Plucińska Kaja, Mody Nimesh, Dekeryte Ruta, Shearer Kirsty, Mcilroy George D, Delibegovic Mirela, Platt Bettina
Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
The Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Integrative Physiology and Environmental Influences, University of Copenhagen, Copenhagen, Denmark.
Nutr Neurosci. 2022 Apr;25(4):719-736. doi: 10.1080/1028415X.2020.1806190. Epub 2020 Aug 29.
The β-site APP-cleaving enzyme 1 (BACE1) is a rate-limiting step in β-amyloid (Aβ) production in Alzheimer's disease (AD) brains, but recent evidence suggests that BACE1 is also involved in metabolic regulation. Here, we aimed to assess the effects of highfat diet (HFD) on metabolic and cognitive phenotypes in the diabetic BACE1 knock-in mice (PLB4) and WT controls; we additionally examined whether these phenotypes can be normalized with a synthetic retinoid (Fenretinide, Fen) targeting weight loss. Five-month old male WT and PLB4 mice were fed either (1) control chow diet, (2) 45%-saturated fat diet (HFD), (3) HFD with 0.04% Fen (HFD + Fen) or (4) control chow diet with 0.04% Fen (Fen) for 10 weeks. We assessed basic metabolic parameters, circadian rhythmicity, spatial habituation (Phenotyper) and working memory (Y-maze). Hypothalami, forebrain and liver tissues were assessed using Western blots, qPCR and ELISAs. HFD feeding drastically worsened metabolism and induced early mortality (-40%) in otherwise viable PLB4 mice. This was ameliorated by Fen, despite no effects on glucose intolerance. In HFD-fed WT mice, Fen reduced weight gain, glucose intolerance and hepatic steatosis. The physiological changes induced in WT and PLB4 mice by HFD (+/-Fen) were accompanied by enhanced cerebral astrogliosis, elevated PTP1B, phopsho-eIF2α and altered hypothalamic transcription of Bace1, Pomc and Mc4r. Behaviourally, HFD feeding exacerbated spatial memory deficits in PLB4 mice, which was prevented by Fen and linked with increased full-length APP, normalized brain Aβ*56 oligomerization and astrogliosis. HFD induces early mortality and worsened cognition in the Alzheimer's-like BACE1 mice- partial prevention was achieved with Fenretinide, without improvements in glucose homeostasis.
β-位点淀粉样前体蛋白裂解酶1（BACE1）是阿尔茨海默病（AD）大脑中β-淀粉样蛋白（Aβ）产生的限速步骤，但最近的证据表明BACE1也参与代谢调节。在这里，我们旨在评估高脂饮食（HFD）对糖尿病BACE1基因敲入小鼠（PLB4）和野生型（WT）对照小鼠代谢和认知表型的影响；我们还研究了这些表型是否可以通过靶向减肥的合成视黄酸（芬维A胺，Fen）恢复正常。将5月龄雄性WT和PLB4小鼠分为四组，分别喂食（1）对照普通饲料、（2）45%饱和脂肪饮食（HFD）、（3）含0.04% Fen的HFD（HFD+Fen）或（4）含0.04% Fen的对照普通饲料（Fen），持续10周。我们评估了基本代谢参数、昼夜节律、空间习惯化（Phenotyper）和工作记忆（Y迷宫）。使用蛋白质免疫印迹法、定量聚合酶链反应（qPCR）和酶联免疫吸附测定（ELISA）评估下丘脑、前脑和肝脏组织。喂食HFD显著恶化了代谢，并导致原本存活的PLB4小鼠早期死亡率增加（-40%）。尽管Fen对葡萄糖不耐受没有影响，但可改善这种情况。在喂食HFD的WT小鼠中，Fen减少了体重增加、葡萄糖不耐受和肝脂肪变性。HFD（±Fen）在WT和PLB4小鼠中诱导的生理变化伴随着脑星形胶质细胞增生增强、蛋白酪氨酸磷酸酶1B（PTP1B）升高、磷酸化真核翻译起始因子2α（phopsho-eIF2α）升高以及下丘脑Bace1、阿黑皮素原（Pomc）和黑皮质素4受体（Mc4r）转录改变。行为学上，喂食HFD加剧了PLB4小鼠的空间记忆缺陷，Fen可预防这种缺陷，且这与全长淀粉样前体蛋白（APP）增加、脑Aβ*56寡聚化正常化和星形胶质细胞增生有关。HFD在类似阿尔茨海默病的BACE1小鼠中诱导早期死亡并恶化认知，芬维A胺可部分预防，且对葡萄糖稳态无改善作用。
