Brain‐derived and circulating vesicle profiles indicate neurovascular unit dysfunction in early Alzheimer’s disease

Abstract

Vascular factors that reduce blood flow to the brain are involved in apparition and progression of dementia. We hypothesized that cerebral hypoperfusion (CH) might alter the molecular compositions of brain intercellular communication mechanisms while affecting the neurovascular unit in preclinical and clinical human dementias. To test that hypothesis, mice were subjected to bilateral common carotid stenosis (BCAS) and the molecular compositions of brain-derived and circulating extracellular vesicles (EVs) were assessed. Murine brain vesicle profiles were then analyzed in parallel with brain EVs from post-mortem subjects affected by preclinical Alzheimer's Disease (AD) and mixed dementias. Brain EVs were identified with molecular mediators of hypoxia responses, neuroprotection and neurotoxicity in BCAS mice, patterns also partially resembled by subjects with preclinical AD and mixed dementias. Together these findings indicate that brain EVs represent a promising source of therapeutic targets and circulating markers of neurovascular insult in idiopathic dementias. Furthermore, the results obtained generate novel and compelling hypotheses about the molecular involvement of the vascular component in the etiology of human dementias.

Carotid artery disease in post‐stroke survivors and effects of enriched environment on stroke pathology in a mouse model of carotid artery stenosis

“…Irrespective, the proteomic data suggest attenuation of coagulation cascade factors and modulation of protective factors such as calmodulin in CAD is possible. Also, we recently reported protein profiles in brain‐derived extracellular vesicles were similarly regulated under conditions of cerebral hypoperfusion in both the human brain and long‐term BCAS mouse brain . Further application of in‐vivo physiological screening, for example, vascular autoregulation, haemodynamic changes as well as assessment of angiogenesis, neurogenesis, neurovascular and gliovascular integrity would enable elucidation of mechanisms associated with effects of EE in long‐term BCAS models.…”

Differential Profile of Systemic Extracellular Vesicles From Sporadic and Familial Alzheimer’s Disease Leads to Neuroglial and Endothelial Cell Degeneration

“…These events lead to infiltration of the parenchyma by leukocytes and parenchymal brain damage (Ramirez et al, 2018;Passamonti et al, 2019). Additionally, recent studies have suggested that EVs may be important mediators of AD (Goetzl et al, 2016;Dickhout and Koenen, 2018;Gallart-Palau et al, 2019). Brain-derived and systemic EVs could mediate systemic inflammation as well as brain and NVU dysfunction.…”

Influence of species and processing parameters on recovery and content of brain tissue-derived extracellular vesicles

“…Since numerous publications have reported tissue-derived EVs without thorough protein characterization of EV-depleted cellular markers and specific EV subtype markers 12,15,16,[49][50][51][52] , we compared the BH and bdEV proteomes with established EV-related databases. Substantial concordance between our data and the databases was clear (Tabe 3).…”