Pharmacological enhancement of slow-wave activity at an early disease stage improves cognition and reduces amyloid pathology in a mouse model of Alzheimer’s disease

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 3, 2025

Improving sleep in murine Alzheimer's disease (AD) is associated with reduced brain amyloidosis. However, the window of opportunity for successful sleep-targeted interventions, regarding reduction pathological hallmarks and related cognitive performance, remains poorly characterized. Here, we enhanced slow-wave activity (SWA) during via sodium oxybate (SO) oral administration 2 weeks at early (6 months old) or moderately late (11 stages Tg2576 mice evaluated resulting neuropathology behavioral performance. We observed that performance 6-month-old significantly improved upon SO treatment, whereas no change was 11-month-old mice. Histochemical assessment amyloid plaques demonstrated SO-treated had less plaque burden than placebo-treated ones, ELISA insoluble protein fractions from brains indicated lower Aβ-42/Aβ-40 ratio group vs. controls. Altogether, our results suggest SWA-dependent amyloidosis leads to alleviated impairment only if administered course, potentially highlighting key importance sleep-based interventions clinical cohorts.

Language: Английский

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Acetylcholine bidirectionally regulates learning and memory

Journal of Neurorestoratology, Journal Year: 2022, Volume and Issue: 10(2), P. 100002 - 100002

Published: June 1, 2022

Acetylcholine (ACh) is one of the most important neurotransmitters in central cholinergic system; it specifically binds to muscarinic and nicotinic receptors degraded by acetylcholinesterase (AChE). ACh plays a crucial role learning memory. It generally believed that, nervous system, promotes conduction brain nerves accelerates information transmission. Besides, increasing levels can enhance memory ability comprehensively improve function. Thus, AChE inhibitors (AChEI), which inhibit degradation AChE, have been used treat Alzheimer's disease (AD) Parkinson's dementia (PDD). However, recent studies shown that excessive system impairs Here we review roles memory; focus on adverse effects ACh, possible mechanisms, bidirectional pathology cure AD PDD. We conclude timing dose administration should be carefully prescreened when using alleviate patients.

Language: Английский

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Multi-transcriptomic analysis points to early organelle dysfunction in human astrocytes in Alzheimer's disease

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 166, P. 105655 - 105655

Published: Feb. 8, 2022

The phenotypic transformation of astrocytes in Alzheimer's disease (AD) is still not well understood. Recent analyses based on single-nucleus RNA sequencing postmortem samples are limited by the low number sequenced astrocytes, small cohort sizes, and differentially expressed genes detected. To optimize detection astrocytic genes, we employed a novel strategy consisting localization pre-determined astrocyte neuronal gene clusters publicly available whole-brain transcriptomes. Specifically, used cortical transcriptomes from 766 individuals, including cognitively normal subjects (Controls), people diagnosed with mild cognitive impairment (MCI) or dementia due to AD. Samples came three independent cohorts organized Mount Sinai Hospital, Mayo Clinic, Religious Order Study/Memory Aging Project (ROSMAP). Astrocyte- neuron-specific were generated human brain cell-type specific RNAseq data using hierarchical clustering enrichment scoring. Genes each cluster manually annotated according functional Categories. Gene Set Variation Analysis (GSVA) Principal Component (PCA) establish changes these categories among clinical cohorts. We highlight findings study. First, individuals same diagnosis molecularly heterogeneous. Particularly Clinic ROSMAP cohorts, over 50% Controls presented down-regulation encoding synaptic proteins typical AD, whereas 30% patients AD Control-like transcriptomic profiles. Second, related coincided, up-regulation perisynaptic processes (PAP) endolysosomal mitochondrial proteins. Third, inversely correlated stages defined Braak CERAD Finally, interpreted as maladaptive adaptive point view biology model phenotypical main prediction that early malfunction system, associated progressive dysfunction, contribute disease. If this correct, therapies preventing organelle dysfunction may be beneficial preclinical

Language: Английский

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Modeling neurodegenerative disorders in zebrafish

Neuroscience & Biobehavioral Reviews, Journal Year: 2022, Volume and Issue: 138, P. 104679 - 104679

Published: April 28, 2022

Language: Английский

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

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: April 21, 2023

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

Language: Английский

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Brain Waste Removal System and Sleep: Photobiomodulation as an Innovative Strategy for Night Therapy of Brain Diseases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3221 - 3221

Published: Feb. 6, 2023

Emerging evidence suggests that an important function of the sleeping brain is removal wastes and toxins from central nervous system (CNS) due to activation waste (BWRS). The meningeal lymphatic vessels (MLVs) are part BWRS. A decrease in MLV associated with Alzheimer’s Parkinson’s diseases, intracranial hemorrhages, tumors trauma. Since BWRS activated during sleep, a new idea now being actively discussed scientific community: night stimulation might be innovative promising strategy for neurorehabilitation medicine. This review highlights trends photobiomodulation BWRS/MLVs deep sleep as breakthrough technology effective unnecessary compounds order increase neuroprotection CNS well prevent or delay various diseases.

Language: Английский

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Insights on benzodiazepines' potential in Alzheimer's disease

Life Sciences, Journal Year: 2023, Volume and Issue: 320, P. 121532 - 121532

Published: Feb. 28, 2023

Language: Английский

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Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5549 - 5549

Published: May 19, 2024

Parvalbumin expressing (PV+) GABAergic interneurons are fast spiking neurons that provide powerful but relatively short-lived inhibition to principal excitatory cells in the brain. They play a vital role feedforward and feedback synaptic inhibition, preventing run away excitation neural networks. Hence, their dysfunction can lead hyperexcitability increased susceptibility seizures. PV+ also key players generating gamma oscillations, which synchronized oscillations associated with various cognitive functions. interneuron particularly vulnerable aging degeneration has been decline memory impairment dementia Alzheimer’s disease (AD). Overall, of disrupts normal excitatory/inhibitory balance within specific neurocircuits brain thus linked wide range neurodevelopmental neuropsychiatric disorders. This review focuses on dysfunctional inhibitory generation epileptic seizures potential as targets design future therapeutic strategies treat these Recent research using cutting-edge optogenetic chemogenetic technologies demonstrated they be selectively manipulated control restore activity brains animal models. suggests could important developing treatments for patients epilepsy comorbid disorders, such AD, where directly deficits.

Language: Английский

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Disease-Modifying Treatments and Their Future in Alzheimer’s Disease Management

Cureus, Journal Year: 2024, Volume and Issue: unknown

Published: March 13, 2024

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment, loss of cholinergic neurons, and cognitive decline that insidiously progresses to dementia. The pathoetiology AD complex, as genetic predisposition, age, inflammation, oxidative stress, dysregulated proteostasis all contribute its development progression. histological hallmarks are the formation accumulation amyloid-β plaques interfibrillar tau tangles within central nervous system. These trigger neuroinflammation disrupt physiological structure functioning leading dysfunction. Most treatments currently available for focus only on symptomatic relief. Disease-modifying (DMTs) target biology in hopes slowing or reversing progression desperately needed. This narrative review investigates novel DMTs their therapeutic targets either phase three have been recently approved U.S. Food Drug Administration (FDA). areas some these consist combatting amyloid accumulation, neuroinflammation, proteostasis, metabolism, circadian rhythm. Neuroprotection neuroplasticity promotion were also key areas. DMT diversity may permit improved responses certain subpopulations AD, particularly if being administered aligns with subpopulation's most prominent pathological findings. Clinicians should be cognizant how drugs differ targets, this knowledge potentially enhance level care they can provide patients future.

Language: Английский

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Hyperactivity Induced by Soluble Amyloid-β Oligomers in the Early Stages of Alzheimer's Disease

Frontiers in Molecular Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: Jan. 7, 2021

Soluble amyloid-beta oligomers (Aβo) start to accumulate in the human brain one two decades before any clinical symptoms of Alzheimer's disease (AD) and are implicated synapse loss, best predictors memory decline that characterize illness. Cognitive impairment AD was traditionally thought result from a reduction synaptic activity which ultimately induces neurodegeneration. More recent evidence indicates early stages failure is, at least partly, induced by neuronal hyperactivity rather than hypoactivity. Here, we review growing body supporting implication soluble Aβo on induction animal models, vitro , humans. We then discuss impact Aβo-induced performance, cell death, epileptiform activity, gamma oscillations, slow wave activity. provide an overview cellular molecular mechanisms emerging explain how induce hyperactivity. conclude providing outlook for development disease-modifying interventions onset AD.

Language: Английский

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