Department of Neurology, MassGeneral Institute of Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, 114 Sixteenth St., Charlestown, MA, 02129, USA.
Sci Rep. 2019 Jun 20;9(1):8964. doi: 10.1038/s41598-019-44964-z.
Neuronal activity patterns are disrupted in neurodegenerative disorders, including Alzheimer's disease (AD). One example is disruption of corticothalamic slow oscillations responsible for sleep-dependent memory consolidation. Slow waves are periodic oscillations in neuronal activity occurring at frequencies of <1 Hz. The power, but not the frequency of slow oscillations is altered in a mouse model of AD. Optogenetic rescue of slow oscillations by increasing activity in cortical pyramidal neurons at the frequency of slow waves restores slow wave power, halts deposition of amyloid plaques and prevents neuronal calcium dysregulation. Here we determined whether driving this circuit at an increased rate would exacerbate the amyloid-dependent calcium dyshomeostasis in transgenic mice. Doubling the frequency of slow waves for one month with optogenetics resulted in increased amyloid beta - dependent disruptions in neuronal calcium homeostasis and loss of synaptic spines. Therefore, while restoration of physiological circuit dynamics is sufficient to abrogate the progression of Alzheimer's disease pathology and should be considered an avenue for clinical treatment of AD patients with sleep disorders, pathophysiological stimulation of neuronal circuits leads to activity - dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction.
神经活动模式在神经退行性疾病中被打乱，包括阿尔茨海默病（AD）。一个例子是负责睡眠依赖性记忆巩固的皮质丘脑慢波的中断。慢波是神经元活动的周期性振荡，其频率<1 Hz。在 AD 的小鼠模型中，慢波的功率而不是频率发生改变。通过增加皮质锥体神经元的活动以慢波的频率对慢波进行光遗传学挽救可恢复慢波功率，阻止淀粉样斑块的沉积并防止神经元钙失调。在这里，我们确定以增加的速率驱动该电路是否会加剧转 AD 基因小鼠中淀粉样蛋白依赖性钙失调。通过光遗传学将慢波的频率增加一倍一个月会导致与淀粉样β相关的神经元钙动态失衡增加和突触棘丧失。因此，虽然恢复生理电路动力学足以消除阿尔茨海默病病理的进展，并且应该被认为是治疗患有睡眠障碍的 AD 患者的临床治疗途径，但神经元电路的病理生理学刺激会导致与活动相关的淀粉样蛋白产生、聚集和下游神经元功能障碍的加速。
