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Is type 2 diabetes associated dementia a microvascular early-Alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?

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-β (Aβ),...

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Detalles Bibliográficos
Autores principales: Takechi, Ryusuke, Sharif, Arazu, Brook, Emily, Majimbi, Maimuna, Chan, Dick C., Lam, Virginie, Watts, Gerald F., Mamo, John C. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978204/
https://www.ncbi.nlm.nih.gov/pubmed/36875491
http://dx.doi.org/10.3389/fendo.2023.1127481
Descripción
Sumario: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-β (Aβ), a hallmark feature of AD. However, contemporary studies find that Aβ 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-Aβ compromises blood-brain barrier (BBB) integrity, resulting in extravasation of the TRL-Aβ moiety to brain parenchyme, neurovascular inflammation and neuronal degeneration concomitant with cognitive decline. Inhibiting secretion of TRL-Aβ 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-Aβ 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.