For those who are interested in AD pathology, the new issue of Science Magazine has interesting article on the role of sleep deprivation in the development of AD. (And no, Xena, A2-73 as a sleeping pill is not going to solve the problem).
Sleep well to slow Alzheimer’s progression?
In Section: Perspectives | Neurodegeneration
Sleep disruption promotes the spread of damaging tau pathology in Alzheimer’s disease
By Wendy Noble 1 and Tara L. Spires-Jones 2
Although sleep disturbances are commonly reported in people with dementia ( Display footnote number: 1 ), whether this is a cause or a consequence of the disease is unclear. Evidence is mounting that alterations to normal sleep patterns affect disease progression, promoting the appearance of ß-amyloid (Aß) and tau aggregates that are progressively deposited in the brains of patients with Alzheimer’s disease (AD). Human and mouse studies support a role for sleep in curbing the accumulation of Aß ( Display footnote number: 2, 3 ); however, tau aggregates are more closely associated with synaptic degeneration and clinical symptoms of AD ( Display footnote number: 4 ). On page 880 of this issue, Holth et al. ( Display footnote number: 5 ) provide direct evidence that disrupting sleep, or stimulating excitatory neurons in brain nuclei that control wakefulness and arousal, promotes the release and spread of damaging tau aggregates across the brains of mice, and that sleep deprivation leads to increased extracellular Ab and tau in people.
sleep deprivation promotes alzheimers pathology
Tau is predominantly a cytosolic neuronal protein with important physiological roles in maintaining the cytoskeleton and regulating axonal transport. In a family of neurodegenerative diseases called tauopathies (which includes AD), pathological forms of tau species develop that are hyperphosphorylated, aggregated, and arranged into filaments that form neurofibrillary tangles ( Display footnote number: 6 ). Tau aggregates spread through neural circuits in the brain, starting in the medial temporal lobe. The presence of pathological tau strongly correlates with synaptic loss, neuronal dysfunction, and the severity of cognitive or motor symptoms ( Display footnote number: 4, 6 ), so understanding how tau neuron depolarization or stimulation of excitatory synapses in vitro ( Display footnote number: 7 ) and in vivo ( Display footnote number: 8 ). Released tau can be measured in the ISF that surrounds neurons and connects the brain vasculature to neural networks.
Overall, the brain is more metabolically and synaptically active during wakefulness; there is a net depression of synaptic activity during sleep ( Display footnote number: 1 ). Holth et al. show in mice that ISF tau is increased during periods of wakefulness. Sleep-deprived mice had an increase of tau release into ISF during light periods when nocturnal mice usually sleep and ISF tau is low. Further, using an elegant chemogenetic approach to stimulate excitatory neurons in the supramammillary nucleus of the hypothalamus (the control center of the sleep-wake cycle), the authors observed increased wakefulness, resulting in increased levels of Ab and tau in ISF.
Proteins can be exchanged between ISF and cerebrospinal fluid (CSF) ( Display footnote number: 9 ). Holth et al. found that CSF Aß, and particularly tau, increased compared to baseline in a sleep-deprived human cohort. This increased release of tau indicates that sleep disruption may promote the spread of tau pathology. In direct support of this hypothesis, Holth et al. show that sleep deprivation promotes disease progression in mice by inducing the spread of pathological tau.
Future longitudinal studies using, for example, positron emission tomography (PET) imaging are needed to determine the effects of sleep disruption on tau pathology spread and AD progression in humans. Nonetheless, a damaging bidirectional cycle likely exists among tau aggregate accumulation, synapse damage, and disrupted sleep, because mice that model AD-like tau pathology sleep poorly and less deeply ( Display footnote number: 10 ), and sleep disruption accelerates tau pathology accumulation in tauopathy mice ( Display footnote number: 5 ).
The evidence is stacking up that disrupted sleep is causally linked with the progression of AD, in part due to increased neuronal activity during wakefulness. Does this imply that dampening down synaptic activity could be beneficial in AD by preventing tau release and spread? Probably not, because strong epidemiologic evidence indicates that promoting neural activity through higher levels of education and exercise reduces the risk of developing AD ( Display footnote number: 11 ). Engaging in activities that provide external stimuli is thought to boost cognitive reserve by building robust networks that are more resilient to diverse insults. However, it is possible that brain networks that are active by default in the absence of external input, and that are known to be dysregulated in AD, could be targeted to slow pathological protein accumulation ( Display footnote number: 12 ).
The benefits of sleep have previously been linked with AD in the context of toxic aggregate clearance, including via the glymphatic system. This pathway, which is most active during sleep, allows exchange of proteins between ISF and CSF and their clearance into perivascular spaces and the lymphatic system ( Display footnote number: 9 ). Damage to molecular and cellular components of the glymphatic system during aging, in the course of neurodegenerative disease, and following physical brain trauma is closely linked with the increased presence of tau and Aß in extracellular fluids, the spread of aggregated proteins (including tau) in the brain, and worsened cognition ( Display footnote number: 13, 14 ).
The contribution of astrocytes, an intrinsic component of the glymphatic system, during AD sleep disruption is also of interest. The astrocyte-neuron lactate shuttle responds to increased energy demands of excitatory neurons during wakefulness, increasing lactate release for conversion to glutamate in neurons ( Display footnote number: 5 ). Sleep disruption in AD will affect astrocyte-directed effects on synaptic activity–driven tau release as well as on tau clearance mechanisms.
Sleep deprivation therefore results in abnormal synaptic activity that increases tau release into extracellular spaces, at times when its clearance is impaired by reduced CSF and ISF flow. If this results in the retention of tau species that are able to seed aggregation, tau pathology will spread across the brain, leading to progressive synapse and neuron dysfunction (see the figure). For those at risk of developing AD, treatments to promote sleep, including those already under investigation for Parkinson’s disease ( Display footnote number: 15 ), may have great benefit. The best advice for everyone is to do all we can to maintain a healthy life balance, sleep well, and engage with activities to keep the body and mind healthy.
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