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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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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
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author Takechi, Ryusuke
Sharif, Arazu
Brook, Emily
Majimbi, Maimuna
Chan, Dick C.
Lam, Virginie
Watts, Gerald F.
Mamo, John C. L.
author_facet Takechi, Ryusuke
Sharif, Arazu
Brook, Emily
Majimbi, Maimuna
Chan, Dick C.
Lam, Virginie
Watts, Gerald F.
Mamo, John C. L.
author_sort Takechi, Ryusuke
collection PubMed
description 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.
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spelling pubmed-99782042023-03-03 Is type 2 diabetes associated dementia a microvascular early-Alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid? Takechi, Ryusuke Sharif, Arazu Brook, Emily Majimbi, Maimuna Chan, Dick C. Lam, Virginie Watts, Gerald F. Mamo, John C. L. Front Endocrinol (Lausanne) Endocrinology 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. Frontiers Media S.A. 2023-02-16 /pmc/articles/PMC9978204/ /pubmed/36875491 http://dx.doi.org/10.3389/fendo.2023.1127481 Text en Copyright © 2023 Takechi, Sharif, Brook, Majimbi, Chan, Lam, Watts and Mamo https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Takechi, Ryusuke
Sharif, Arazu
Brook, Emily
Majimbi, Maimuna
Chan, Dick C.
Lam, Virginie
Watts, Gerald F.
Mamo, John C. L.
Is type 2 diabetes associated dementia a microvascular early-Alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?
title Is type 2 diabetes associated dementia a microvascular early-Alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?
title_full Is type 2 diabetes associated dementia a microvascular early-Alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?
title_fullStr Is type 2 diabetes associated dementia a microvascular early-Alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?
title_full_unstemmed Is type 2 diabetes associated dementia a microvascular early-Alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?
title_short Is type 2 diabetes associated dementia a microvascular early-Alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?
title_sort is type 2 diabetes associated dementia a microvascular early-alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?
topic Endocrinology
url 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
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