Small cerebral vessel disease in familial amyloid and non-amyloid angiopathies: FAD-PS-1 (P117L) mutation and CADASIL. Immunohistochemical and ultrastructural studies

Introduction
The “muscularis” tunica media characterised for cerebral and leptomeningeal arteries and arterioles contains numerous smooth muscle cells in which elastic fibres predominate. This vessel wall layer is mainly involved in several sporadic and inherited vascular diseases contributing to various dementia syndromes.
A progressive loss of vascular smooth muscle cells (VSMCs) replaced with vascular amyloid or non-amyloid protein deposits and fibrosis in the tunica media is characteristic of two different hereditary forms of angiopathy: cerebral amyloid associated with rare familial form of AD (FAD/CAA), and systemic non-amyloid, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Recently, attention has turned to progressive changes, and also other elements of the vessel wall [24,29,43]. VSMCs are surrounded by extracellular matrix (ECM) which appears to increase to replace the VSMCs, progressive with aging and disease-related vessel wall destruction [3].
Although both presented small cerebral vessels diseases are heterogeneous in aetiology, their clinical manifestations are similar to recurrent, mainly ischaemic or haemorrhagic cerebral episodes leading to early-adult onset dementia and death [32,45].
Cerebral amyloid angiopathy (CAA) presented in our two FAD patients were caused by presenilin-1 gene mutation ( P117L) found on chromosome 14, reported previously in the first Polish FAD family [41]. At present, there are known three of various pathogenic mutations mainly responsible for early onset familial AD usually with co-occurrence of CAA: of the amyloid precursor gene (APP) on chromosome 21, the PS-1 gene on chromosome 14, and the PS-2 gene on chromosome 1 [12,25]. Presenilin is a unique multifunctional protein, including a role as an intramembrane-cleaving protease that may facilitate membrane protein turnover [36]. In the central nervous system, PS-1 protein is principally located in neurones, mainly in the membrane of the endoplasmic reticulum, (ER) [31] and is involved in βAPP processing and Aβ generation [10]. Presenilins are a gene family of the key mediators of Notch signalling, processing both Notch and APP [36]. Mutation in the PS-1 gene especially facilitates amyloid angiopathy, early-adult onset disease and vessel destruction [36,37], then familial CAAs are generally more severe than sporadic forms [31,35,45].
CADASIL is a...


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