Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia.
Departments of Cardiology and Internal Medicine, Royal Perth Hospital, School of Medicine, University of Western Australia, Perth, WA, Australia.
Front Endocrinol (Lausanne). 2023 Feb 16;14:1127481. doi: 10.3389/fendo.2023.1127481. eCollection 2023.
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.
越来越多的证据表明 2 型糖尿病与阿尔茨海默病（AD）之间存在正相关关系，AD 是最常见的痴呆症形式。有几种假说途径，包括脑血管功能障碍；中枢胰岛素抵抗，或大脑中潜在细胞毒性淀粉样蛋白-β（Aβ）含量增加，这是 AD 的一个显著特征。然而，当代研究发现 Aβ在外周由生脂器官分泌，并以新生富含甘油三酯的脂蛋白（TRL）的形式分泌。临床前模型表明，血液中 TRL-Aβ 的含量过高会损害血脑屏障（BBB）的完整性，导致 TRL-Aβ 部分向脑实质渗漏，神经血管炎症和神经元退化，同时伴有认知能力下降。抑制外周生脂器官分泌 TRL-Aβ 可减轻动物模型中早期 AD 表型，这与因果关系一致。由于 TRL 分泌增加和分解代谢率降低，控制不佳的 2 型糖尿病通常会出现高甘油三酯血症。因此，糖尿病中的阿尔茨海默病可能是由于血液中脂蛋白-Aβ含量增加和 BBB 加速破裂所致。本综述调和了淀粉样蛋白相关细胞毒性作为迟发性 AD 的主要危险因素的流行观点，以及大量证据表明糖尿病中的微血管轴与痴呆症有关。考虑到治疗 2 型糖尿病中的胰岛素抵抗、血脂异常以及由此延伸的血浆淀粉样蛋白血症的潜在相关药物治疗。
