Morphological and Pathological Evolution of the Brain Microcirculation in Aging and Alzheimer’s Disease

• Published in: PloS one Vol. 7; no. 5; p. e36893
• Main Authors: Hunter, Jesse M., Kwan, Jason, Malek-Ahmadi, Michael, Maarouf, Chera L., Kokjohn, Tyler A., Belden, Christine, Sabbagh, Marwan N., Beach, Thomas G., Roher, Alex E.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.05.2012; Public Library of Science (PLoS)
• Subjects: Acetylcholine; Advertising executives; Age; Aged; Aged, 80 and over; Aging; Aging - metabolism; Aging - pathology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Angiogenesis; Apolipoprotein E4 - metabolism; Apolipoproteins; Biochemistry; Biology; Biomarkers; Brain; Brain - blood supply; Brain research; Capillaries; Capillaries - metabolism; Capillaries - pathology; Cardiovascular disease; Carriers; Cerebral amyloid angiopathy; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Cerebrovascular system; Cholinergic Neurons - metabolism; Cholinergic Neurons - pathology; Cognitive ability; Cohort Studies; Consortia; Cortex; Dementia; Dementia - metabolism; Dementia - pathology; Dementia disorders; Ethnicity; Evolution; Female; Humans; Hydroxylase; Immunohistochemistry; Immunohistochemistry - methods; Immunotherapy; Innervation; Macular degeneration; Male; Medical imaging; Medical research; Medicine; Microcirculation; Microvasculature; Microvessels - metabolism; Microvessels - pathology; Morphology; Neurodegenerative diseases; Neurofibrillary tangles; Neurons, Afferent - metabolism; Neurons, Afferent - pathology; Neuropathology; Norepinephrine; Pathogenesis; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Review boards; Rodents; Senile plaques; Staining; Structural integrity; Substantia grisea; Tyrosine; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - metabolism; Vasoconstriction; Vasoconstriction - physiology; Vasodilation; Vasodilation - physiology; Vesicular Acetylcholine Transport Proteins - metabolism; Vesicular acetylcholine transporter; United States > US; Glendale Arizona
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0036893

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.