Role of Blood Vessels in Producing Pathological Changes in the Brain with Alzheimer's Disease

Abstract

Vascular factors have been shown to be highly involved in the deposition of the amyloid beta-protein (A beta) in the brain of Alzheimer's disease (AD). However, the detailed mechanism remains unknown. Here, we showed that more numerous deposits of A beta 40 and A beta 42 in the brain were found in AD patients than in controls. Together with evidence of no difference in the level of A beta 40 and A beta 42 in sera between sporadic AD and controls, a certain dysfunction of the blood-brain barrier could induce an abnormal transport of A beta from sera to the parenchyma in AD. In addition, vascular A beta deposits and mature A beta plaques stained by Congo red in AD brains contained more A beta 40 than A beta 42, whereas Congo red-negative immature plaques mainly consisted of A beta 42. Our confocal laser scanning microscopy demonstrated an intimate relationship between A beta 40 and the vascular network. The amount of mature plaques but not that of immature plaques was reportedly correlated with the severity of dementia in AD patients. These results suggest that serum-derived A beta 40 and/or A beta 42 cause A beta 40 deposition in and around blood vessels through unknown but possible mechanisms such as (1) endocytosis of A beta 40, (2) selective transport A beta 40 and A beta 42 into blood vessels and the parenchyma, respectively, and (3) proteolysis of A beta 42 into A beta 40 induced by a putative carboxyl dipeptidase in blood vessels including vascular feet, which is involved in A beta fibrillation and cognitive deterioration in the patients. Therefore, the accumulation of A beta 40 associated with blood vessels may play a critical role in the development of AD.

High-definition characterization of cerebral β-amyloid angiopathy in Alzheimer's disease

“…In a study by Miyakawa et al [30] on parahippocampal tissue from 10 AD and 10 control brains, close spatial association of almost all dense-core Aβ40 plaques with capillaries was shown on double immunofluorescent staining for Aβ and collagen IV. On electron microscopy, they found that some degenerated capillaries containing amyloid fibrils in their walls were localized in close proximity to dense-core amyloid plaques [30]. An immunoelectron microscopic study of AD brains by Yamaguchi et al [16] has suggested that the capillary basement membrane was one of the predilection sites for early Aβ deposition.…”

“…In Tg2576 and PSAPP mouse models of AD, the majority of dense-core Aβ plaques were shown to be centered on capillaries [15]. In a study by Miyakawa et al [30] on parahippocampal tissue from 10 AD and 10 control brains, close spatial association of almost all dense-core Aβ40 plaques with capillaries was shown on double immunofluorescent staining for Aβ and collagen IV. On electron microscopy, they found that some degenerated capillaries containing amyloid fibrils in their walls were localized in close proximity to dense-core amyloid plaques [30].…”

“…On the other hand, by using double immunostaining for Aβ and collagen IV on the entorhinal cortex of two AD patients, Kawai et al [31] suggested that spatial association between capillaries and both diffuse and dense-core Aβ plaques occurred by chance, depending on the size of Aβ plaques. Aβ-laden capillaries originally associated with diffuse plaques may progressively be loaded with Aβ and undergo degeneration, as diffuse plaques evolve into dense-core plaques [30]. Therefore, there would be a higher probability for identifying Aβ-laden capillaries within diffuse Aβ plaques than in dense-core Aβ plaques on immunohistologic sections studied either at the light or electron microscopic level.…”

Blood-Cerebrospinal Fluid Barrier Permeability in Alzheimer's Disease

“…The hypothesis advanced regarding the role of CSF sPLA2 in BCB dysfunction was the activation of the arachidonic acid pathway. Another mechanism generally advanced in order to explain BCB impairment in AD, is an Aβ accumulation at CP epithelium which alters the CP function [43] as it has been observed at the BBB interface [33, 44, 45], and may in return increase both the clearance from CSF of CSF-derived protein, for instance Aβ [46] and the accumulation in CSF of blood-derived compounds, e.g., amino acids [47]. Would an increase of BCB impairment be the mechanism involved in the decrease of Aβ level in AD CSF?…”

Specific Mechanism for Blood Inflow Stimulation in Brain Area Prone to Alzheimer’s Disease Lesions

“…Abetas concentrations in CSF are increased in healthy humans over 59 years of age (Shoji et al, 2001), and just during aging in the brain of neurologically intact humans Abetas in monomeric, oligomeric, and aggregated forms appear. Of significance, increased amyloid quantities are found exactly in the AHBC area (Tomlinson et al, 1968;Dayan, 1970;Ulrich, 1982;Averback, 1983;Miller et al, 1984;Ulrich, 1985;Mann et al, 1987;Crystal et al, 1988;Mann et al, 1990;Arriagada et al, 1992b;Dickson et al, 1992;Bouras et al, 1994;Morys et al, 1994;Vermersch et al, 1995;Ogeng'o et al, 1996;Yasha et al, 1997;Davis et al, 1999;Miyakawa et al, 2000;Schmitt et al, 2000), which, in all likelihood, is the most suitable (if not the sole) place for intensive formation of these peptides.…”