Fig. 3

Proteostasis of Aβ and tau is disrupted by Alzheimer’s-related sleep loss, driving proteinopathy, neuronal network dysfunction and cognitive impairment. Sleep is intimately linked to homeostatic processes that control protein accumulation, and when disturbed, can exacerbate and trigger proteinopathy. a Shows decrease in SWS and a concomitant decline in the metabolite clearance which is usually highest during SWS. Glymphatics involve brain influx of cerebrospinal fluid (CSF), travelling by bulk flow along periarterial spaces, which crosses the blood–brain barrier (BBB) via an astrocytic AQP4-mediated process, mixes with brain interstitial fluid (ISF), metabolites and solutes, and is cleared along perivenous spaces, driven by vasomotive forces. Bulk CSF/ISF efflux along veins drives metabolite clearance to dural lymphatic systems. Acutely, loss of SWS impairs glymphatic-mediated clearance of β-amyloid (Aβ) and tau, which chronically can feedback in cerebral amyloid angiopathy (CAA), tortuosity, enlarged perivascular spaces, and reduced blood flow, furthering glymphatic disruptions and increasing extracellular protein levels [226, 227]. b Sleep disturbance, circadian arrhythmicity, age and AD pathology all impact cellular proteostasis, contributing to an in general overactivation to clear protein; however, in cases of disease, proteostasis is overwhelmed and this activation exacerbates an already damaged system. BiP, and active levels of PERK, IRE1 and ATF6 are increased with sleep loss indicating UPR recruitment, which is insufficient to clear misfolded protein in aged- and diseased-states (indicated by red dashed line). Autophagy activation via Beclin-1 and atg4a, leads to nucleation and upregulated formation of autophagosomes (grey vacuoles), yet with a failure of autophagic flux there is reduced lysosomal (red vacuoles) fusion (indicated by red line). Notably, this can reduce Aβ and tau degradation, impart neurodegeneration through abundant axonal and dendritic autophagosomes, and promote proteinopathy through exosomal release of autophagosomes, as is seen in Alzheimer’s disease (AD) progression. Autophagy is regulated on a circadian cycle, and further impaired when this rhythm is disturbed. UPS failure occurs with disease state contributing to higher levels of intracellular protein that the ALP is unable to compensate for (indicated by red dashed line to p62). Dysregulated UPS-mediated degradation (indicated by red dashed line) of PERIOD proteins (including PER1 and PER2) may further circadian alterations. c During periods of prolonged wakefulness, higher frequency neuronal activity without restorative sleep promotes Aβ and tau cell-to-cell spread. Because of elevated synaptic strength, the neuronal signal:noise ratio decreases and synaptic plasticity saturates, leading to non-specific network activity [69]. Without rest, these potentially aberrant neuronal connections, in consort with accumulation of extra- and intracellular uncleared protein, exacerbate neuronal dysfunction, and cognitive processes such as memory can become impaired. d Finally, memory consolidation is impaired from loss of REM and NREM stage 2 and 3 sleep, contributing to transient memory loss. Neuronal activity of NREM UP- (i.e., spindles, sharp-wave ripples) and DOWN- (i.e., delta waves, K-complexes) states and REM theta oscillations consolidate memory circuits formed throughout the day [65,66,67,68]. Chronically, impairments in proteostasis can progress to rampant accumulation of Aβ and tau in plaques and tangles, respectively, increasing disease spread and neuronal network dysfunction, all of which can further impair sleep and drive cognitive decline. Red text indicates impairments/decreases in AD and sleep disruption, green text indicates increases with AD and sleep disruption. Created with BioRender.com