Abstract
Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid-β (Aβ) deposition, which leads to lobar hemorrhage and dementia. Biological molecules affecting the development of CAA have not been fully characterized. In this study, we performed proteome analysis of biopsied leptomeningeal and cortical vessels obtained from 6 CAA patients and 5 non-CAA patients who underwent surgery for large lobar hemorrhages. We found that 6 proteins, including Aβ, apolipoprotein E (apoE), clusterin (CLU), albumin, complement C4 and vitronectin were significantly upregulated in the vessels of CAA patients as compared to non-CAA patients. ApoE and CLU were found in all CAA patients. We next examined the effects of apoE and CLU on the early phase of Aβ aggregation, using a simple yet powerful in vitro model of CAA, which recapitulates the intramural periarterial drainage pathway model. We found that physiological concentrations of apoE and CLU delayed the initiation time of amyloid growth kinetics in a concentration-dependent manner. These data indicate that apoE and CLU may act as extracellular chaperones to inhibit Aβ amyloid deposition in CAA.
Highlights
Sporadic cerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in the cortical and leptomeningeal arteries, which leads to lobar hemorrhage, infarction, encephalopathies and dementia [40, 41]
Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid-β (Aβ) deposition, which leads to lobar hemorrhage and dementia
We found that 6 proteins, including Aβ, apolipoprotein E, clusterin (CLU), albumin, complement C4 and vitronectin were significantly upregulated in the vessels of CAA patients as compared to non-CAA patients
Summary
Sporadic cerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in the cortical and leptomeningeal arteries, which leads to lobar hemorrhage, infarction, encephalopathies and dementia [40, 41]. We first performed proteome analysis of biopsied leptomeningeal and cortical vessels obtained from 6 CAA patients and 5 non-CAA patients who underwent surgery for large lobar hemorrhages [18]. We examined the effects of apoE and CLU on the early phase of Aβ aggregation, using a powerful, physiologically relevant in vitro model of CAA [10]. This model was previously established to test the hypothesis that intramural periarterial drainage (IPAD) flow carries Aβ to the vascular basement membrane (BM), which may trap Aβ and induce amyloid fibril formation in vivo [1, 22]
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