Disruptions in sleep‐dependent brain rhythms contribute to Alzheimer’s pathogenesis

Abstract

Sleep-dependent brain rhythms are important for memory consolidation during sleep, and Alzheimer's disease (AD) patients experience memory disturbances. We sought to examine sleep-dependent brain rhythms, slow oscillations, in an animal model of AD (APP mice). The power of slow oscillations was decreased early in the disease progression. Soluble amyloid-beta was sufficient to disrupt the slow waves. Cortical GABA levels were low in APP mice and application of exogenous GABA restored the slow oscillations, indicating that aberrant excitatory activity within the cortical circuit was responsible for slow oscillation dysfunction. Next we sought to manipulate slow waves in APP mice with optogenetics. Driving slow oscillations at normal frequency with light activation of channelrhodopsin-2 (ChR2) expressed in cortical neurons restored slow wave power by synchronizing neuronal activity. Using multiphoton microscopy, we performed longitudinal imaging of senile plaques and monitored intracellular calcium. Cytosolic calcium is a surrogate marker of neuronal activity and is normally tightly regulated. We had previously demonstrated that resting calcium levels measured with the genetically encoded calcium sensor YellowCameleon 3.6 were elevated in a subset of neurons in APP transgenics, and hypothesized that an effective treatment would restore calcium to control levels. Driving slow oscillation activity with optogenetics halted amyloid plaque deposition and prevented calcium overload associated with this pathology. On the other hand, driving slow oscillation activity at twice the normal frequency resulted in increased amyloid production, increased amyloid plaque deposition, 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 patients with sleep disorders, pathophysiological stimulation of neuronal circuits leads to activity dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction.