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1.
J Alzheimers Dis ; 56(2): 743-761, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28059792

RESUMO

There exist several dozen lines of transgenic mice that express human amyloid-ß protein precursor (AßPP) with Alzheimer's disease (AD)-linked mutations. AßPP transgenic mouse lines differ in the types and amounts of Aß that they generate and in their spatiotemporal patterns of expression of Aß assemblies, providing a toolkit to study Aß amyloidosis and the influence of Aß aggregation on brain function. More complete quantitative descriptions of the types of Aß assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aß toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AßPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ∼4.5 times that of 21-month-old Tg2576 mice and ∼15 times that of 21-24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded those measured in the human cohort.


Assuntos
Doença de Alzheimer/patologia , Córtex Cerebral/patologia , Hipocampo/patologia , Placa Amiloide/patologia , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Benzotiazóis , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Camundongos Transgênicos , Placa Amiloide/metabolismo , Especificidade da Espécie , Tiazóis
2.
Cell Rep ; 11(11): 1760-71, 2015 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-26051935

RESUMO

The accumulation of amyloid-ß (Aß) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer's disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Aß oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Aß oligomers in vivo.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo , Agregação Patológica de Proteínas/metabolismo , Estrutura Quaternária de Proteína , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/classificação , Animais , Humanos , Camundongos , Placa Amiloide/química
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