4.6 Article

Molecular Pathobiology of the Cerebrovasculature in Aging and in Alzheimers Disease Cases With Cerebral Amyloid Angiopathy

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FRONTIERS IN AGING NEUROSCIENCE
卷 13, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fnagi.2021.658605

关键词

cerebrovasculature; Alzheimers disease; cerebral amyloid angiopathy; endothelial cells; mural cells; proteomics; mass spectrometry; perivascular cells

资金

  1. National Institute on Aging of the National Institutes of Health [R01AG041971]
  2. National Institute of Neurological Disorders and Stroke [U24 NS072026]
  3. National Institute on Aging [P30 AG19610]
  4. Arizona Department of Health Services [211002]
  5. Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
  6. Michael J. Fox Foundation for Parkinson's Research

向作者/读者索取更多资源

Cerebrovascular dysfunction and cerebral amyloid angiopathy are hallmark features of Alzheimer's disease. Molecular damage to cerebrovessels can lead to alterations in vascular clearance mechanisms and amyloid deposition. Proteomic analysis revealed significant changes in protein expression in cerebrovessels with aging and AD, with dysregulation of pathways related to chemokine signaling, HIF1 alpha, and mitochondrial function. These findings provide insights into the pathogenesis of AD and suggest potential therapeutic targets for improving cerebrovascular function.
Cerebrovascular dysfunction and cerebral amyloid angiopathy (CAA) are hallmark features of Alzheimer's disease (AD). Molecular damage to cerebrovessels in AD may result in alterations in vascular clearance mechanisms leading to amyloid deposition around blood vessels and diminished neurovascular-coupling. The sequelae of molecular events leading to these early pathogenic changes remains elusive. To address this, we conducted a comprehensive in-depth molecular characterization of the proteomic changes in enriched cerebrovessel fractions isolated from the inferior frontal gyrus of autopsy AD cases with low (85.5 +/- 2.9 yrs) vs. high (81 +/- 4.4 yrs) CAA score, aged-matched control (87.4 +/- 1.5 yrs) and young healthy control (47 +/- 3.3 yrs) cases. We employed a 10-plex tandem isobaric mass tag approach in combination with our ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method. Enriched cerebrovascular fractions showed very high expression levels of proteins specific to endothelial cells, mural cells (pericytes and smooth muscle cells), and astrocytes. We observed 150 significantly regulated proteins in young vs. aged control cerebrovessels. The top pathways significantly modulated with aging included chemokine, reelin, HIF1 alpha and synaptogenesis signaling pathways. There were 213 proteins significantly regulated in aged-matched control vs. high CAA cerebrovessels. The top three pathways significantly altered from this comparison were oxidative phosphorylation, Sirtuin signaling pathway and TCA cycle II. Comparison between low vs. high CAA cerebrovessels identified 84 significantly regulated proteins. Top three pathways significantly altered between low vs. high CAA cerebrovessels included TCA Cycle II, Oxidative phosphorylation and mitochondrial dysfunction. Notably, high CAA cases included more advanced AD pathology thus cerebrovascular effects may be driven by the severity of amyloid and Tangle pathology. These descriptive proteomic changes provide novel insights to explain the age-related and AD-related cerebrovascular changes contributing to AD pathogenesis. Particularly, disturbances in energy bioenergetics and mitochondrial biology rank among the top AD pathways altered in cerebrovessels. Targeting these failed mechanisms in endothelia and mural cells may provide novel disease modifying targets for developing therapeutic strategies against cerebrovascular deterioration and promoting cerebral perfusion in AD. Our future work will focus on interrogating and validating these novel targets and pathways and their functional significance.

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