Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease Model DOI Open Access
Qian Shi, Cheng Chang,

Afaf Saliba

et al.

Journal of Neuroscience, Journal Year: 2022, Volume and Issue: 42(27), P. 5294 - 5313

Published: June 7, 2022

The mechanistic target of rapamycin (mTOR) signaling pathway plays a major role in key cellular processes including metabolism and differentiation; however, the mTOR microglia its importance Alzheimer9s disease (AD) have remained largely uncharacterized. We report that selective loss Tsc1, negative regulator mTOR, mice both sexes, caused activation upregulation Trem2 with enhanced β-Amyloid (Aβ) clearance, reduced spine loss, improved cognitive function 5XFAD AD mouse model. Combined Tsc1 Trem2 led to Aβ clearance increased plaque burden revealing functions downstream mTOR. mutant showed phagocytosis CD68 Lamp1 lysosomal proteins. In vitro studies using Tsc1-deficient revealed endocytosis tracker indicator Green DND-26 suggesting activity. Incubation fluorescent-labeled uptake which was blunted by rapamycin, an inhibitor. vivo treatment relevant genotypes background affected microglial activity, decreased expression causing increase burden. Prolonged even further reduction expression, levels. Together, our findings reveal is critically linked regulation biogenesis, through could be exploited toward better therapeutic avenues Aβ-related pathologies. SIGNIFICANCE STATEMENT Mechanistic for metabolic processes. However, link between not well understood. In this study, we provide compelling in evidence would benefit (Aβ)-related pathologies, as it upregulates Trem2, receptor uptake. Inhibition well-established immunosuppressant, downregulated indicating inactivation may detrimental Aβ-associated patients. This finding will significant public health impact benefit, regarding usage patients, believe aggravate

Language: Английский

Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies DOI Creative Commons
Jifa Zhang, Yinglu Zhang, Jiaxing Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

Citations

135
Mouse Models of Alzheimer’s Disease DOI Creative Commons
Miyabishara Yokoyama,

Honoka Kobayashi,

Lisa Tatsumi

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: June 21, 2022

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, eventually leading to dementia. The pathological hallmarks of AD are senile plaques neurofibrillary tangles, which comprise abnormally aggregated β-amyloid peptide (Aβ) hyperphosphorylated tau protein. To develop preventive, diagnostic, therapeutic strategies for AD, it essential establish animal models that recapitulate the pathophysiological process AD. In this review, we will summarize advantages limitations various mouse including transgenic, knock-in, injection based on Aβ tau. We also discuss other neuroinflammation because recent genetic studies have suggested microglia crucial in pathogenesis Although each model has its disadvantages, further research pathobiology lead establishment more accurate models, accelerate development innovative therapeutics.

Language: Английский

Citations

133
Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques DOI Creative Commons
Ethan R. Roy,

Gabriel S. Chiu,

Sanming Li

et al.

Immunity, Journal Year: 2022, Volume and Issue: 55(5), P. 879 - 894.e6

Published: April 19, 2022

Language: Английский

Citations

131
Extracellular vesicles mediate the communication of adipose tissue with brain and promote cognitive impairment associated with insulin resistance DOI Creative Commons
Jin Wang, Liang Li, Zhou Zhang

et al.

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(9), P. 1264 - 1279.e8

Published: Sept. 1, 2022

Language: Английский

Citations

130
iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders DOI Creative Commons
Hideyuki Okano, Satoru Morimoto

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(2), P. 189 - 208

Published: Feb. 1, 2022

Language: Английский

Citations

121
Clinical diagnostic utility of transcranial magnetic stimulation in neurological disorders. Updated report of an IFCN committee DOI Creative Commons
Steve Vucic, Kai-Hsiang Chen, Matthew C. Kiernan

et al.

Clinical Neurophysiology, Journal Year: 2023, Volume and Issue: 150, P. 131 - 175

Published: March 30, 2023

The review provides a comprehensive update (previous report: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. clinical diagnostic utility of transcranial magnetic stimulation: report an IFCN committee. Clin Neurophysiol 2008;119(3):504-32) on stimulation (TMS) in neurological diseases. Most TMS measures rely motor cortex and recording evoked potentials. Paired-pulse techniques, incorporating conventional amplitude-based threshold tracking, have established neurodegenerative, movement, episodic (epilepsy, migraines), chronic pain functional Cortical hyperexcitability has emerged as aid amyotrophic lateral sclerosis. Single-pulse are stroke, myelopathy even the absence radiological changes. Short-latency afferent inhibition, related to central cholinergic transmission, is reduced Alzheimer's disease. triple technique (TST) may enhance detect upper neuron involvement. potentials can be used perform mapping or preoperative assessment eloquent brain regions before surgical resection tumors. exhibits assessing lumbosacral/cervical nerve root function, especially demyelinating neuropathies, localizing site facial palsies. also high sensitivity detecting subclinical corticospinal lesions multiple Abnormalities conduction time TST correlate with impairment disability MS. Cerebellar cerebellum cerebello-dentato-thalamo-motor cortical pathways. Combining electroencephalography, novel method measure parameters altered disorders, including excitability, effective connectivity, response complexity.

Language: Английский

Citations

110
The amyloid plaque proteome in early onset Alzheimer’s disease and Down syndrome DOI Creative Commons
Eleanor Drummond, Tomas Kavanagh, Geoffrey Pires

et al.

Acta Neuropathologica Communications, Journal Year: 2022, Volume and Issue: 10(1)

Published: April 13, 2022

Amyloid plaques contain many proteins in addition to beta amyloid (Aβ). Previous studies examining plaque-associated have shown these additional are important; they provide insight into the factors that drive plaque development and potential biomarkers or therapeutic targets for Alzheimer's disease (AD). The aim of this study was comprehensively identify enriched using unbiased proteomics two subtypes early onset AD: sporadic AD (EOAD) Down Syndrome (DS) with AD. We focused our on as drivers more aggressive pathology cases is unknown it unclear whether amyloid-plaque differ between neighbouring non-plaque tissue were microdissected from human brain sections laser capture microdissection label-free LC-MS used quantify present. 48 consistently EOAD DS. Many significantly than Aβ. most both DS were: COL25A1, SMOC1, MDK, NTN1, OLFML3 HTRA1. Endosomal/lysosomal particularly highly plaques. Fluorescent immunohistochemistry validate enrichment four (moesin, ezrin, ARL8B SMOC1) compare amount total Aβ, Aβ40, Aβ42, phosphorylated pyroglutamate Aβ species oligomeric These showed SMOC1 higher plaques, while oligomers EOAD. Overall, we observed largely contained same proteins, however some different Our highlights significant which may be and/or

Language: Английский

Citations

105
Properties of Poly (Lactic-co-Glycolic Acid) and Progress of Poly (Lactic-co-Glycolic Acid)-Based Biodegradable Materials in Biomedical Research DOI Creative Commons
Yue Lü, Dongfang Cheng, Ben Niu

et al.

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(3), P. 454 - 454

Published: March 17, 2023

In recent years, biodegradable polymers have gained the attention of many researchers for their promising applications, especially in drug delivery, due to good biocompatibility and designable degradation time. Poly (lactic-co-glycolic acid) (PLGA) is a functional polymer made from polymerization lactic acid (LA) glycolic (GA) widely used pharmaceuticals medical engineering materials because its biocompatibility, non-toxicity, plasticity. The aim this review illustrate progress research on PLGA biomedical as well shortcomings, provide some assistance future development.

Language: Английский

Citations

99
Lecanemab: First Approval DOI

Sheridan M. Hoy

Drugs, Journal Year: 2023, Volume and Issue: 83(4), P. 359 - 365

Published: March 1, 2023

Language: Английский

Citations

88
Mild cognitive impairment among rural‐dwelling older adults in China: A community‐based study DOI Creative Commons
Lin Cong, Yifei Ren, Yongxiang Wang

et al.

Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 19(1), P. 56 - 66

Published: March 9, 2022

Epidemiological studies of mild cognitive impairment (MCI) and subtypes MCI have rarely focused on rural residents in China.This population-based study included 5068 participants (age ≥60 years) who were living communities. We defined MCI, amnestic (aMCI), non-amnestic (naMCI) following the Petersen's criteria that integrated neuropsychological assessments with in-person clinical evaluations.The overall prevalence aMCI, naMCI was 26.48%, 22.30%, 4.18%, respectively. The increased age. adjusted odds ratio (OR) 0.71 (95% confidence interval [CI] 0.61 to 0.82) for primary school (vs. illiteracy), 0.30 (0.24 0.39) middle or above, 1.35 (1.09 1.67) being farmers, 0.65 (0.54 0.78) alcohol consumption, 1.43 (1.20 1.70) stroke history, 1.14 (0.95 1.36) any apolipoprotein E (APOE) ε4 allele (vs ε3/ε3).MCI affects over one-fourth older adults China. Overall associated demographic factors, non-alcohol stroke, but not APOE genotype cardiometabolic factors.

Language: Английский

Citations

84