Slow Wave Sleep Is a Promising Intervention Target for Alzheimer’s Disease DOI Creative Commons

Yee Fun Lee,

Dmitry Gerashchenko, Igor Timofeev

et al.

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: June 30, 2020

Alzheimer’s disease (AD) is the major cause of dementia, characterized by presence amyloid-beta plaques and neurofibrillary tau tangles. Plaques tangles are associated with sleep-wake cycle disruptions, including disruptions in non-rapid eye movement (NREM) slow wave sleep. patients spend less time NREM sleep exhibit decreased activity. Consistent critical role memory consolidation, reduced activity impaired consolidation AD patients. The aberrant can be modeled transgenic mouse models amyloidosis tauopathy. Animal exhibited impairments early progression, prior to deposition however abundant oligomeric amyloid-beta. Optogenetic rescue successfully halted amyloid accumulation restored intraneuronal calcium levels mice. On other hand, optogenetic acceleration frequency exacerbated disrupted neuronal homeostasis. In this review, we summarize evidence mechanisms underlying existence a positive feedback loop between amyloid/tau pathology that lead further accumulations AD. Moreover, since occur plaque deposition, provide an biomarker for disease. Finally, propose therapeutic targeting might effective treatment

Language: Английский

Regulatory genomic circuitry of human disease loci by integrative epigenomics DOI Creative Commons
Carles A. Boix, Benjamin T. James, Yongjin Park

et al.

Nature, Journal Year: 2021, Volume and Issue: 590(7845), P. 300 - 307

Published: Feb. 3, 2021

Abstract Annotating the molecular basis of human disease remains an unsolved challenge, as 93% loci are non-coding and gene-regulatory annotations highly incomplete 1–3 . Here we present EpiMap, a compendium comprising 10,000 epigenomic maps across 800 samples, which used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators downstream target genes. We this resource annotate 30,000 genetic that were associated with 540 traits 4 , predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers candidate tissue-specific genes for each. partitioned multifactorial into contributing factors distinct functional enrichments comorbidity patterns, revealed both single-factor monotropic multifactor pleiotropic loci. Top-scoring frequently had multiple predicted driver variants, converging through common gene, or indicating extensive pleiotropy. Our results demonstrate importance dense, rich, investigation complex traits.

Language: Английский

Citations

342
Synaptic degeneration in Alzheimer disease DOI
Makis Tzioras, Robert I. McGeachan, Claire S. Durrant

et al.

Nature Reviews Neurology, Journal Year: 2022, Volume and Issue: 19(1), P. 19 - 38

Published: Dec. 13, 2022

Language: Английский

Citations

250
The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease DOI Creative Commons
Martí Colom‐Cadena, Tara L. Spires‐Jones, Henrik Zetterberg

et al.

Alzheimer s Research & Therapy, Journal Year: 2020, Volume and Issue: 12(1)

Published: March 2, 2020

Abstract Background Synapse damage and loss are fundamental to the pathophysiology of Alzheimer’s disease (AD) lead reduced cognitive function. The goal this review is address challenges forging new clinical development approaches for AD therapeutics that can demonstrate reduction synapse or loss. key points include following: a downstream effect amyloidosis, tauopathy, inflammation, other mechanisms occurring in AD. correlates most strongly with decline because synaptic function underlies performance. Compounds halt reduce have strong rationale as treatments Biomarkers measure degeneration patients will facilitate such drugs. ability methods sensitively density brain living patient through vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations proteins (e.g., neurogranin synaptotagmin) cerebrospinal fluid (CSF), functional imaging techniques quantitative electroencephalography (qEEG) provides compelling case use these types measurements biomarkers quantify trials Conclusion A number emerging able injury may correlate These hold promise both diagnostics measurement therapeutic successes.

Language: Английский

Citations

249
Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer’s disease DOI Creative Commons

Jing‐Fei Chen,

Kun Liu, Bo Hu

et al.

Neuron, Journal Year: 2021, Volume and Issue: 109(14), P. 2292 - 2307.e5

Published: June 7, 2021

Language: Английский

Citations

243
Neuroinflammation in Alzheimer’s Disease DOI Creative Commons
Isaac G. Onyango, Gretsen Velezmoro Jáuregui, Mária Čarná

et al.

Biomedicines, Journal Year: 2021, Volume and Issue: 9(5), P. 524 - 524

Published: May 7, 2021

Alzheimer's disease (AD) is a neurodegenerative associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise increasing age. There are currently no effective modifying treatments for AD, resulting in increasingly large socioeconomic personal costs. Increasing age an increase low-grade chronic inflammation (inflammaging) that may contribute the process AD. Although exact mechanisms remain unclear, aberrant elevation reactive oxygen nitrogen species (RONS) levels from several endogenous exogenous processes brain not only affect cell signaling, but also trigger cellular senescence, inflammation, pyroptosis. Moreover, compromised immune privilege allows infiltration peripheral cells infectious agents play role. Additionally, meta-inflammation as well gut microbiota dysbiosis drive neuroinflammatory process. Considering inflammatory/immune pathways dysregulated parallel cognitive dysfunction elucidating relationship between central nervous system facilitate development safe therapy We discuss some current ideas on inflammaging appear summarize details few immunomodulatory strategies being developed selectively target detrimental aspects neuroinflammation without affecting defense against pathogens tissue damage.

Language: Английский

Citations

204
N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer’s disease DOI Creative Commons
Andrew M. Shafik, Feiran Zhang, Zhenxing Guo

et al.

Genome biology, Journal Year: 2021, Volume and Issue: 22(1)

Published: Jan. 5, 2021

N6-methyladenosine (m

Citations

196
GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease DOI

Danlei Bi,

Lang Wen,

Zujun Wu

et al.

Alzheimer s & Dementia, Journal Year: 2020, Volume and Issue: 16(9), P. 1312 - 1329

Published: June 16, 2020

To propose a new hypothesis that GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease (AD).Synaptic E/I emerge decades before appearance cognitive decline AD patients, which contribute to neurodegeneration. Initially, was thought occur first, due glutamatergic cholinergic systems. However, evidence has demonstrated system, counterpart balance major neurotransmitter system central nervous is altered enormously this contributes further pathogenesis.Alterations induced by multiple pathogenic or risk factors, pathogenesis.This accounts for many critical questions common challenges confronting pathogenesis. More specifically, it explains why amyloid beta (Aβ), β-secretase (BACE1), apolipoprotein E4 gene (APOE ε4), hyperactive glia cells, age sex are factors AD. promotes spread Aβ pathology throughout brain associated impairments, induction these varied shares neurobiology leading imbalance. In turn, some exacerbate Moreover, modulates various functions thus, nonamnestic manifestations. Furthermore, corrections through manipulation have shown positive outcomes preclinical clinical studies, suggesting potential as therapeutic target AD.Dysfunction signaling pathways, include existing theories pathogenesis, such neuroinflammation hypotheses. perspective, related excitotoxicity, Therefore, could be key restore, at least partially, function patients.

Language: Английский

Citations

151
Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer’s Disease DOI Creative Commons

Eleanor K. Pickett,

Abigail G. Herrmann,

Jamie McQueen

et al.

Cell Reports, Journal Year: 2019, Volume and Issue: 29(11), P. 3592 - 3604.e5

Published: Dec. 1, 2019

A key knowledge gap blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack understanding how amyloid beta (Aβ) peptide and pathological forms tau protein cooperate in causing phenotypes. Within a mouse tau-deficient background, we probed molecular, cellular, behavioral disruption triggered by influence wild-type human on Aβ-induced pathology. We find that Aβ work cooperatively to cause hyperactivity phenotype downregulation transcription genes involved synaptic function. In both our model postmortem tissue, observe accumulation synapses, supporting potential importance tau. Importantly, reduction mice initiated after deficits emerge corrects deficits, reduces levels, substantially reverses transcriptional perturbations, suggesting lowering levels may be beneficial AD.

Language: Английский

Citations

147
Nrf2 Suppresses Oxidative Stress and Inflammation inAppKnock-In Alzheimer’s Disease Model Mice DOI
Akira Uruno, Daisuke Matsumaru, Rie Ryoke

et al.

Molecular and Cellular Biology, Journal Year: 2020, Volume and Issue: 40(6)

Published: Jan. 9, 2020

Nrf2 (NF-E2-related-factor 2) is a stress-responsive transcription factor that protects cells against oxidative stresses. To clarify whether prevents Alzheimer's disease (AD), AD model AppNL-G-F/NL-G-F knock-in (AppNLGF) mice were studied in combination with genetic induction Keap1FA/FA mice. While AppNLGF displayed shorter latency to escape than wild-type the passive-avoidance task, impairment was improved AppNLGF::Keap1FA/FA Matrix-assisted laser desorption ionization–mass spectrometry imaging revealed reduced glutathione levels elevated by mouse brains compared brains. Genetic markedly suppressed elevation of stress marker 8-OHdG and Iba1-positive microglial cell number. We also determined plasmalogen-phosphatidylethanolamine (PlsPE) level as an biomarker. PlsPE containing polyunsaturated fatty acids decreased brain, but attenuated this decline. evaluate pharmacological elicits beneficial effects for treatment, we tested natural compound 6-MSITC [6-(methylsulfinyl)hexyl isothiocyanate]. Administration impaired cognition task. These results demonstrate ameliorates cognitive suppressing neuroinflammation, suggesting important therapeutic target AD.

Language: Английский

Citations

139
Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer’s disease DOI
Hu Zeng, Jiahao Huang, Haowen Zhou

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 2, 2023

Language: Английский

Citations

114