TGR5 deficiency in excitatory neurons ameliorates Alzheimer’s pathology by regulating APP processing DOI Creative Commons
Chenli Li, Liangjie Wang,

Wenting Xie

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(26)

Published: June 28, 2024

Bile acids (BAs) metabolism has a significant impact on the pathogenesis of Alzheimer’s disease (AD). We found that deoxycholic acid (DCA) increased in brains AD mice at an early stage. The enhanced production DCA induces up-regulation bile receptor Takeda G protein-coupled (TGR5), which is also specifically neurons mouse accumulation exogenous impairs cognitive function wild-type mice, but not TGR5 knockout mice. This suggests primary mediating these effects DCA. Furthermore, excitatory neuron-specific ameliorates Aβ pathology and cognition impairments underlying mechanism linking relies downstream effectors APP production, succinctly concluded as “p-STAT3–APH1–γ-secretase” signaling pathway. Our studies identified critical role pathological development AD.

Language: Английский

Genetic and multi‐omic risk assessment of Alzheimer's disease implicates core associated biological domains DOI Creative Commons
Gregory A. Cary, Jesse C. Wiley, Jake Gockley

et al.

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2024, Volume and Issue: 10(2)

Published: April 1, 2024

Abstract INTRODUCTION Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence mixed pathologies, potential subtypes, numerous associated endophenotypes. Beyond difficulty designing treatments that address core pathological characteristics disease, therapeutic development challenged by uncertainty which endophenotypic areas specific targets implicated those endophenotypes to prioritize for further translational research. However, publicly funded consortia driving large‐scale open science efforts have produced multiple omic analyses both risk relevance biological process involvement genes across genome. METHODS Here we report an informatic pipeline draws from genetic association studies, predicted variant impact, linkage phenotypes create a score. This paired multi‐omic score utilizing extensive sets transcriptomic proteomic studies identify system‐level changes in expression AD. These two elements combined constitute our target ranks AD genome‐wide. The ranked are organized into space through 19 domains described genetics genomics accompanying literature. constructed exhaustive Gene Ontology (GO) term compilations, allowing automated assignment objectively defined disease‐associated biology. rank‐and‐organize approach, performed genome‐wide, allows characterization aggregations domains. RESULTS top AD‐risk‐associated Synapse, Immune Response, Lipid Metabolism, Mitochondrial Structural Stabilization, Proteostasis, slightly lower levels enrichment present within other 13 DISCUSSION provides objective methodology localize drill down most significantly GO terms annotated targets.

Language: Английский

Citations

12
Recent Advances in Targeting Transition Metals (Copper, Iron, and Zinc) in Alzheimer’s Disease DOI

Raghuraj Singh,

Archna Panghal,

Krishna Jadhav

et al.

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(12), P. 10916 - 10940

Published: May 29, 2024

Language: Английский

Citations

10
Modulation of Oxidative Stress and Neuroinflammation by Cannabidiol (CBD): Promising Targets for the Treatment of Alzheimer’s Disease DOI Creative Commons
Jordan P. Hickey, Andrila E. Collins,

Mackayla L. Nelson

et al.

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(5), P. 4379 - 4402

Published: May 6, 2024

Alzheimer’s disease (AD) is a progressive neurodegenerative and the most common form of dementia globally. Although direct cause AD remains under debate, neuroinflammation oxidative stress are critical components in its pathogenesis progression. As result, compounds like cannabidiol (CBD) being increasingly investigated for their ability to provide antioxidant anti-inflammatory neuroprotection. CBD primary non-psychotropic phytocannabinoid derived from Cannabis sativa. It has been found beneficial outcomes variety medical conditions gaining increasing attention potential therapeutic application AD. not psychoactive lipophilic nature allows rapid distribution throughout body, including across blood–brain barrier (BBB). also possesses anti-inflammatory, antioxidant, neuroprotective properties, making it viable candidate treatment. This review outlines CBD’s mechanism action, role AD, effectiveness limitations preclinical models

Language: Английский

Citations

9
Strategies for modeling aging and age-related diseases DOI Creative Commons

D. Jothi,

Linda Anna Michelle Kulka

npj Aging, Journal Year: 2024, Volume and Issue: 10(1)

Published: July 10, 2024

Abstract The ability to reprogram patient-derived-somatic cells IPSCs (Induced Pluripotent Stem Cells) has led a better understanding of aging and age-related diseases like Parkinson’s, Alzheimer’s. established patient-derived disease models mimic pathology can be used design drugs for diseases. However, the age genetic mutations donor cells, employed reprogramming, differentiation protocol might often pose challenges in establishing an appropriate model. In this review, we will focus on various strategies successful reprogramming diseases, emphasizing accuracy recapitulation ways overcome limitations its potential application cell replacement therapy drug development.

Language: Английский

Citations

8
The Effect of APOE ε4 on Alzheimer's Disease Fluid Biomarkers: A Cross‐Sectional Study Based on the COAST DOI Creative Commons

Bote Zhao,

Peixi Zang,

Meina Quan

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(1)

Published: Jan. 1, 2025

ABSTRACT Aims To analyze the effect of APOE ε 4 on fluid biomarkers and correlations between blood molecules CSF in AD patients. Methods This study enrolled 575 patients, 131 patients with non‐AD dementia, 112 cognitively normal (CN) participants, were divided into carriers non‐carriers. Cerebrospinal (CSF) blood‐derived biomolecules compared CN groups, dementia as well within subgroups Utilizing Spearman's correlation analysis quantile regression analysis, relationships analyzed Results The levels exhibited significant differences including Aβ42, t‐tau, p‐tau 181, high‐density lipoprotein, low‐density lipoprotein (LDL), uric acid. In had increased plasma LDL. analyses, negative TG 181 levels, positive relationship serum IgA observed significantly 4+ but not 4− group. Conclusion is associated accelerated progression pathology. correlated are related to neuroinflammation lipid metabolism, which may indicate role pathophysiology offer insights for diagnostic therapeutic strategies AD. Trial Registration ClinicalTrials.gov identifier: NCT03653156

Language: Английский

Citations

1
Neuronal CD59 isoforms IRIS-1 and IRIS-2 as regulators of neurotransmitter release with implications for Alzheimer’s disease DOI Creative Commons

Ewelina Golec,

Robin Olsson, Emre Can Tüysüz

et al.

Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 7, 2025

Abstract We have previously demonstrated that the intracellular, non-GPI anchored CD59 isoforms IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 2) are necessary for insulin secretion from pancreatic β-cells. While investigating their expression across human tissues, we identified mRNA in brain, though protein function remained unclear. This study shows presence of both 2 proteins specifically neurons astrocytes. In neuroblastoma cell line (SH-SY5Y), increases upon differentiation into mature neurons. Silencing SH-SY5Y cells reduces SNARE complex formation, essential synaptic vesicle exocytosis, leading to a reduction noradrenaline secretion. Notably, observed diminished neuronal patients with Alzheimer’s disease (AD) non-demented individuals type diabetes (T2D). cells, knockdown all including not only elevates phosphorylated tau but also cyclin-dependent kinase 5 (CDK5) expression, known promoter hyperphosphorylation accumulation tau, key pathological feature AD. Additionally, found prolonged exposure high glucose or cytokines markedly suggesting link between AD pathology metabolic stress through modulation these isoforms.

Language: Английский

Citations

1
AdipoRon’s Impact on Alzheimer’s Disease—A Systematic Review and Meta-Analysis DOI Open Access
Sandra Maria Barbalho, Lucas Fornari Laurindo,

Bárbara de Oliveira Zanuso

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 484 - 484

Published: Jan. 8, 2025

Alzheimer's disease (AD) remains a leading cause of cognitive decline and mortality worldwide, characterized by neurodegeneration, synaptic deficiencies, neuroinflammation. Despite advancements in early detection, diagnosis, treatment, AD presents substantial challenges due to its complex pathology, heterogeneity, the limited efficacy current therapies. Consequently, there is pressing need for novel therapeutic agents target multifaceted aspects enhance treatments, minimize adverse effects. AdipoRon, an adiponectin receptor agonist, has garnered interest potential neuroprotective effects, including reducing neuroinflammation, improving mitochondrial function, mitigating tau hyperphosphorylation. This review aimed evaluate effects AdipoRon-based replacement therapy against AD, using comprehensive approach grounded PICO framework-Population, Intervention, Comparison, Outcomes. A total six studies were reviewed, vitro vivo investigations examining AdipoRon's impact on various models. These involved different cell lines transgenic mouse models, assessing outcomes such as phosphorylation, relevant molecular pathways. By synthesizing data from these studies, our thoroughly explains mechanisms action, agent AD. analysis aims highlight state knowledge, identify gaps research, suggest directions future clinical applications.

Language: Английский

Citations

1
Exploring the Role of GLP-1 Receptor Agonists in Alzheimer’s Disease: A Review of Preclinical and Clinical Evidence DOI Creative Commons
Lívia Cristina Ribeiro Teixeira, Marcelo R. Luizon, Karina Braga Gomes

et al.

Receptors, Journal Year: 2025, Volume and Issue: 4(1), P. 2 - 2

Published: Jan. 26, 2025

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including dulaglutide, liraglutide, semaglutide, and exenatide, are effective treatments for type 2 diabetes mellitus (T2DM) obesity. These agents mimic the action of endogenous incretin glucagon-like (GLP-1) by enhancing insulin secretion, inhibiting glucagon release, promoting weight loss through appetite suppression. GLP-1RAs have recently been suggested to neuroprotective effects, suggesting their potential as treatment neurodegenerative disorders, such Alzheimer’s disease (AD). AD T2DM share several common pathophysiological mechanisms, resistance, chronic inflammation, oxidative stress, mitochondrial dysfunction. shared mechanisms suggest that therapeutic targeting metabolic dysfunction may also be beneficial conditions. Preclinical studies on in models, both vitro vivo, demonstrated promising reductions amyloid-beta accumulation, decreased tau hyperphosphorylation, improved synaptic plasticity, enhanced neuronal survival. Despite encouraging results from preclinical challenges need addressed before can widely used treatment. Ongoing clinical trials investigating cognitive benefits patients, aiming establish role a option AD. This review aimed examine current literature GLP-1

Language: Английский

Citations

1
Oxidative Stress as a Potential Mechanism Underlying Membrane Hyperexcitability in Neurodegenerative Diseases DOI Creative Commons
Ricardo Pardillo-Díaz, Patricia Pérez-García, Carmen Castro

et al.

Antioxidants, Journal Year: 2022, Volume and Issue: 11(8), P. 1511 - 1511

Published: Aug. 2, 2022

Neurodegenerative diseases are characterized by gradually progressive, selective loss of anatomically or physiologically related neuronal systems that produce brain damage from which there is no recovery. Despite the differences in clinical manifestations and vulnerability, pathological processes appear to be similar, suggesting common neurodegenerative pathways. It well known oxidative stress production reactive oxygen radicals plays a key role cell damage. has been proposed this stress, among other mechanisms, could contribute degeneration might one factors triggering development these pathologies. Another feature most neuron hyperexcitability, an aberrant electrical activity. This review, focusing mainly on primary motor cortex pyramidal neurons, critically evaluates idea inflammation may involved neurodegeneration via their capacity increase membrane excitability.

Language: Английский

Citations

31
Role of SUMOylation in Neurodegenerative Diseases DOI Creative Commons

Nicolas Mandel,

Nitin Agarwal

Cells, Journal Year: 2022, Volume and Issue: 11(21), P. 3395 - 3395

Published: Oct. 27, 2022

Neurodegenerative diseases (NDDs) are irreversible, progressive with no effective treatment. The hallmark of NDDs is the aggregation misfolded, modified proteins, which impair neuronal vulnerability and cause brain damage. loss synaptic connection neurons result in cognitive defects. Several dysregulated proteins overlapping molecular mechanisms contribute to pathophysiology NDDs. Post-translational modifications (PTMs) essential regulators protein function, trafficking, maintaining hemostasis. conjugation a small ubiquitin-like modifier (SUMO) reversible, dynamic PTM required for function. onset progression neurodegenerative associated aberrant SUMOylation. In this review, we have summarized role SUMOylation regulating critical involved several

Language: Английский

Citations

30