P4‐109: Spatial Brain Proteomics to Understand Racial/ethnic Disparities in Alzheimer's Disease
Year: 2019
Type: article
Study design: Observational Study
Abstract: African Americans (AAs) have 2–3 times greater incidence of Alzheimer's disease (AD) than non-Hispanic whites (NHWs). The molecular basis of these disparities remains unknown as AD is understudied in AAs. Primary AD neuropathological hallmarks are similar between AAs and NHWs; however, AAs often have mixed dementia pathology. Previously, a proteomics pilot study revealed race-specific changes in hippocampal proteins in AAs and NHWs who were cognitively normal (CN) or neuropathologically diagnosed with AD. This study expands the previous proteomics workflow to inferior parietal lobule (IPL) and globus pallidus (GP) regions in the same cohort, as functional differences and differential effects of AD neuropathology lead to protein changes varying across regions. This analysis of spatial brain changes in AAs and NHWs is the first to employ proteomics to understand the molecular basis of racial/ethnic disparities in AD. A pilot cohort (N=18) of hippocampus, IPL, and GP tissues from AA and NHW CN and AD individuals were obtained from the University of Pittsburgh Alzheimer's Disease Research Center (56% male; average age and postmortem interval: 74 years and 11 hours, respectively). Brain tissues were homogenized, and protein was extracted and digested using trypsin/Lys-C. Resulting peptides were tagged with tandem mass tags prior to high pH reversed-phase fractionation. Fractions were analyzed using liquid chromatography-mass spectrometry on an Orbitrap Fusion Lumos. Data were processed using Proteome Discoverer 2.2. Proteomics analysis of three brain regions from AAs and NHWs identified 7351 proteins. Each region consisted of over 3000 proteins; 400, 86, and 197 proteins were differentially expressed in AD in hippocampus, IPL, and GP, respectively. The majority of differentially expressed proteins were race-specific, and a smaller subset overlapped in both racial groups. Mitochondrial dysfunction and oxidative phosphorylation were commonly enriched overall. Metabolic pathways were significantly represented in AAs across all regions. Coagulation in IPL and GP and signaling pathways in hippocampus were enriched in NHWs. These data suggest that protein changes in AD differ by racial/ethnic background, while shared pathways between races highlight robust features of AD. This study is the first of its kind to use proteomics to understand molecular changes underlying racial/ethnic disparities in AD.
Source: Alzheimer s & Dementia
Authors: Kaitlyn E. Stepler, Renã A.S. Robinson
Institutions: Vanderbilt University, Vanderbilt University Medical Center
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980792962