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),...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-02-01
|
| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1127481/full |
| _version_ | 1797905043348783104 |
|---|---|
| author | Ryusuke Takechi Arazu Sharif Emily Brook Maimuna Majimbi Dick C. Chan Virginie Lam Gerald F. Watts John C. L. Mamo |
| author_facet | Ryusuke Takechi Arazu Sharif Emily Brook Maimuna Majimbi Dick C. Chan Virginie Lam Gerald F. Watts John C. L. Mamo |
| author_sort | Ryusuke Takechi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T09:58:47Z |
| format | Article |
| id | doaj.art-580703ccfe8447e7b3f3a4348b7307be |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-10T09:58:47Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-580703ccfe8447e7b3f3a4348b7307be2023-02-16T11:11:43ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-02-011410.3389/fendo.2023.11274811127481Is type 2 diabetes associated dementia a microvascular early-Alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?Ryusuke Takechi0Arazu Sharif1Emily Brook2Maimuna Majimbi3Dick C. Chan4Virginie Lam5Gerald F. Watts6John C. L. Mamo7Curtin Health Innovation Research Institute, Curtin University, Perth, WA, AustraliaCurtin Health Innovation Research Institute, Curtin University, Perth, WA, AustraliaCurtin Health Innovation Research Institute, Curtin University, Perth, WA, AustraliaCurtin Health Innovation Research Institute, Curtin University, Perth, WA, AustraliaDepartments of Cardiology and Internal Medicine, Royal Perth Hospital, School of Medicine, University of Western Australia, Perth, WA, AustraliaCurtin Health Innovation Research Institute, Curtin University, Perth, WA, AustraliaDepartments of Cardiology and Internal Medicine, Royal Perth Hospital, School of Medicine, University of Western Australia, Perth, WA, AustraliaCurtin Health Innovation Research Institute, Curtin University, Perth, WA, AustraliaThere 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.https://www.frontiersin.org/articles/10.3389/fendo.2023.1127481/fullamyloiddiabetesAlzheimer’slipoproteintriglycerides |
| spellingShingle | Ryusuke Takechi Arazu Sharif Emily Brook Maimuna Majimbi Dick C. Chan Virginie Lam Gerald F. Watts John C. L. Mamo Is type 2 diabetes associated dementia a microvascular early-Alzheimer’s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid? Frontiers in Endocrinology amyloid diabetes Alzheimer’s lipoprotein triglycerides |
| 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 | amyloid diabetes Alzheimer’s lipoprotein triglycerides |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1127481/full |
| work_keys_str_mv | AT ryusuketakechi istype2diabetesassociateddementiaamicrovascularearlyalzheimersphenotypeinducedbyaberrationsintheperipheralmetabolismoflipoproteinamyloid AT arazusharif istype2diabetesassociateddementiaamicrovascularearlyalzheimersphenotypeinducedbyaberrationsintheperipheralmetabolismoflipoproteinamyloid AT emilybrook istype2diabetesassociateddementiaamicrovascularearlyalzheimersphenotypeinducedbyaberrationsintheperipheralmetabolismoflipoproteinamyloid AT maimunamajimbi istype2diabetesassociateddementiaamicrovascularearlyalzheimersphenotypeinducedbyaberrationsintheperipheralmetabolismoflipoproteinamyloid AT dickcchan istype2diabetesassociateddementiaamicrovascularearlyalzheimersphenotypeinducedbyaberrationsintheperipheralmetabolismoflipoproteinamyloid AT virginielam istype2diabetesassociateddementiaamicrovascularearlyalzheimersphenotypeinducedbyaberrationsintheperipheralmetabolismoflipoproteinamyloid AT geraldfwatts istype2diabetesassociateddementiaamicrovascularearlyalzheimersphenotypeinducedbyaberrationsintheperipheralmetabolismoflipoproteinamyloid AT johnclmamo istype2diabetesassociateddementiaamicrovascularearlyalzheimersphenotypeinducedbyaberrationsintheperipheralmetabolismoflipoproteinamyloid |