Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies

Abstract

In cerebral amyloid angiopathy (CAA), amyloid fibrils deposit in walls of arteries, arterioles and less frequently in veins and capillaries of the central nervous system, often resulting in secondary degenerative vascular changes. Although the amyloid-β peptide is by far the commonest amyloid subunit implicated in sporadic and rarely in hereditary forms of CAA, a number of other proteins may also be involved in rare familial diseases in which CAA is also a characteristic morphological feature. These latter proteins include the ABri and ADan subunits in familial British dementia and familial Danish dementia, respectively, which are also known under the umbrella term BRI2 gene-related dementias, variant cystatin C in hereditary cerebral haemorrhage with amyloidosis of Icelandic-type, variant transthyretins in meningo-vascular amyloidosis, disease-associated prion protein (PrPSc) in hereditary prion disease with premature stop codon mutations and mutated gelsolin (AGel) in familial amyloidosis of Finnish type. In this review, the characteristic morphological features of the different CAAs is described and the implication of the biochemical, genetic and transgenic animal data for the pathogenesis of CAA is discussed.

Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum

“…In contrast with amyloid plaques found in AD—which are predominantly composed of the 42 amino acid residue fragment (Aβ 42 )—the vascular amyloid in CAA is mostly composed of the more soluble, 40 amino acid fragment (Aβ 40 ), suggesting different pathophysiological mechanisms for pathological deposition (see below) 60–63. Cerebral vessels with moderate to severe CAA show an acellular wall thickening with a strongly eosinophilic smudgy appearance on haematoxylin–eosin stained sections 64. Congo red staining, under polarised light, reveals amyloid deposits as ‘apple green’ birefringence (hence the term congophilic angiopathy)2 65 although immunological stains for Aβ are highly specific and now widely used (figure 3).…”

“…In severe CAA, detachment and delamination of the outer part of the tunica media result in the so-called ‘double barrel’ appearance (figure 3)3; fibrinoid necrosis and microaneurysm formation also occur in advanced disease. There may also be microbleeding with perivascular deposition of erythrocytes and blood breakdown products 64. Endothelial cells are usually preserved even in vessels severely affected by CAA 66.…”

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

“…In addition to the well‐known neurodegenerative pathology caused by the parenchymal deposition of Aβ (mainly in its 42 amino acids form), CAA is known to cause vascular damage, micro‐ and macro‐ hemorrhage, apoptosis, and dysfunction of the entire neurovascular unit. These neurovascular effects further exacerbate the pathology and progression of the disease (Revesz et al., 2009; Zlokovic, 2008). Mutations in the Aβ peptide generate variants such as the Aβ40‐Q22 mutant, which are associated with CAA, hemorrhagic stroke, and early‐onset dementia in AD familiar forms, induce aggressive endothelial cell damage, and can represent useful tools to study amyloid‐mediated vascular pathology (Fossati et al., 2010).…”

Matrix Metalloproteinase 2 (MMP-2) Degrades Soluble Vasculotropic Amyloid-β E22Q and L34V Mutants, Delaying Their Toxicity for Human Brain Microvascular Endothelial Cells

“…A␤ Peptides-Synthetic homologues of WT A␤40, the C-terminal-truncated fragment A␤- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), and the A␤40 genetic variants containing the E22Q and L34V substitutions as well as the standards for quantitative mass spectrometry (MS) A␤40 and the C-terminal-truncated fragment A␤-(1-16) labeled with deuterated ( 2 H) phenylalanine residues (A␤-(1-16) deuterated at position 4, mass ϭ 1963.0 Da, mass difference with unlabeled A␤-(1-16) ϩ8 Da; A␤40 labeled at positions 4, 19, and 20, mass ϭ 4353.9 Da, mass difference with unlabeled A␤40 ϩ24 Da) were synthesized using N-tert-butyloxycarbonyl chemistry by James I. Elliott at Yale University. All synthetic homologues were purified by reverse phase-high performance liquid chromatography, molecular masses were corroborated by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MS, and concentrations were assessed by amino acid analysis as previously described (26,29).…”

“…CAA is mainly a sporadic disorder concomitant with the deposition of wild-type (WT) A␤40; nevertheless, a relatively small group of cases consist of autosomal dominant hereditary forms. Patients carrying mutations within the A␤ precursor protein concentrated in the amino acid cluster comprising A␤ residues 21-23 primarily develop severe CAA while presenting with dissimilar clinical manifestations (12)(13)(14). One of the most aggressive clinical phenotypes described among the intra-A␤ mutations is associated with the replacement of a Glu for Gln at residue 22 (A␤E22Q) in a disorder known as hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D) (15)(16)(17).…”