New age of neuroproteomics in Alzheimer's disease research

Abstract

Alzheimer's disease (AD) is the leading cause of dementia, a condition that gradually destroys brain cells and leads to progressive decline in mental functions. The disease is characterized by accumulation of misfolded neuronal proteins, amyloid and tau, into insoluble aggregates known as extracellular senile plaques and intracellular neurofibrillary tangles, respectively. However, only tau pathology appears to correlate with the progression of the disease and it is believed to play a central role in the progression of neurodegeneration. In AD, tau protein undergoes various types of posttranslational modifications, most notably hyperphosphorylation and truncation. Using four proteomics approaches we aimed to uncover the key steps leading to neurofibrillary degeneration and thus to identify therapeutic targets for AD. Functional neuroproteomics was employed to generate the first transgenic rat model of AD by expressing a truncated misordered form of tau, "Alzheimer's tau". The rat model showed that Alzheimer's tau toxic gain of function is responsible for the induction of abnormal tau cascade and is the driving force in the development of neurofibrillary degeneration. Structural neuroproteomics allowed us to determine partial 3D structure of the Alzheimer's filament core at a resolution of 1.6 A. Signaling neuroproteomics data lead to the identification and characterization of relevant phosphosites (the tau phosphosignalome) contributing to neurodegeneration. Interaction neuroproteomics revealed links to a new group of proteins interacting with Alzheimer's tau (tau interactome) under normal and pathological conditions, which would provide novel drug targets and novel biomarkers for treatment of AD and other tauopathies.

Fig. 1

The AD tau proteome. Tau is expressed as six isoforms in adult human brain. This complexity is multiplied by phosphorylation at least 45 known sites in AD, truncation, ubiquitination, and other known modifications taking place in AD. This multitude of tau proteins makes it difficult to identify the key molecular steps of the transition of the disordered normal tau into misordered aggregated protein

Fig. 2

Expression of Alzheimer’s tau in the rat brain induces complete tau cascade of neuropathology including the sarcosyl-insoluble tau with the A68 triplet characteristic of human AD neurofibrillary degeneration. The western blot represents sarcosyl insoluble brain extracts from wild type (WT), transgenic rat expressing Alzheimer’s tau (TG) and human AD brain. The blot was probed with a pan tau antibody (DC25) or with PHF1 antibody specific for phosphorylated Ser396/Ser404. Numbers on the left indicate positions of molecular mass markers (kDa)