Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Abstract

SummaryDevelopment of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-b (Ab) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of Ab contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble Ab into the hippocampus or thalamus showed an agerelated reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of Ab in the brain in AD and may facilitate development of improved therapeutic strategies to remove Ab from the brain in AD.

Incidence of cerebral microbleeds in preclinical Alzheimer disease

“…38,39 Presence of severe WMH may reflect impaired perivascular drainage in the setting of severe CAA, with stasis of interstitial fluid, and chronic white matter edema. 40,e1 In addition, severe subcortical small-vessel disease (encompassing lacunar infarction and WMH) may act in concert with CAA to increase risk of LMBs.…”

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

“…32 They are key components of the BBB and they have been shown to be implicated in drainage of Ab. 9,31 Perlecan and fibronectin have been proposed to participate in Ab accumulation by accelerating its aggregation by providing a higher stability of Ab in the basement membrane. 10,11 Interestingly, perlecan and fibronectin levels are also elevated during aging in mice, and this could in part explain the impaired drainage of Ab in the aging brain.…”

“…10,11 Interestingly, perlecan and fibronectin levels are also elevated during aging in mice, and this could in part explain the impaired drainage of Ab in the aging brain. 9,31 However, whereas perlecan is normally expressed in abundance around healthy cerebral blood vessels, it is absent around amyloid-laden blood vessels in the brains of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type patients, 33 raising the intriguing possibility that diminished perivascular perlecan expression could contribute to cerebral amyloid angiopathy. Our observations suggest that jTBI-induced expression of perlecan and fibronectin participate in the establishment of accelerated brain aging.…”

Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex

“…Several other effects of hypertension may also play a role. These could include impaired perivascular drainage as a consequence of collagenous thickening and reduced pulsatility of arteries and arterioles [48][49][50]; reduced receptor-mediated transport of Aβ across the endothelium into the bloodstream; degeneration of pericytes [51], leading to reduced clearance of soluble Aβ40 and Aβ42 from the interstitial fluid [52];…”