title: Morphological and pathological evolution of the brain microcirculation in aging and Alzheimer's disease.
abstract: Key pathological hallmarks of Alzheimer's disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular "dysfunction" compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD.
authors.affiliation: The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute, Sun City, Arizona, United States of America.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Hunter
authors.forename: Jason
authors.initials: J
authors.lastname: Kwan
authors.forename: Michael
authors.initials: M
authors.lastname: Malek-Ahmadi
authors.forename: Chera L
authors.initials: CL
authors.lastname: Maarouf
authors.forename: Tyler A
authors.initials: TA
authors.lastname: Kokjohn
authors.forename: Christine
authors.initials: C
authors.lastname: Belden
authors.forename: Marwan N
authors.initials: MN
authors.lastname: Sabbagh
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.forename: Alex E
authors.initials: AE
authors.lastname: Roher
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D053327:Apolipoprotein E4 / Q000378:metabolism; D001921:Brain / Q000098:blood supply*; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D059329:Cholinergic Neurons / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008833:Microcirculation; D055806:Microvessels / Q000378:metabolism / Q000473:pathology*; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
chemical_list: D053327:Apolipoprotein E4; D050494:Vesicular Acetylcholine Transport Proteins; D014446:Tyrosine 3-Monooxygenase