Dataset Information

Proteomics of 2 postmortem Human Brain Regions for Identification of Cognitive Resilience Factors

ABSTRACT: We implemented an integrative systems-level analysis of multi-region postmortem human brain proteomics derived from the Religious Order and Rush Memory and Aging Project (ROSMAP) to identify proteins and pathways significantly altered in resilient cases. ROSMAP is an information-rich longitudinal cohort-based study in which participants enroll without dementia, undergo annual cognitive and clinical assessments and donate their brains at death (12). Multiplex tandem mass tag mass spectrometry (TMT-MS)-based proteomic data was implemented for a correlation network analysis. Data from an independent brain proteome wide association study (PWAS) of cognitive trajectory was integrated with the brain network to robustly prioritize protein communities associated with cognitive resilience. This revealed proteins linked to synaptic biology and cellular energetics. Neuritin (NRN1) was prioritized as a hub that co-expressed with a community of proteins with high correlation to cognitive stability in life and is known for important roles in synaptic maturation and stability.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Eric Dammer

LAB HEAD: Nicholas T. Seyfried, DPhil

PROVIDER: PXD040224 | Pride | 2023-07-20

REPOSITORIES: Pride

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Publications

Integrated Proteomics to Understand the Role of Neuritin (NRN1) as a Mediator of Cognitive Resilience to Alzheimer's Disease.

Hurst Cheyenne C Pugh Derian A DA Abreha Measho H MH Duong Duc M DM Dammer Eric B EB Bennett David A DA Herskowitz Jeremy H JH Seyfried Nicholas T NT

Molecular & cellular proteomics : MCP 20230405 5

The molecular mechanisms and pathways enabling certain individuals to remain cognitively normal despite high levels of Alzheimer's disease (AD) pathology remain incompletely understood. These cognitively normal people with AD pathology are described as preclinical or asymptomatic AD (AsymAD) and appear to exhibit cognitive resilience to the clinical manifestations of AD dementia. Here we present a comprehensive network-based approach from cases clinically and pathologically defined as asymptomat ...[more]

PMID: 37024090

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Project description:Genome-wide transcriptional profiling allows characterization of the molecular underpinnings of neocortical organization, including cortical areal specialization, laminar cell type diversity and functional anatomy. Microarray analysis of individual cortical layers across sensorimotor and association cortices in rhesus macaque demonstrated robust and specific laminar and areal molecular signatures driven by differential expression of genes associated with specialized neuronal function. Gene expression corresponding with laminar architecture was generally similar across cortical areas, although genes with robust areal patterning were often highly laminar as well, and these patterns were more highly conserved between macaque and human as compared to mouse. Layer 4 of primate primary visual cortex displayed a distinct molecular signature compared to other cortical regions, a specialization not observed in mouse. Overall, transcriptome-based relationships were strongest between proximal layers in a cortical area, and between neighboring areas along the rostrocaudal axis, reflecting in vivo cortical spatial topography and therefore a developmental imprint. Tissue from male and female monkeys (n = 2-3 animals/gender) was collected from anterior cingulate gyrus (ACG), layers 2, 3, 5, 6; orbitofrontal cortex (OFC), layers 2, 3, 5, 6; dorsolateral prefrontal cortex (DLPFC), layers 2-6; primary motor cortex (M1), layers 2, 3, 5, 6; primary somatosensory cortex (S1), layers 2-6; primary auditory cortex (A1), layers 2-6; primary visual cortex (V1), layers 2-6 including 4A, 4B, 4Calpha (4Ca), 4Cbeta (4Cb); secondary visual cortex (V2), layers 2-6; middle temporal area (MT), layers 2-6; temporal area (TE), layers 2-6; hippocampus, CA1, CA2, CA3, dentate gyrus (DG); and dorsal lateral geniculate nucleus (LGN), magnocellular, parvocellular and koniocellular divisions. Due to the limited number of samples that could be amplified concurrently, amplifications were performed in 3 batches (batches A-C, containing 102, 119 and 10 experimental samples, respectively). To control for batch effects, common RNA pool control samples were amplified and hybridized in each batch. These included LCM extracted hippocampus CA3 samples from the current study and a whole rhesus brain RNA pool (Biochain). These control samples were hybridized in 6 replicates in batch A and B and in 3 replicates in batch C (3 replicates per 96 well plate).

Dataset Information

Proteomics of 2 postmortem Human Brain Regions for Identification of Cognitive Resilience Factors

Publications

Integrated Proteomics to Understand the Role of Neuritin (NRN1) as a Mediator of Cognitive Resilience to Alzheimer's Disease.

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