Invited Review - Understanding cause and effect in Alzheimer's pathophysiology: Implications for clinical trials.
Neuropathol Appl Neurobiol
; 46(7): 623-640, 2020 12.
Article
em En
| MEDLINE
| ID: mdl-32643143
Alzheimer's disease (AD) pathology is multi-faceted, including extracellular accumulation of amyloid-ß (Aß), accumulation of tau within neurons, glial activation and loss of neurons and synapses. From a neuropathological perspective, usually at a single time-point and often at the end-stage of the disease, it is challenging to understand the cause and effect relationships between these components. There are at least four ways of trying to unravel these relationships. First, genetic studies demonstrate mutations that influence Aß production, but not tau, can initiate AD; whereas genetic variants influencing AD risk are related to innate immunity and lipid metabolism. Second, studies at early time points show that pathology begins decades before the onset of dementia and indicate different anatomical locations for initiation of Aß and tau accumulation. Third, cause and effect can be studied in experimental models, but most animal models do not fully replicate AD pathology. However, induced pluripotent stem cells (iPSCs) to study live human neurons has introduced a new perspective. Fourth, clinical trials may alter AD pathology giving insights into cause and effect relationships. Therefore, a sequence of (i) neocortical Aß accumulation followed by (ii) a microglial inflammatory reaction to Aß, causing neuritic dystrophy which promotes (iii) spread of tau from the limbic system to the neocortex with (iv) progressive tau accumulation and spread resulting in (v) neurodegeneration, explains the evidence. It is proposed that different therapeutic targets are required for different stages of the disease process: Aß for primary prevention, microglia for secondary prevention, and tau for established disease.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Emaranhados Neurofibrilares
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Microglia
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Doença de Alzheimer
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Neurônios
Limite:
Animals
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Humans
Idioma:
En
Revista:
Neuropathol Appl Neurobiol
Ano de publicação:
2020
Tipo de documento:
Article