Wai Haung Yu

Proper sleep and stress maintenance are essential for health and may contribute to disease progression when dysregulated. This review highlights the intricate links between sleep, stress, and Alzheimer’s disease, including underlying neural circuitry and mechanisms that contribute to disease. Sleep is essential for protein clearance pathways including autophagy and the glymphatic system, which are impaired in neurodegenerative diseases. Similarly, chronic stress incites neuroinflammatory responses known to be elevated in brains of patients with neurodegeneration. As a result, it is perhaps unsurprising that tau pathology and neurodegeneration affect sleep and stress circuitry in the brain, including the Locus Coeruleus and Lateral Hypothalamus, beginning in prodromal phases of Alzheimer’s disease. Though the precise mechanisms underscoring these vulnerabilities are incompletely understood, this provides a unique therapeutic opportunity for targeting these pathways in early Alzheimer’s disease patients with concomitant sleep impairments and/or chronic stress. In this review, we offer insights into these relationships including specific brain region involvements, the contribution of molecular mechanisms of disease, and these translational opportunities which may arise.

INTRODUCTION: Sleep impairments likely contribute to Alzheimer's pathology, though specific contributions to disease progression are incompletely understood. We propose that autophagic impairment is associated with chronic sleep disruption and examine how sleep loss and stress influence disease development, including having impacts on proteostasis, cognition, and neural circuitry. METHODS: We sleep‐disrupted 6‐month‐old APP ^NL‐G‐F mice for 2 weeks and behaviorally assessed sleep recovery, nesting, stress, and cognition. Subsequently, we analyzed markers of Alzheimer's pathology, stress, neuroinflammation, and proteostasis in hippocampal and subcortical brain regions. RESULTS: Sleep‐deprived mice had altered sleep‐related behaviors, increased stress, and signs of disease‐acceleration including sex‐dependent neurodegeneration, proteinopathy, and changes to autophagy and the neuroinflammatory response. DISCUSSION: Chronic sleep disruption accelerates the pathological cascade of Alzheimer's, including cognitive impairment and Alzheimer's pathology in a sex‐dependent manner. This work enhances our understanding of the sleep–stress–Alzheimer's relationship, including sex‐based differences, and may point to a novel therapeutic avenue to limit Alzheimer's progression.

Background: Sleep impairments has been proposed to contribute to Alzheimer's disease (AD) progression, though understanding of the mechanism and association with neural networks remains relatively unexplored. This presentation identifies the relationship between chronic and acute sleep disruption, and relationship to accelerated AD pathology. We propose that autophagic impairment is prominent loss of sleep and circadian rhythmicity, and examine the impact on proteostasis, cognition and AD pathologies. Methods: We chronically disrupted sleep in 6‐month APPNL‐G‐F and acutely in 4/8/12‐month in APPNL‐G‐FxMAPT (DKI) mice before assessing behaviour, stress and pathological hallmarks of autophagy and AD to identify changes associated with sleep impairment. Results: Sleep disruption, both acute and chronic, impaired sleep patterns and resulted in behavioral deficits. In acute sleep impairment modeling in DKI mice, we noted hippocampal‐based AD and autophagy changes, alongside increased p62 aggregates in hypothalamic pathology along with neuronal loss. Orexinergic (hypothalamus), but not GABAergic neurons (GAD67, preoptic area), were vulnerable to autophagic disruption. With aging, we observed neuronal loss and preoptic excitatory neuronal p62 increase. In early‐stage dKI, neurons in the locus coeruleus had slight increases in p62+/PHF1+ tau deposition, which were robust at late‐stage. In hippocampal and cortical memory circuits, p62 deposition is predominantly axonal/dendritic, greater in female mice and preceded hippocampal neurodegeneration at later stages, with tau pathology greater in male dKIs. Circadian arrhythmicity and loss of rapid eye movement sleep begins in early‐stage dKI mice and declines over age, more prominently in females. Under chronic sleep loss, we noted elevated corticosterone in female mice that increased neurodegeneration as seen by reduced mature neurons and increased p62 in the hippocampus, indicative of impaired proteostasis. Males, however, demonstrated autophagic impairments through reductions in the autophagy‐initiating ATG5‐12 complex as well as increased levels of hippocampal phospho‐tau, amyloid plaque deposition and probable neuroinflammatory response. Conclusion: We identify that both acute and chronic sleep disruption can impair autophagic function in the orexinergic and LC sleep‐regulating regions, negatively impacting behavior. We further note linkages to stress and sex‐based differences that are relevant to the etiology of AD and may represent the need for targeted approaches to treatment in the future.

Background: Proteostasis, in particular the impairment of autophagic activity, is linked to sleep dysregulation and is an early sign of dementias including Alzheimer’s disease (AD). This coupling of events may be a critical alteration driving proteinopathy and AD progression. In the present study, we investigated sleep–wake and memory regulating neurons for vulnerability to autophagic impediment, and related these findings to progression of the sleep and cognitive phenotype. Methods: Using the double knock-in AD mouse model, App ^NL−G−FxMAPT, we examined phenotypic and pathological alterations at several timepoints and compared to age-matched single knock-in MAPT mice. Spatial learning, memory and executive Function were investigated in the Barnes maze. Sleep was investigated by 24-h locomotor activity and EEG. Immunostaining for autophagic, neuronal and pathological markers was conducted in brain regions related to memory (hippocampus, prefrontal cortex, entorhinal cortex) and the sleep–wake cycle (hypothalamus, locus coeruleus). Hippocampal electrophysiological recordings were conducted to probe neuronal Function during object investigation. A 3-day sleep disruption was conducted in MAPT mice to investigate autophagic changes following sleep loss. Autophagy was activated in MAPT mice with trehalose to probe effects on sleep recovery. Results: We identified that disrupted sleep occurred from early-stages in App ^NL−G−FxMAPT mice, that sleep declined over age, and sleep deficits preceded cognitive impairments in late-stages. Cytoplasmic autophagic impediment in hypothalamic and locus coeruleus sleep–wake neurons occurred in early-stage App ^NL−G−FxMAPT mice, prior to significant β-amyloid deposition in these regions, with a failure of lysosomal flux over disease progression. Autophagic changes in the hippocampus and cortex at early-stage were predominantly in processes and less frequently associated with the lysosome. Plaque-associated autophagic and lysosomal accumulations were frequent from the early-stage. Sex differences in the AD phenotype were prominent, including greater cognitive decline in males than females, linked to increased proteostasis burden in EC layer II neurons and hippocampal tau in the late-stage. Conversely, sleep impairments were more rapid in females including less REM sleep recovery than males, along with greater autophagic burden in hippocampal processes of female App ^NL−G−FxMAPT mice. We probed the sleep-cognition linkage demonstrating hippocampal electrophysiological slowing during cognitive processing in mid-stage App ^NL−G−FxMAPT mice, prior to cognitive decline. We provide evidence for a positive feedback loop in the autophagic-sleep relationship by demonstrating that disrupted sleep in MAPT mice led to arrhythmic sleep patterns and accumulations of autophagic aggregates in the hippocampus and hypothalamus, similar to as was seen in the early Alzheimer’s phenotype. We further probed the autophagy-sleep linkage by treating MAPT mice with trehalose to activate autophagy and demonstrate an improvement in sleep recovery following a sleep disruption. Conclusions: These findings demonstrate the vulnerability of sleep-regulating neurons to proteostatic dysfunction and the sleep-autophagy linkage as an early, and treatable, Alzheimer’s disease mechanism. Graphical Morrone et al provide evidence for the linkage between sleep and autophagic disruptions in Alzheimer’s disease (AD) progression. At early AD stages, sleep-wake regulating neurons in the hypothalamus and locus coeruleus exhibit increased cytoplasmic inclusions concomitant with the onset of sleep disturbances. Early-stage autophagic aggregates in the hippocampus appear more prominently in neuronal processes and in the cortex linked to plaques. This pathology worsens over AD progression, including advanced sleep and cognitive deficits, autophagic aggregates in entorhinal cortex-hippocampus projecting neurons. Disrupting sleep in control mice mimics the hippocampal, hypothalamic and sleep patterns impairments observed in early-stage AD, and therapeutic activation of autophagy improves sleep recovery. See also Table 1 for a summary of changes along with sex differences in autophagy and behavioral readouts.

Alzheimer’s disease (AD) and related dementia cases are increasing globally, emphasizing the urgent need to clarify disease mechanisms for translational application in diagnoses and treatment. Vascular alterations represent a major pathological feature of AD, and beyond the well-established roles of small vessel disease and large artery atherosclerosis, our group has previously demonstrated that brain large artery dilatation is associated with elevated risk of dementia and Alzheimer pathology. The most severe manifestation of this non-atherosclerotic arterial phenotype is dolichoectasia, an enlargement of large blood vessels (Gutierrez et al., 2019; Melgarejo et al., 2024). Despite consistent epidemiological evidence across populations, the mechanistic link between arterial dilatation and AD remains poorly understood. To address this gap, we induced dolichoectasia in App ^NL-G-F mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. After three months, brains were examined using biochemical and immunohistochemical methods. Elastase-treated mice exhibited a significant increase in amyloid plaques in the hippocampus ( p = 0.021 ) and cortex ( p = 0.029 ) compared with vehicle-treated controls. Neuronal loss was evident in the CA1 region of the hippocampus ( p = 0.036 ), with a trend towards neurodegeneration in CA3 (p = 0.055). We also observed elevated p62 in the hippocampus and cortex ( p = 0.009 and p = 0.001 , respectively), suggesting impaired protein or autophagic-lysosomal clearance. Although no overt increase in neuroinflammation or astrogliosis was detected at this time point, matrix metalloproteinase-9 (MMP-9) levels were trending towards elevated levels (p = 0.058). Combined, these findings indicate successful elastase-induced brain arterial dilatation accelerates AD-related pathology in App ^NL-G-F mice, providing mechanistic evidence that large artery dilatation may contribute directly to Alzheimer’s disease progression.

Amylin, also known as islet amyloid polypeptide (IAPP), is a pancreatic β‐cell peptide hormone involved in satiation and control food intake. It is also produced in smaller quantities by neurons, the gastrointestinal tract, and spinal ganglia. Numerous studies have revealed that patients with type 2 diabetes mellitus (T2DM) and cognitive deficits exhibit IAPP deposits in the pancreas, brain, and blood vessels. IAPP has also been shown to exert neuroprotective effects against Alzheimer's disease (AD) and cognitive impairments. The objective of this review paper is to provide recent information about the pathophysiological roles of IAPP in metabolic and in neurological disorders, and its potential as a druggable target. We have reviewed preclinical and clinical human and animal research studies of IAPP. We discuss the IAPP structure, its receptors, and its physiological functions in metabolism, satiation, adiposity, obesity, and in the brain. Then we discuss its role in metabolic and neurological disorders like diabetes, obesity, bone disorder, neurodegeneration, cerebrovascular disorders, depression, alcohol use disorder, epilepsy, and in ovarian cysts. Overall, this review provides information on the progress of research into the roles of IAPP and its receptor in food intake, energy homeostasis, glucose regulation, satiation, and its role in metabolic and neurological disorders making it a potential target for therapeutic approaches. This review also suggests that the utilization of rodents overexpressing human IAPP in neurodegeneration models may unearth some significant therapeutic potentials for neurological disorders.

Neurodegenerative disorders of ageing such as Alzheimer disease, Parkinson disease and Huntington disease are characterized by the presence of neurotoxic misfolded and aggregated proteins. One reason underlying the accumulation of these proteins is insufficient clearance by intracellular and extracellular pathways such as the autophagic–lysosomal network and the glymph system. This article reviews the potential for therapeutically enhancing the clearance of neurotoxic proteins to curtail the onset and slow the progression of neurodegenerative disorders of ageing. Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic–lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin–proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood–brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.

The development of insoluble, intracellular neurofibrillary tangles composed of the microtubule-associated protein tau is a defining feature of tauopathies, including Alzheimer’s disease (AD). Accumulating evidence suggests that tau pathology co-localizes with RNA binding proteins (RBPs) that are known markers for stress granules (SGs). Here we used proteomics to determine how the network of tau binding proteins changes with disease in the rTg4510 mouse, and then followed up with immunohistochemistry to identify RNA binding proteins that co-localize with tau pathology. The tau interactome networks revealed striking disease-related changes in interactions between tau and a multiple RBPs, and biochemical fractionation studies demonstrated that many of these proteins including hnRNPA0, EWSR1, PABP and RPL7 form insoluble aggregates as tau pathology develops. Immunohistochemical analysis of mouse and human brain tissues suggest a model of evolving pathological interaction, in which RBPs co-localize with pathological phospho-tau but occur adjacent to larger pathological tau inclusions. We suggest a model in which tau initially interacts with RBPs in small complexes, but evolves into isolated aggregated inclusions as tau pathology matures.