Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline

Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.阿尔茨海默病（Alzheimer's disease, AD）是最常见的痴呆类型。中年肥胖会增加阿尔茨海默病的发病风险与病情严重程度，鉴于全球肥胖患病率在中年达到峰值且肥胖率仍在加速攀升，这一关联令人警惕。研究显示，仅中年（而非晚年）肥胖会提升阿尔茨海默病风险，提示这种交互作用具有阿尔茨海默病临床前期特异性。阿尔茨海默病的病理改变始于中年阶段，在认知症状出现的数十年前，便已出现β淀粉样蛋白（amyloid beta, Aβ）沉积、tau蛋白过度磷酸化、代谢功能下降以及神经炎症等病理变化。 本研究采用转录组学发现策略，以过表达突变型人淀粉样前体蛋白与早老素-1的青年成年（6.5月龄）雌雄TgF344-AD大鼠，以及野生型（wild-type, WT）对照大鼠为研究对象，旨在明确在阿尔茨海默病临床前期，通过高脂高糖“西式”饮食诱导肥胖是否会加重背侧海马（dorsal hippocampus, dHC）——这一易受肥胖与早期阿尔茨海默病影响的脑区——的脑代谢功能障碍。 对背侧海马基因表达数据的分析显示，线粒体与神经递质传递通路存在失调，且胆固醇合成相关基因表达上调。西式饮食不仅扩大了AD大鼠与野生型大鼠之间的差异基因数量，还新增了去甲肾上腺素能信号通路失调、胆固醇合成抑制异常以及细胞内脂质转运蛋白表达下调相关的通路。 值得注意的是，西式饮食仅在AD大鼠中损伤了依赖背侧海马的空间工作记忆，并未影响野生型大鼠，这证实饮食干预加速了认知衰退进程。为探究早期转录失调的后续影响，本研究在长期饲喂普通饲料或西式饮食的老年（13月龄）雌雄AD与野生型大鼠中，检测了背侧海马的单胺类神经递质水平。结果发现，AD大鼠的去甲肾上腺素（norepinephrine, NE）含量显著降低，去甲肾上腺素周转速率升高，而西式饮食则缓解了AD诱导的周转速率升高。 综上，本研究结果表明，阿尔茨海默病前驱期肥胖会损伤记忆功能，加剧AD诱导的代谢衰退，这可能导致胆固醇过量生成，并干扰去甲肾上腺素能传递的代偿性升高。