Shared proteomic effects of cerebral atherosclerosis and Alzheimer’s disease on the human brain

Abstract

Cerebral atherosclerosis contributes to dementia via unclear processes. We performed proteomic sequencing of dorsolateral prefrontal cortex in 438 older individuals and found associations between cerebral atherosclerosis and reduced synaptic signaling and RNA splicing and increased oligodendrocyte development and myelination. Consistently, single-cell RNA sequencing showed cerebral atherosclerosis associated with higher oligodendrocyte abundance. A subset of proteins and modules associated with cerebral atherosclerosis was also associated with Alzheimer’s disease, suggesting shared mechanisms.

Quantitative phosphoproteomics uncovers dysregulated kinase networks in Alzheimer’s disease

“…In addition, Oligo is strongly anti-correlated with the Neuro cluster which contains SYT1 and SNAP25 (Figure 2f, 2i) , two synaptic markers of neurodegeneration 63,64 . This myelination/oligodendrocyte protein module has been found to be associated with the trajectory of cognitive decline in AD 28 and has been observed in other forms of dementia caused by cerebral atherosclerosis 65 . These findings suggest that Oligo represents a general remyelination response that occurs concomitant to neurodegeneration, while Tau is most closely associated with development of AD-specific pathologies that precede neurodegeneration 66 .…”

“…One major question arising from our work is the nature of this myelination response. Previous proteomics analyses have linked myelination to cerebral atherosclerosis as well as the trajectory of cognitive decline in AD 26,28,65 . In addition, a subset of these proteins were found to be upregulated at a transcript level in single-nuclei RNA-seq analyses of AD oligodendrocytes 54 .…”

Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau

“…In a comparison of this transcriptome network to an independently constructed proteomic network from AD brain tissue, the authors found at least 50% overlap between oligodendrocyte modules of the two datasets, including the AD risk candidate BIN1.Additional transcriptomic network analyses have similarly found enrichment of genes associated with either AD risk or Aβ processing among oligodendrocyte-specific modules[131,132].The mechanisms by which oligodendrocyte dysfunction contribute to AD pathogenesis remain unclear. In an intriguing network proteomic analysis of over 400 brains (DLPFC), Wingo et al found that cerebral atherosclerosis may be the missing link between oligodendrocytes and AD dementia[107]. In this study, cerebral atherosclerosis was pathologically assessed by visual inspection of Circle of Willis vessels and their proximal branches and graded independently of gross infarcts, microinfarcts, or other white matter lesions.…”

“…Nearly a dozen informative network-based analyses of the AD proteome have been performed in the human brain[62][63][64]74,78,96,[104][105][106][107][108], including the dorsolateral prefrontal cortex (DLPFC), temporal cortex, and other cortical regions heavily affected in AD. Using highthroughput MS techniques, these studies have revealed a highly reproducible network of modules across the AD proteome, several of which consistently demonstrate strong correlations to AD diagnosis, Aβ burden, and other phenotypic traits of disease.…”

Susceptibility to gingipains and transcriptomic response to P. gingivalis highlights the ribosome, hypothalamus, and cholinergic neurons

“…Ding et al 2005;Sajdel-Sulkowska and Marotta 1984;Langstrom et al 1989;Hernández-Ortega et al 2016;Nyhus et al 2019) . In agreement with gingipain susceptibility, a proteomic study found a lower abundance of RNA splicing proteins in cerebral atherosclerosis (Wingo et al 2020) . Dysregulated splicing is also demonstrated by increased intron retention in Alzheimer's disease (Adusumalli et al 2019) .…”