Cerebral amyloid angiopathy and gene polymorphisms

Abstract

Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid deposition, associated with intracerebral hemorrhage and other cerebrovascular disorders and dementia. Several types of CAA have been identified in association with various amyloid proteins including amyloid β protein (Aβ), cystatin C, prion protein, ABri/ADan, transthyretin, and gelsolin. Hereditary forms of CAA are associated with mutations in the genes coding these proteins or their precursors. Sporadic CAA of Aβ type is most common in elderly individuals as well as patients with Alzheimer disease (AD). Several gene polymorphisms have been reported to be associated with sporadic CAA or CAA-related hemorrhage, including apolipoprotein E (APOE), presenilin 1 (PS1), and α1-antichymotrypsin (ACT). As for the APOE, which has been well studied for CAA as well as AD and Aβ deposition, the ɛ4 allele is found to be associated with CAA, and the ɛ2 with CAA-related hemorrhage. Recently, we investigated whether gene polymorphisms of neprilysin (NEP), an Aβ-degrading enzyme, and the transforming growth factor (TGF)-β1 (TGF-β1), a multifunctional cytokine implicated in Aβ deposition, are associated with sporadic CAA. Concerning a GT repeat polymorphism in the enhancer/promoter region of the NEP, the shorter repeat alleles were associated with the CAA severity. The T/C polymorphism at codon 10 in exon 1 of the TGF-β1 was also associated with the severity of CAA.

These data suggest that multiple gene polymorphisms, including molecules related to the Aβ cascade, could be associated with the risk of sporadic CAA.

Introduction

Cerebral amyloid angiopathy (CAA) is a cerebrovascular amyloid deposition and causes intracerebral hemorrhage and other cerebrovascular disorders (see reviews [1], [2], [3]). Several types of CAA have been identified in association with various amyloid proteins including amyloid amyloid β protein (Aβ), cystatin C, prion protein, transthyretin, gelsolin, and ABri/ADan [2], [3].

Hereditary forms of CAA are associated with mutations in the genes coding these proteins or their precursors. Sporadic CAA of Aβ type, the most common form of CAA, is frequently found in elderly individuals as well as patients with Alzheimer disease (AD), indicating that aging and AD are definite risk of sporadic CAA. Risk factors of sporadic CAA would include genetic factors such as polymorphisms of disease-susceptible genes [2]. Identification of risk factors of sporadic CAA is important to predict the presence of CAA, because cerebral hemorrhages after thrombolytic or heparin therapy are often attributable to CAA, and Aβ vaccination therapy against AD may induce CAA-related cerebral hemorrhages [4], [5], [6].

Although a major molecular species is the 40-amino-acid Aβ (Aβ40) for cerebrovascular deposition and Aβ42 for parenchymal deposition, CAA and AD have a common neuropathological feature, Aβ deposition, which indicates that two conditions would share risk factors. The source and mechanisms of cerebrovascular Aβ deposition have not been elucidated yet. However, recent studies have shown that a neuronal source of Aβ is sufficient to induce cerebrovascular amyloid deposition [7]; and Aβ in the brain extracellular fluid may be internalized to cerebrovascular smooth muscle cells via a lipoprotein pathway, leading to vascular Aβ deposition [8], [9]. Vascular extracellular matrix (ECM) components and inflammation, which may be associated with expression of cytokines, would also influence cerebrovascular Aβ deposition and destruction of vascular walls [10], [11].

From these viewpoints, polymorphisms of genes related to AD pathogenesis, lipoprotein metabolism, and vascular factors have been investigated for association with sporadic CAA, including apolipoprotein E (APOE), presenilin 1 (PS1), α1-antichymotrypsin (ACT), butyrylcholinesterase, α2-macroglobulin, paraoxonase, and neprilysin (NEP) [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]; among them, positive associations of the APOE, PS1, ACT, and NEP with CAA have been described. In this report, the author focuses on APOE, which has been widely studied in CAA as well as AD, and NEP, which we have recently studied.