Proteomic Atlas of the Human Brain in Alzheimer’s Disease

Abstract

The brain represents one of the most divergent and critical organs in the human body. Yet, it can be afflicted by a variety of neurodegenerative diseases specifically linked to aging, about which we lack a full biomolecular understanding of onset and progression, such as Alzheimer's Disease (AD). Here we provide a proteomic resource comprising nine anatomically distinct sections from three aged individuals, across a spectrum of disease progression, categorized by quantity of neurofibrillary tangles. Using state-of-the-art mass spectrometry, we identify a core brain proteome that exhibits only small variance in expression, accompanied by a group of proteins that are highly differentially expressed in individual sections and broader regions. AD affected tissue exhibited slightly elevated levels of tau protein with similar relative expression to factors associated with the AD pathology. Substantial differences were identified between previous proteomic studies of mature adult brains and our aged cohort. Our findings suggest considerable value in examining specifically the brain proteome of aged human populations from a multiregional perspective. This resource can serve as a guide, as well as a point of reference for how specific regions of the brain are affected by aging and neurodegeneration.

Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease

“…To overcome this issue, we removed all proteins significantly associated with age from the list of differentially expressed proteins. Investigating the set of age-associated proteins we found that our findings were consistent with a previous report (McKetney et al, 2019), as a little overlap was presented between regions, and a large proportion of these age-related proteins was associated with extracellular exosome (p-value = 6.2e-86) and membrane (p-value = 8.9e-29).…”

“…Other authors focused on the temporal advancement of AD by investigating changes that occur in one brain area at different disease stages (Bossers et al, 2010;Hondius et al, 2016;Kim et al, 2018;Lachén-Montes et al, 2017;Lau et al, 2013;Sultana et al, 2010;Triplett et al, 2016;Zelaya et al, 2015). Both strategies were also merged through transcriptomic/proteomic investigation of brain areas considering distinct disease stages (Matarin et al, 2015;McKetney et al, 2019;Miyashita et al, 2014;Savas et al, 2017;Seyfried et al, 2017).…”

Proteins and microRNAs are differentially expressed in tear fluid from patients with Alzheimer’s disease

“…However, exactly how these 12 proteins are mechanistically involved in AD remains unclear. Notably 4 of the 12 proteins are among the 1651 proteins previously differentially expressed in various regions of the brain by MS; Serine-threonine kinase receptor-associated protein, Complement factor H-related protein 1, Tropomyosin alpha-4 chain and Complement component C8 alpha chain 48 . Asparagine-tRNA ligase, cytoplasmic and Corticosteroid-binding globulin were not detected in AD and the remaining 6 were unchanged from controls 48 .…”

Proteomics Landscape of Alzheimer’s Disease

“…Thus, there is a requirement for systematic analysis of neuronal proteome from different regions of brain. A study by McKetney et al has tried to address this by developing a proteomic atlas of nine anatomical regions of brain from three aged individuals [ 19 ]. Such atlases are helpful for understanding region specific neurodegeneration of brain.…”