Proteostasis failure exacerbates neuronal circuit dysfunction and sleep impairments in Alzheimer's disease.

Failed proteostasis is a well-documented feature of Alzheimer's disease, particularly, reduced protein degradation and clearance. However, the contribution of failed proteostasis to neuronal circuit dysfunction is an emerging concept in neurodegenerative research and will prove critical in understanding cognitive decline. Our objective is to convey Alzheimer's disease progression with the growing evidence for a bidirectional relationship of sleep disruption and proteostasis failure. Proteostasis dysfunction and tauopathy in Alzheimer's disease disrupts neurons that regulate the sleep-wake cycle, which presents behavior as impaired slow wave and rapid eye movement sleep patterns. Subsequent sleep loss further impairs protein clearance. Sleep loss is a defined feature seen early in many neurodegenerative disorders and contributes to memory impairments in Alzheimer's disease. Canonical pathological hallmarks, ß-amyloid, and tau, directly disrupt sleep, and neurodegeneration of locus coeruleus, hippocampal and hypothalamic neurons from tau proteinopathy causes disruption of the neuronal circuitry of sleep. Acting in a positive-feedback-loop, sleep loss and circadian rhythm disruption then increase spread of ß-amyloid and tau, through impairments of proteasome, autophagy, unfolded protein response and glymphatic clearance. This phenomenon extends beyond ß-amyloid and tau, with interactions of sleep impairment with the homeostasis of TDP-43, α-synuclein, FUS, and huntingtin proteins, implicating sleep loss as an important consideration in an array of neurodegenerative diseases and in cases of mixed neuropathology. Critically, the dynamics of this interaction in the neurodegenerative environment are not fully elucidated and are deserving of further discussion and research. Finally, we propose sleep-enhancing therapeutics as potential interventions for promoting healthy proteostasis, including ß-amyloid and tau clearance, mechanistically linking these processes. With further clinical and preclinical research, we propose this dynamic interaction as a diagnostic and therapeutic framework, informing precise single- and combinatorial-treatments for Alzheimer's disease and other brain disorders.

Parvalbumin neuroplasticity compensates for somatostatin impairment, maintaining cognitive function in Alzheimer's disease.

BACKGROUND: Patient-to-patient variability in the degree to which ß-amyloid, tau and neurodegeneration impact cognitive decline in Alzheimer's disease (AD) complicates disease modeling and treatment. However, the underlying mechanisms leading to cognitive resilience are not resolved. We hypothesize that the variability in cognitive function and loss relates to neuronal resilience of the hippocampal GABAergic network. METHODS: We compared TgF344-AD and non-transgenic littermate rats at 9, 12, and 15 months of age. Neurons, ß-amyloid plaques and tau inclusions were quantified in hippocampus and entorhinal cortex. Somatostatin (SST) and parvalbumin (PVB) interneurons were traced to examine hippocampal neuroplasticity and cognition was tested in the Barnes maze. RESULTS: The 9-month-old TgF344-AD rats exhibited loss of neurons in the entorhinal cortex and hippocampus. Hippocampal neuronal compensation was observed in 12-month TgF344-AD rats, with upregulation of GABAergic interneuronal marker. By 15 months, the TgF344-AD rats had robust loss of excitatory and inhibitory neurons. ß-Amyloid and tau pathology accumulated continuously across age. SST interneurons exhibited tau inclusions and atrophy from 9 months, whereas PVB interneurons were resilient until 15 months. The hippocampal PVB circuit underwent neuroplastic reorganization with increased dendritic length and complexity in 9- and 12-month-old TgF344-AD rats, before atrophy at 15 months. Strikingly, 12-month-old TgF344-AD rats were resilient in executive function and cognitive flexibility. Cognitive resilience in TgF344-AD rats occurred as maintenance of function between 9 and 12 months of age despite progressive spatial memory deficits, and was sustained by PVB neuroplasticity. CONCLUSIONS: Our results demonstrate the inherent neuronal processes leading to cognitive maintenance, and describe a novel finding of endogenous cognitive resilience in an AD model.

Concurrent behavioral and electrophysiological longitudinal recordings for in vivo assessment of aging.

Electrophysiological and behavioral alterations, including sleep and cognitive impairments, are critical components of age-related decline and neurodegenerative diseases. In preclinical investigation, many refined techniques are employed to probe these phenotypes, but they are often conducted separately. Herein, we provide a protocol for one-time surgical implantation of EMG wires in the nuchal muscle and a skull-surface EEG headcap in mice, capable of 9-to-12-month recording longevity. All data acquisitions are wireless, making them compatible with simultaneous EEG recording coupled to multiple behavioral tasks, as we demonstrate with locomotion/sleep staging during home-cage video assessments, cognitive testing in the Barnes maze, and sleep disruption. Time-course EEG and EMG data can be accurately mapped to the behavioral phenotype and synchronized with neuronal frequencies for movement and the location to target in the Barnes maze. We discuss critical steps for optimizing headcap surgery and alternative approaches, including increasing the number of EEG channels or utilizing depth electrodes with the system. Combining electrophysiological and behavioral measurements in preclinical models of aging and neurodegeneration has great potential for improving mechanistic and therapeutic assessments and determining early markers of brain disorders.

Functional Amyloids and their Possible Influence on Alzheimer Disease.

Amyloids play critical roles in human diseases but have increasingly been recognized to also exist naturally. Shared physicochemical characteristics of amyloids and of their smaller oligomeric building blocks offer the prospect of molecular interactions and crosstalk amongst these assemblies, including the propensity to mutually influence aggregation. A case in point might be the recent discovery of an interaction between the amyloid ß peptide (Aß) and somatostatin (SST). Whereas Aß is best known for its role in Alzheimer disease (AD) as the main constituent of amyloid plaques, SST is intermittently stored in amyloid-form in dense core granules before its regulated release into the synaptic cleft. This review was written to introduce to readers a large body of literature that surrounds these two peptides. After introducing general concepts and recent progress related to our understanding of amyloids and their aggregation, the review focuses separately on the biogenesis and interactions of Aß and SST, before attempting to assess the likelihood of encounters of the two peptides in the brain, and summarizing key observations linking SST to the pathobiology of AD. While the review focuses on Aß and SST, it is to be anticipated that crosstalk amongst functional and disease-associated amyloids will emerge as a general theme with much broader significance in the etiology of dementias and other amyloidosis.