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

Abstract

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 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.

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

“…Cerebrovascular dysfunction has been observed in both AD and IS ( Fossati et al, 2010 , 2012a , b ; Guo et al, 2010 ; Lochhead et al, 2010 ; Jiao et al, 2011 ; Shin et al, 2016 ; Freitas-Andrade et al, 2020 ; Parodi-Rullán et al, 2020 ; Quintana et al, 2021 ). Aging, as well as cardiovascular risk factors, such as hypertension and diabetes, contribute to cerebrovascular pathology ( Huang et al, 1995 ; Girouard and Iadecola, 2006 ; Price et al, 2012 ; Cortes-Canteli and Iadecola, 2020 ; Ojo et al, 2021 ). The reduction of tight junction proteins such as zona occludin-1 (ZO-1) and occludin is observed in models of stroke and AD ( Marco and Skaper, 2006 ; Jiao et al, 2011 ; Engelhardt et al, 2014 ; Freitas-Andrade et al, 2020 ; Parodi-Rullán et al, 2020 ).…”

“…The contraction of SMCs provides the motive force for IPAD ( Carare et al, 2008 ; Aldea et al, 2019 ). This system is dysregulated in models of CAA and aging ( Ojo et al, 2021 ). Another brain clearance pathway, the glymphatic system, has been observed to import cerebrospinal fluid along periarterial space and export interstitial fluid along perivenous spaces, in perivascular tunnels, formed by astroglial cells.…”

“…AD is the most common form of dementia and has been historically characterized by extracellular amyloid beta (Aβ) plaques and intracellular hyperphosphorylated tau tangles in specific brain regions ( Day et al, 2015 ; Castillo-Carranza et al, 2017 ; Cortes-Canteli and Iadecola, 2020 ; Ojo et al, 2021 ). Interestingly, Aβ and tau intermediate aggregation species, such as oligomers, have been shown to have toxic effects on multiple cell types of the NVU ( Fossati et al, 2010 , 2012b ; Parodi-Rullán et al, 2019 ; Canepa and Fossati, 2020 ).…”

“…Importantly, up to 90% of AD patients also present with cerebral amyloid angiopathy (CAA), defined as Aβ deposition around the brain vasculature and/or within the vessel walls ( Iadecola, 2017 ; Sweeney et al, 2019a ; Zlokovic et al, 2020 ). CAA is also common in the non-demented elderly population and constitutes an important contributor to NVU dysfunction in both normal aging and AD ( Provensi et al, 2019 ; Cortes-Canteli and Iadecola, 2020 ; Ojo et al, 2021 ).…”

“…Shared risk factors between AD and stroke are reduced CBF, cardiovascular diseases and age ( Sarvari et al, 2020 ; Ojo et al, 2021 ). Cardiovascular risk factors like obesity, diabetes, hypertension and atherosclerosis have been observed to exacerbate cerebrovascular pathology as well as neurodegeneration, including AD ( Girouard and Iadecola, 2006 ; de Bruijn and Ikram, 2014 ; Cortes-Canteli and Iadecola, 2020 ; Sarvari et al, 2020 ).…”