wnt signaling impairment accelerates the onset of the disease and provokes the development of three AD hallmarks: (i) the production and aggregation of β-amyloid; (ii) tau protein hyper-phosphorylation process that involves GSK3β and Dikkopf 1 (DKK1), and generates neurofibrillary tangles within neurons; (iii) hippocampal-dependent cognitive impairment [ 73 , 74 , 75 ].…”

Computational Analysis of the Inhibition Mechanism of NOTUM by the ONIOM Method

“…In addition, Wnt signaling was found to be dysregulated in Alzheimer’s disease. 8 A recent study showed that increased Wnt signaling is associated with colorectal cancer. 9 On the basis of these results, Notum appears as an important therapeutical target for a number of diseases.…”