Tau-driven degeneration of sleep- and wake-regulating neurons in Alzheimer's disease

Abstract

Disturbances of the sleep/wake cycle in Alzheimer's disease (AD) are common, frequently precede cognitive decline, and tend to worsen with disease progression. Sleep is critical to the maintenance of homeostatic and circadian function, and chronic sleep disturbances have significant cognitive and physical health consequences that likely exacerbate disease severity. Sleep-wake cycles are regulated by neuromodulatory centers located in the brainstem, the hypothalamus, and the basal forebrain, many of which are vulnerable to the accumulation of abnormal protein deposits associated with neurodegenerative conditions. In AD, while sleep disturbances are commonly attributed to the accumulation of amyloid beta, patients often first experience sleep issues prior to the appearance of amyloid beta plaques, on a timeline that more closely corresponds to the first appearance of abnormal tau neurofibrillary tangles in sleep/wake regulating areas of the brainstem. Sleep disturbances also occur in pure tauopathies, providing further support that tau is a major contributor. Here, we provide an overview of the neuroanatomy of sleep/wake centers discovered in animal models, and review the evidence that tau-driven neuropathology is a primary driver of sleep disturbance in AD.

Keywords: Alzheimer's disease; Human; Neuropathology; Progressive supranuclear palsy; Sleep-promoting; Tauopathies; Wake-promoting.

Fig. 1.

Brain areas containing tau neuropathology shown in purple in Braak stages 0 through VI in Alzheimer’s disease. Darker shades indicate increasing severity of tau pathology. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2.

Brain regions in the brainstem, hypothalamus, and basal forebrain that contain sleep- and wake-promoting neurons, with areas containing abnormal tau and/or neurofibrillary tangles in AD noted. Red arrows indicate wake-promoting projections. Blue lines indicate sleep-promoting projections. DRN = dorsal raphe nucleus; LC = locus coeruleus; LHA = lateral hypothalamic area; MnPO = median preoptic nucleus; NbM = nucleus basalis of Meynert; PAG = periaqueductal gray; PBN = parabrachial nucleus; PPN = pedunculopontine nucleus; PZ = parafacial zone; SLD = sublaterodorsal nucleus; SN = substantia nigra; TMN = tuberomammillary nucleus; VLPO = ventrolateral preoptic nucleus; VTA = ventral tegmental area; ZI = zona incerta. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)