Abstract
BackgroundCerebral amyloid angiopathy (CAA) refers to the deposition of β-amyloid (Aβ) peptides in the wall of brain vasculature, commonly involving capillaries and arterioles. Also being considered a part of CAA is the Aβ deposition in leptomeninge. The cellular origin of angiopathic Aβ and the pathogenic course of CAA remain incompletely understood.MethodsThe present study was aimed to explore the pathogenic course of CAA in the human cerebrum via examination of changes in β-secretase-1 (BACE1), the obligatory Aβ producing enzyme, relative to Aβ and other cellular markers, by neuroanatomical and biochemical characterizations with postmortem brain samples and primary cell cultures.ResultsImmunoreactivity (IR) for BACE1 was essentially not visible at vasculature in cases without cerebral amyloidosis (control group, n = 15, age = 86.1 ± 10.3 year). In cases with brain amyloid pathology (n = 15, age = 78.7 ± 12.7 year), increased BACE1 IR was identified locally at capillaries, arterioles and along the pia, localizing to endothelia, perivascular dystrophic neurites and meningeal cells, and often coexisting with vascular iron deposition. Double immunofluorescence with densitometric analysis confirmed a site-specific BACE1 elevation at cerebral arterioles in the development of vascular Aβ deposition. Levels of BACE1 protein, activity and its immediate product (C99) were elevated in leptomeningeal lysates from cases with CAA relative to controls. The expression of BACE1 and other amyloidogenic proteins in the endothelial and meningeal cells was confirmed in primary cultures prepared from human leptomeningeal and arteriolar biopsies.ConclusionThese results suggest that BACE1 elevation in the endothelia and perivascular neurites may be involved in angiopathic Aβ deposition, while BACE1 elevation in meningeal cells might contribute Aβ to leptomeningeal amyloidosis.
Highlights
Cerebral amyloid angiopathy (CAA) refers to the deposition of β-amyloid (Aβ) peptides in the wall of brain vasculature, commonly involving capillaries and arterioles
While essentially no vascular BACE1 IR was identifiable in sections from the control group (Figure 1C,G,H), increased BACE1 IR was seen at some vascular profiles in the cortex and hippocampal formation in the cases with neuritic amyloid pathology (Figure 1B,E,I,J)
When comparing intracortical arterioles without (Figure 2E) to those with BACE1 IR, the labeling appeared to occur initially intensify in the tunica intima (TI) or endothelial layer (Figure 2F)
Summary
Cerebral amyloid angiopathy (CAA) refers to the deposition of β-amyloid (Aβ) peptides in the wall of brain vasculature, commonly involving capillaries and arterioles. Many studies explored the role of reduced brain-to-blood efflux and/or increased periphery-to-central transportation of Aβ in cerebral amyloidosis e.g., [15,16,17,18]. CAA may occur as a consequence of interstitial Aβ elevation in the brain together with impaired drainage of the peptides from parenchyma to blood [19,20,21,22]. Retrograde Aβ transportation from blood into the brain is considered to cause vascular amyloidosis, with some studies explored a role for platelets in Aβ production and the development of CAA [23,24]
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