Abstract
SummaryDysregulated 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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder accounting for the vast majority of dementias
If mean firing rate (MFR) fluctuates between stable homeostatic set-points across sleepwake cycle, the observed MFR dysregulation during non-rapid eye movement (NREM) sleep may be caused by familial AD (fAD)-related impairment of downward MFR homeostasis (Figure 6) that is typically induced during extended sleep periods (Torrado Pacheco et al, 2021)
Further studies may shed some light on malfunctions in neuromodulatory signaling pathway(s) that underlie dyshomeostasis of CA1 firing rates by NREM sleep in the presymptomatic AD stages
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder accounting for the vast majority of dementias. The onset of amyloid-b (Ab) depositions precedes cognitive impairments by at least 10– 20 years, marking a significant presymptomatic disease stage (Bateman et al, 2012; Long and Holtzman, 2019; Vermunt et al, 2019). By the time the earliest AD clinical symptoms are detectable, Ab accumulation is close to reaching its peak, followed by intracellular aggregation of tau (Morris and Price, 2001). This suggests that homeostatic mechanisms successfully maintain critical aspects of neural circuits during early impairments of Ab and tau proteostasis, but fail at some point, driving the emergence of the first symptoms (Frere and Slutsky, 2018; Styr and Slutsky, 2018). Identifying how circuit-level signatures are altered during the presymptomatic AD stage is crucial for understanding the transition from ‘‘silent’’ pathophysiology to clinically evident impairments
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