Wnt Signalling is a Relevant Pathway Contributing to Amyloid Beta-Peptide-Mediated Neuropathology in Alzheimers Disease

Odete      A.B. da Cruz e Silva; Ana      Gabriela Henriques; Sara      Catarina Timoteo Santos Domingues; Edgar      F. da Cruz e Silva

Abstract

One of the most important contributions to our understanding of neurodegenerative diseases in the last decade has been the demonstration that several disorders have a common biochemical cause, involving aggregation and deposition of abnormal proteins. Abnormal protein deposition leads to neuronal degeneration with consequences to impaired brain function. Protein deposition can be extracellular (beta-amyloid peptide (Abeta), prion protein) or intracellular (Tau, alpha-synuclein, huntingtin). Individuals with Alzheimers disease (AD) exhibit extracellular senile plaques (SPs) of aggregated Abeta and intracellular neurofibrillary tangles that contain hyperphosphorylated Tau protein (NFTs), and also an extensive loss in basal forebrain cholinergic neurons that innervate the hippocampus and neocortex. The SPs and NFTs contribute to neurodegeneration, although the mechanisms inducing basal forebrain cholinergic cell loss and cognitive impairment remain unclear. Furthermore, the pathophysiological relationship between NFTs and SPs remains undefined, and controversy still rages over which of the two hallmark pathologies of AD is the primary cause of neurodegeneration in the brain. However, consensus is beginning to develop that the two pathologies are not separate processes, and the Wnt signalling pathway may provide a pathological link between both. In fact, work in transgenic mice showed that Abeta or the amyloid precursor protein can influence the formation of Tau tangles in areas of the brain known to be affected in AD. Furthermore, Abeta can contribute to synaptic dysfunction. Thus, Abeta appears to be a recurring player affecting protein phosphorylation, signal transduction mechanisms, cytoskeletal organization, multiprotein complex formation, synaptotoxicity and ultimately culminating in protein aggregation. Consequently this peptide and the downstream signalling cascades are presently considered as potential therapeutic targets.

Keywords: Alzheimer's disease, wnt signalling, synaptic function, phosphatases, NFTs, neurofibrillary tangles, paired helical filaments, Mass spectroscopy, amyloid precursor protein, acetylcholine, nAChR, Tau dephosphorylation, GSK-3beta phosphorylation, Abeta Mediated Signalling, cofilin, endocytosis, synaptic transmission, synaptotoxicity, Tau pathology, Abeta neurotoxicity, acetylcholinesterase