Cerebral amyloidosis: amyloid subunits, mutants and phenotypes

Abstract

Cerebral amyloid diseases are part of a complex group of chronic and progressive entities bracketed together under the common denomination of protein folding disorders and characterized by the intra- and extracellular accumulation of fibrillar aggregates. Of the more than 25 unrelated proteins known to produce amyloidosis in humans only about a third of them are associated with cerebral deposits translating in cognitive deficits, dementia, stroke, cerebellar and extrapyramidal signs, or a combination thereof. The familial forms reviewed herein, although infrequent, provide unique paradigms to examine the role of amyloid in the mechanism of disease pathogenesis and to dissect the link between vascular and parenchymal amyloid deposition and their differential contribution to neurodegeneration.

Fig. 1

Immunohistochemical analysis of amyloid deposits in cerebral amyloidosis. a Aβ-positive plaques (arrow) and b cerebral amyloid angiopathy (double arrow) in a case of Alzheimer’s disease. c Neurofibrillary tangles (arrow), neuropil threads and plaque-associated abnormal neurites (double arrow) demonstrated with tau immunohistochemistry in Alzheimer’s disease. d Aβ deposition in blood vessels (double arrow) and diffuse parenchymal plaques (arrow) in the cerebral cortex in HCHWA-D. e Deposition of Aβ-peptide in characteristic cotton wool plaques (arrow) together with severe CAA (double arrow) is a feature of familial Alzheimer’s disease with ΔI83/ΔM84 PS1 mutation. f Accumulation of mutated cystatin C in leptomeningeal blood vessels in a case of HCHWA-Icelandic type. g AGel deposition in skin blood vessels in familial amyloidosis of the Finnish type. h ATTR deposition in leptomeningeal blood vessels in the Hungarian form of meningovascular amyloidosis. i Widespread ABri deposition in large parenchymal plaques (arrow) and ABri CAA (double arrow) in familial British dementia. j Severe CAA (double arrow) and diffuse plaques (arrow) due to ADan deposition in familial Danish dementia

Fig. 2

Pathogenic mutations in exons 16 and 17 of APP. The diagram summarizes the location, nucleotide change, disease onset, and frequency of each of the known pathogenic mutations. Variations in Aβ40 and Aβ42 concentrations secreted by transfected cells in culture are also indicated