Cerebrovascular Disease Is a Major Factor in the Failure of Elimination of Aβ from the Aging Human Brain

Abstract

Alzheimer's disease (AD) is characterized by the intracellular deposition of ubiquitinated tau and by the extracellular accumulation of soluble, insoluble, and fibrillary Abeta. Previous studies suggest that Abeta is normally eliminated from the brain along perivascular pathways that may become blocked in the aging brain, resulting in cerebral amyloid angiopathy. As age is a major risk factor for AD and for cerebrovascular disease (CVD), we test the hypothesis that CVD inhibits the elimination of Abeta from the aging human brain. Sections from 100 aged and AD brains were stained for Abeta by immunohistochemistry and by reticulin and Masson trichrome techniques. Early deposition of Abeta in brain parenchyma was related to individual arterial territories in the cortex. In areas of more extensive accumulation of Abeta, there was an inverse relationship between capillary amyloid angiopathy and plaques of Abeta. Thus, arterial territories with extensive capillary amyloid angiopathy were devoid of Abeta plaques, whereas in areas with abundant diffuse plaques there was no capillary amyloid angiopathy. Serial sections showed that cortical arteries feeding capillary beds with Abeta angiopathy were occluded by thrombus. We conclude that CVD inhibits the elimination of Abeta along capillary walls and changes the distribution of Abeta in the cerebral cortex. Loss of pulsations in thrombosed or arteriosclerotic arteries may thus abolish the motive force necessary for the drainage of Abeta and inhibit the elimination of Abeta. Therapies to increase elimination of Abeta in AD need to consider the effects of CVD on the elimination of Abeta from the aging human brain.

Risk of Alzheimer’s Disease in Relation to Diabetes: A Population-Based Cohort Study

“…Aging-related atherosclerosis is also considered to contribute to the pathogenesis of AD [25]. As arteries stiffen and lymph drainage is impaired [26], the drainage of amyloid-β protein is also impaired, leading to deposition in the brain parenchyma and consequent AD [27]. Women had a slightly higher HR for AD compared to men.…”

“…Diabetes is a complex metabolic disorder which is closely associated with other vascular risk factors such as cerebrovascular disease [27], cardiovascular disease [32] and hypertension [33]. Vascular risk factors have been linked to the development of AD and contribute to the deposition of amyloid-β protein in the brain [34].…”

Amyloid β-Protein Stimulates the Expression of Urokinase-type Plasminogen Activator (uPA) and Its Receptor (uPAR) in Human Cerebrovascular Smooth Muscle Cells

“…DISCUSSION CAA is a common pathological feature of most patients with Alzheimer's disease and is prominently found in several rare hereditary cerebrovascular amyloidosis disorders involving mutations within A␤ (1,16,19). The reasons for the accumulation of A␤ in cerebral blood vessels remain unresolved although recent studies (47,48) suggest that it may involve the flow of parenchymal A␤ through interstitial fluid drainage pathways and ineffective transport into the circulation. A profound deleterious consequence of CAA, particularly in the hereditary forms, is cerebral hemorrhage that can result in serious debilitation or death (19,49,50).…”

Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report

“…The vascular amyloid deposits, which comprise predominantly Aβ40 (unlike plaques, which are predominantly Aβ42), may be more stable, more rapidly replenished or less accessible, for example to Aβ-specific antibody or phagocytes 4 . A further possibility is that efflux of Aβ from the brain through perivascular drainage pathways may be stimulated by the immunotherapy and contribute to CAA 11 . Whatever the mechanism, this relative persistence of vascular Aβ may be relevant to the observation that CAA-related hemorrhage in APP transgenic mice was increased by one Aβ-specific antibody 12 .…”