| Title: |
Molecular Pathobiology of the Cerebrovasculature in Aging and in Alzheimers Disease Cases With Cerebral Amyloid Angiopathy |
| Authors: |
Ojo, Joseph O.; Reed, Jon M.; Crynen, Gogce; Vallabhaneni, Prashanthi; Evans, James; Shackleton, Benjamin; Eisenbaum, Maximillian; Ringland, Charis; Edsell, Anastasia; Mullan, Michael; Crawford, Fiona; Bachmeier, Corbin |
| Publication Year: |
2021 |
| Collection: |
The Open University: Open Research Online (ORO) |
| Description: |
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, HIF1α 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 ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://oro.open.ac.uk/77194/1/fnagi-13-658605.pdf; Ojo, Joseph O. ; Reed, Jon M.; Crynen, Gogce; Vallabhaneni, Prashanthi; Evans, James; Shackleton, Benjamin ; Eisenbaum, Maximillian ; Ringland, Charis ; Edsell, Anastasia; Mullan, Michael; Crawford, Fiona and Bachmeier, Corbin (2021). Molecular Pathobiology of the Cerebrovasculature in Aging and in Alzheimers Disease Cases With Cerebral Amyloid Angiopathy. Frontiers in Aging Neuroscience, 13, article no. 658605. |
| Availability: |
https://oro.open.ac.uk/77194/ |
| Rights: |
cc_by_4 |
| Accession Number: |
edsbas.EC1911A7 |
| Database: |
BASE |