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.
Highlights
Alzheimer’s disease (AD) is a chronic age-related neurodegenerative disorder and the predominant type of dementia, marked by deposits of amyloid plaques and neurofibrillary tangles composed of hyperphosphorylated tau (Holtzman et al, 2012)
We used 44 total brain cerebrovascular specimens from the inferior frontal gyrus obtained from young healthy controls (9 cases), aged non-demented controls (15 cases) and Alzheimer’s disease (AD) patients (20 cases; 10 cases each with Low or High cerebral amyloid angiopathy (CAA) score) — (Table 1)
We noted that AD cases with low or high CAA scores consisted of 40 or 67% APOE4 allele carriers, respectively, while only 20% of aged non-demented control cases were APOE4 allele carriers, suggesting that APOE4 genotype may be a driver of the events we reported in this study
Summary
Alzheimer’s disease (AD) is a chronic age-related neurodegenerative disorder and the predominant type of dementia, marked by deposits of amyloid plaques and neurofibrillary tangles composed of hyperphosphorylated tau (Holtzman et al, 2012). Neuroimaging abnormalities have demonstrated early preclinical features such as cerebral perfusion and metabolic deficits (De la Torre and Mussivand, 1993; de la Torre, 2018), and diminished cortical blood flow beginning many years prior to the onset of neurological symptoms (Binnewijzend et al, 2016; Hays et al, 2016). One of the most common vascular associated lesions in AD is cerebral amyloid angiopathy (CAA), typified by the accumulation of Aβ in leptomeninges and along cerebral blood vessels. Similar large cohort aging studies have likewise confirmed the presence of underlying cerebrovascular abnormalities such as cerebrovascular small vessel disease (CSVD) lesions as a strong predictor of clinical presentation or cognitive deficits in AD patients (Nagy et al, 1997). Vascular dementia and AD related dementia both share a significant degree of overlap in their clinical and neuropathological profiles (Kalaria and Ballard, 1999; Kalaria, 2003; Erkinjuntti et al, 2004; Custodio et al, 2017)
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