10个方法远离阿兹海默（阿尔茨海默病）

10个方法远离阿兹海默（阿尔茨海默病）关键词：因此，海马回路的放电频率失调在主动觉醒期间被掩盖，但在低觉醒大脑状态下表现出来，代表疾病沉默阶段的早期功能障碍。然而，在fAD小鼠模型中，在非快速眼动（NREM）睡眠和全身麻醉期间，CA1 MFR的稳态下调被破坏。线粒体二氢乳酸脱氢酶（DHODH）酶抑制剂减弱了由此产生的高兴奋性，该抑制剂将MFR调到较低的设定值。体外fAD突变损害下调的MFR内稳态，导致病理性MFR设定点对麻醉药物和抑制阻断的反应。

文献导读‖麻醉和睡眠的神经相关性紊乱揭示阿尔茨海默病模型的早期回路功能障碍

神经活动的失调稳态被认为是阿尔茨海默病（AD）发病机制的驱动因素。

AD开始于一个长达数十年的症状前阶段，但体内平衡机制是否已经在这个沉默阶段开始失调尚不清楚。

我们发现，在出现记忆衰退和睡眠障碍之前，家族性AD（fAD）模型小鼠在主动觉醒期间的CA1平均放电率（MFR）没有出现缺陷。

然而，在fAD小鼠模型中，在非快速眼动（NREM）睡眠和全身麻醉期间，CA1 MFR的稳态下调被破坏。

线粒体二氢乳酸脱氢酶（DHODH）酶抑制剂减弱了由此产生的高兴奋性，该抑制剂将MFR调到较低的设定值。

体外fAD突变损害下调的MFR内稳态，导致病理性MFR设定点对麻醉药物和抑制阻断的反应。

因此，海马回路的放电频率失调在主动觉醒期间被掩盖，但在低觉醒大脑状态下表现出来，代表疾病沉默阶段的早期功能障碍。

关键词：

阿尔茨海默病；

DHODH；

NREM；

钙显像；

放电频率稳态；

全身麻醉；

海马；

过度兴奋性；

单单元录音；

睡觉

Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models

Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states representing an early failure of the silent disease stage.

Keywords: Alzheimer's disease; DHODH; NREM; calcium imaging; firing rate homeostasis; general anesthesia; hippocampus; hyperexcitability; single-unit recordings; sleep.