Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease.
Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease.
复制标题
阿尔茨海默病转基因大鼠模型中蓝斑放电的年龄依赖性失调。
DOI：
10.1016/j.neurobiolaging.2023.01.016
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发表时间：
2023
影响因子：
4.2
通讯作者：
Weinshenker,David
中科院分区：
文献类型：
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作者：
Kelberman,MichaelA;Rorabaugh,JackiM;Anderson,ClaireR;Marriott,Alexia;DePuy,SethD;Rasmussen,Kurt;McCann,KatharineE;Weiss,JayM;Weinshenker,David
前驱阿尔茨海默病(AD)患者中普遍存在蓝斑(LC)中的过度磷酸化tau，且LC神经元随着AD的进展而退化。过度磷酸化的tau改变了其他脑区的放电频率，但它对LC神经元的影响尚不清楚。我们在6个月时评估了麻醉野生型(WT)和TgF344-AD大鼠的单位LC活性，这代表了一个前驱阶段，在TgF344-AD动物中LC神经元是唯一含有过度磷酸化tau的细胞，在15个月时，淀粉样蛋白-β(Aβ)和tau病理在前脑中都很丰富。在基线时，TgF344-AD大鼠的LC神经元在两个年龄段与WT仔鼠相比都处于低活动状态，但表现出更高的自发爆发特性。足底电击诱发的LC放电的差异取决于年龄，6月龄的TgF344-AD大鼠表现出多动的方面，而15月龄的转基因大鼠则表现出活动不足。早期LC多动与前驱神经精神症状的出现相一致，随后是LC低活动，从而导致认知功能障碍。这些结果支持进一步研究依赖于疾病分期的去甲肾上腺素对AD的干预。
Hyperphosphorylated tau in the locus coeruleus (LC) is ubiquitous in prodromal Alzheimer's disease (AD), and LC neurons degenerate as AD progresses. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons are unknown. We assessed single unit LC activity in anesthetized wild-type (WT) and TgF344-AD rats at 6 months, which represents a prodromal stage when LC neurons are the only cells containing hyperphosphorylated tau in TgF344-AD animals, and at 15 months when amyloid-β (Aβ) and tau pathology are both abundant in the forebrain. At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates but showed elevated spontaneous bursting properties. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and 15-month transgenic rats showing hypoactivity. Early LC hyperactivity is consistent with appearance of prodromal neuropsychiatric symptoms and is followed by LC hypoactivity which contributes to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD.