Sleep Disturbances in MCI and AD: Neuroinflammation as a Possible Mediating Pathway

Abstract

Mild cognitive impairment (MCI) and Alzheimer's disease (AD) affect a high proportion of the elderly population with an increasing prevalence. Sleep disturbances are frequent in those with MCI and AD. This review summarizes existing research on sleep disturbances and neuroinflammation in MCI and AD. Although strong evidence supports various pathways linking sleep and AD pathology, the temporal direction of this central relationship is not yet known. Improved understanding of sleep disturbance and neuroinflammation in MCI and AD may aid in the identification of targets for their prevention.

Keywords: Alzheimer’s disease; aging; mild cognitive impairment; neuroinflammation; sleep.

FIGURE 1

A central pathway through which sleep disturbance and AD pathology is connected is through neuroinflammation caused by Aβ deposition (Heneka et al., 2015). Microglia and astrocytes are both activated and release inflammatory factors in response to Aβ (Krabbe et al., 2013). Additionally, disruption of internal clock gene function in microglia causes an increase in their release (Ni et al., 2019). AD pathology may damage neural pathways and lead to calcification within the pineal gland (Bumb et al., 2013, 2014). This leads to a reduction in the amount of melatonin which in turn causes sleep disturbance (Matsuoka et al., 2017). This relationship is bidirectional, as sleep disturbance is linked to disruptions of melatonin release (Wu and Swaab, 2005). Melatonin has anti-inflammatory properties, reducing the release of these factors by attenuating the release of NF-κB (Cecon et al., 2015). Additionally, melatonin reduces amyloid precursor protein (APP), thus protecting against Aβ creation (Lahiri, 1999). However, Aβ, by binding toll-like receptors of the pineal gland, may block melatonin release, leading to sleep disturbance in AD (Cecon et al., 2015). Noradrenaline, released from the locus coeruleus (LC) also plays an anti-inflammatory role, as the neurotransmitter can reduce the release of inflammatory factors (Feinstein et al., 2016). Low adrenergic input from the LC to the extracellular space (ECS, location of astrocytes) during sleep is required to allow Aβ and other metabolite clearance to occur (Mander et al., 2016). The LC-noradrenergic system activates with cortico-hippocampal neuronal replay during NREM EEG slow oscillations, suggesting a prominent role in sleep dependent memory consolidation (Rosenzweig et al., 2016; Twigg et al., 2010). Thus, inappropriate activation of the LC may compromise its role in memory consolidation during sleep and reduce Aβ clearance, leading to AD pathology. Finally, sleep disturbance has been independently linked to the release of inflammatory factors and increased blood brain barrier (BBB) permeability (He et al., 2014; Montagne et al., 2015). Sleep disturbance is correlated with increased Aβ deposition and may be occurring through any of the above pathways (Ju et al., 2017; Ooms et al., 2014; Spira et al., 2013).