Is type 2 diabetes associated dementia a microvascular early-Alzheimer's phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?
Front Endocrinol (Lausanne)
; 14: 1127481, 2023.
Article
em En
| MEDLINE
| ID: mdl-36875491
There is increasing evidence of a positive association of type 2 diabetes with Alzheimer's disease (AD), the most prevalent form of dementia. Suggested pathways include cerebral vascular dysfunction; central insulin resistance, or exaggerated brain abundance of potentially cytotoxic amyloid-ß (Aß), a hallmark feature of AD. However, contemporary studies find that Aß is secreted in the periphery by lipogenic organs and secreted as nascent triglyceride-rich lipoproteins (TRL's). Pre-clinical models show that exaggerated abundance in blood of TRL-Aß compromises blood-brain barrier (BBB) integrity, resulting in extravasation of the TRL-Aß moiety to brain parenchyme, neurovascular inflammation and neuronal degeneration concomitant with cognitive decline. Inhibiting secretion of TRL-Aß by peripheral lipogenic organs attenuates the early-AD phenotype indicated in animal models, consistent with causality. Poorly controlled type 2 diabetes commonly features hypertriglyceridemia because of exaggerated TRL secretion and reduced rates of catabolism. Alzheimer's in diabetes may therefore be a consequence of heightened abundance in blood of lipoprotein-Aß and accelerated breakdown of the BBB. This review reconciles the prevailing dogma of amyloid associated cytotoxicity as a primary risk factor in late-onset AD, with substantial evidence of a microvascular axis for dementia-in-diabetes. Consideration of potentially relevant pharmacotherapies to treat insulin resistance, dyslipidaemia and by extension plasma amyloidemia in type 2 diabetes are discussed.
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Base de dados:
MEDLINE
Assunto principal:
Doenças Autoimunes
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Resistência à Insulina
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Diabetes Mellitus Tipo 2
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Doença de Alzheimer
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article