Regional protein expression in human Alzheimer’s brain correlates with disease severity

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently affects 36 million people worldwide with no effective treatment available. Development of AD follows a distinctive pattern in the brain and is poorly modelled in animals. Therefore, it is vital to widen both the spatial scope of the study of AD and prioritise the study of human brains. Here we show that functionally distinct human brain regions show varying and region-specific changes in protein expression. These changes provide novel insights into the progression of disease, novel AD-related pathways, the presence of a ‘gradient’ of protein expression change from less to more affected regions, and the presence of a ‘protective’ protein expression profile in the cerebellum. This spatial proteomics analysis provides a framework which can underpin current research and opens new avenues of interest to enhance our understanding of molecular pathophysiology of AD, provides new targets for intervention and broadens the conceptual frameworks for future AD research.

MiR-219 deficiency in Alzheimer’s disease contributes to neurodegeneration and memory dysfunction through post-transcriptional regulation of tau-kinase network

“…This finding prompted us to explore the AD brain proteome 27 . We found alterations in the protein expression of the three miR-219 predicted targets, TTBK1, CAMK2 and GSK3 in the human entorhinal cortex of brains with AD ( Figure 1C).…”

Alzheimer cells on their way to derailment show selective changes in protein quality control network

“…To test the hypothesis that the PQC capacity decreases in AD, we performed a meta-analysis of the proteomics data provided by the Unwin laboratory, which is freely available at http://www.dementia-proteomesproject.manchester.ac.uk/Proteome/Search (Xu et al, 2019) (Fig. 1).…”

“…This study reveals a quantitative overview on protein levels of nine AD brains and nine healthy age-matched control brains, separated per brain region. The six distinct brain regions studied range from mostly unaffected in AD (cerebellum) to mildly affected (motor cortex and sensory cortex) and strongly affected (hippocampus, entorhinal cortex and cingulate gyrus) (Smith, 2002;Xu et al, 2019). We analysed 94 distinct proteins involved in different pathways of the PQC to obtain a comprehensive overview of protein levels of components of the PQC in AD ( Fig.…”

“…Heat map of neuronal and glial protein markers in different brain regions, differently affected in Alzheimer's Disease. Protein levels are calculated as fold change compared to control brain, with baseline set at 1.0 in white (averaged numbers from nine Alzheimer patients and nine controls of similar age, based on the proteome analysis of Xu et al (Xu et al, 2019) increase in protein levels, blue gradient; decrease, red gradient). Grey boxes represent unavailable data.…”

“…Recently, the Unwin group performed a widescale proteomics analysis on protein levels of nine AD brain in comparison to nine age-matched healthy controls (Xu et al, 2019). Their analysis revealed that an AD brain shows significant changes in specific signalling pathways, including the innate immune response and pathways involved in cell cycle regulation and apoptosis.…”