Human cerebral vascular amyloid contains both antiparallel and parallel in-register Aß40 fibrils.
J Biol Chem
; 297(5): 101259, 2021 11.
Article
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| MEDLINE
| ID: mdl-34599967
ABSTRACT
The accumulation of fibrillar amyloid-ß (Aß) peptides alongside or within the cerebral vasculature is the hallmark of cerebral amyloid angiopathy (CAA). This condition commonly co-occurs with Alzheimer's disease (AD) and leads to cerebral microbleeds, intracranial hemorrhages, and stroke. CAA also occurs sporadically in an age-dependent fashion and can be accelerated by the presence of familial Aß mutant peptides. Recent studies using Fourier transform infrared (FTIR) spectroscopy of vascular Aß fibrils derived from rodents containing the double E22Q/D23N mutations indicated the presence of a novel antiparallel ß-sheet structure. To address whether this structure is associated solely with the familial mutations or is a common feature of CAA, we propagated Aß fibrils from human brain vascular tissue of patients diagnosed with nonfamilial CAA. Aß fibrils were isolated from cerebral blood vessels using laser capture microdissection in which specific amyloid deposits were removed from thin slices of the brain tissue. Transmission electron microscopy revealed that these deposits were organized into a tight meshwork of fibrils, which FTIR measurements showed could serve as seeds to propagate the growth of Aß40 fibrils for structural studies. Solid-state NMR measurements of the fibrils propagated from vascular amyloid showed they contained a mixture of parallel, in-register, and antiparallel ß-sheet structures. The presence of fibrils with antiparallel structure derived from vascular amyloid is distinct from the typical parallel, in-register ß-sheet structure that appears in fibrils derived from parenchymal amyloid in AD. These observations reveal that different microenvironments influence the structures of Aß fibrils in the human brain.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
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Encéfalo
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Péptidos beta-Amiloides
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Mutación Missense
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Enfermedad de Alzheimer
Límite:
Aged
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Humans
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Male
Idioma:
En
Revista:
J Biol Chem
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos