International Journal of Neuroscience, Год журнала: 2023, Номер 134(12), С. 1663 - 1673
Опубликована: Дек. 15, 2023
Background Diabetes-associated cognitive dysfunction (DACD) is a chronic ailment that exerts substantial influence on the overall well-being of individuals. The hippocampus assumes pivotal role in progression and sustenance impairment. identification differentially expressed proteins (DEPs) crucial for understanding mechanisms DACD.
Язык: Английский
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Фев. 17, 2025
Abstract Despite recent approval of monoclonal antibodies that reduce amyloid (Aβ) accumulation, the development disease-modifying strategies targeting underlying mechanisms Alzheimer’s disease (AD) is urgently needed. We demonstrate mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signaling, benefiting AD mouse models with Aβ and p-Tau pathologies. Rational design structure‒activity relationship studies yielded novel mtCI inhibitors profiled in drug discovery funnel designed to address their safety, selectivity, efficacy. The new lead compound C458 highly protective against toxicity, has favorable pharmacokinetics, minimal off-target effects. exhibited excellent brain penetrance, activating pathways single dose. Preclinical APP/PS1 mice were conducted via functional tests, metabolic assessment, vivo 31 P- NMR spectroscopy, blood cytokine panels, ex electrophysiology, Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress inflammation, enhanced biogenesis, antioxidant cellular energetics. These provide further evidence restoration function energetics response mild energetic promising disease- modifying strategy for AD.
Язык: Английский
Процитировано
0
Cell Death and Differentiation, Год журнала: 2025, Номер unknown
Опубликована: Фев. 27, 2025
Язык: Английский
Процитировано
0
Scientific Reports, Год журнала: 2025, Номер 15(1)
Опубликована: Фев. 23, 2025
Loss of synaptic activity correlates best with cognitive dysfunction in Alzheimer's disease (AD). We have previously shown that mild inhibition mitochondrial complex I the small molecule tricyclic pyrone compound CP2 restores long-term potentiation and function assessed by electrophysiology behavior tests multiple mouse models AD. Using serial block-face scanning electron microscopy three-dimensional reconstruction, we examined effect treatment on synapses, distribution morphology mitochondria hippocampus APP/PS1 mice. Structural data confirmed loss synapses compared to non-transgenic (NTG) littermates. Mitochondrial pre- postsynaptic compartments was significantly altered AD model demonstrating increased presence around dendritic spines NTG mice, indicating ability support function. restored number control levels. Improved CP2-treated mice supported RNA-seq analysis upregulation genes involved axonal guidance, maturation function, Western blot brain tissue. Taken together, functional, imaging, biochemistry structural findings further potential targeting as a therapeutic approach for
Язык: Английский
Процитировано
0
npj Drug Discovery., Год журнала: 2025, Номер 2(1)
Опубликована: Май 2, 2025
Abstract Despite substantial research and drug discovery efforts, Alzheimer’s Disease (AD) remains the sixth leading cause of death in United States, underscoring urgent need for novel therapeutic targets. A mutation clusterin (CLU) gene that hinders expression cyto-protective secreted isoform (sCLU) affects aggregation clearance two key proteins implicated AD, Aβ tau, is third most significant genetic risk factor late-onset AD. Here, we present findings from our program to identify small molecules enhance sCLU levels assess their impact on AD pathology cognition a murine model high-throughput screening campaign identified classes epigenetic modulators increase with subsequent medicinal chemistry efforts bromodomain extra-terminal (BET) inhibitor new chemical entities (NCEs) enhanced potency, drug-like properties, oral brain bioavailability. The lead candidate NCE, DDL-357, increased ApoE4TR-5XFAD subchronic study. In follow-up chronic study 3xTg-AD model, DDL-357 reduced phospho-tau led improvements mouse performance memory Barnes maze testing paradigm. Proteomic analysis tissue both models revealed changes involved mitochondrial function synaptic plasticity. These reveal potential enhancement as target development support continued preclinical candidate.
Язык: Английский
Процитировано
0
Biomedicine & Pharmacotherapy, Год журнала: 2025, Номер 188, С. 118167 - 118167
Опубликована: Май 24, 2025
Язык: Английский
Процитировано
0
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Фев. 21, 2024
Abstract Mitochondrial dysfunction is well documented in Alzheimer’s Disease (AD). However, whether it instigates the onset of AD remains unclear. We demonstrate that a reduction complex I activity wild type (WT) mice caused by global knockout Ndufs4 , an accessory mitochondrial subunit, was sufficient to induce transcriptomic changes brain reminiscent those observed patients and familial mouse models AD. Reduced affected expression genes networks related homeostasis, neuronal synaptic function. Transcriptomic signatures male female -/- reflected different severity phenotype. Unexpectedly, these were partially rescued neuroprotective small molecule mild inhibitor CP2. Consistent with studies mice, CP2 treatment augmented associated biogenesis turnover, activity, autophagy, redox balance, reduced inflammation. Female demonstrated greater reversal gene toward WT mice. These provide further support for mitochondria as causative factor pathophysiology putative therapeutic target.
Язык: Английский
Процитировано
2
Frontiers in Aging Neuroscience, Год журнала: 2024, Номер 16
Опубликована: Дек. 18, 2024
Anxiety and depression-like symptoms occur in the early stages of Alzheimer's disease. Hippocampal Sirtuin 1 (SIRT1) signaling mediates anxiety- behavior. Exercise training improves anxiety behavior various disease models, such as rat chronic restraint stress model, model posttraumatic disorder, fetal alcohol spectrum disorders. Here, we aimed to investigate whether exercise ameliorates depression like behaviors APP/PS1 mice explore potential mechanisms.
Язык: Английский
Процитировано
1
Cells, Год журнала: 2024, Номер 13(9), С. 762 - 762
Опубликована: Апрель 29, 2024
The antipsychotic drug clozapine demonstrates superior efficacy in treatment-resistant schizophrenia, but its intracellular mode of action is not completely understood. Here, we analysed the effects (2.5–20 µM) on metabolic fluxes, cell respiration, and ATP human HL60 cells. Some results were confirmed leukocytes clozapine-treated patients. Neuroreceptor inhibition under reduced Akt activation with decreased glucose uptake, thereby inducing ER stress unfolded protein response (UPR). Metabolic profiling by liquid-chromatography/mass-spectrometry revealed downregulation glycolysis pentose phosphate pathway, saving to keep electron transport chain working. Mitochondrial respiration was dampened upregulation F0F1-ATPase inhibitory factor 1 (IF1) leading 30–40% lower oxygen consumption Blocking IF1 expression cotreatment epigallocatechin-3-gallate (EGCG) increased apoptosis Upregulation mitochondrial citrate carrier shifted excess cytosol for use lipogenesis storage as triacylglycerol lipid droplets (LDs). Accordingly, cells from patients contain more LDs than untreated Since disturbances are described pathophysiology clozapine-induced mitohormesis an excellent way escape energy deficits improve survival.
Язык: Английский
Процитировано
1
Brazilian Journal of Implantology and Health Sciences, Год журнала: 2023, Номер 5(5), С. 3239 - 3250
Опубликована: Ноя. 17, 2023
A abordagem terapêutica no tratamento do Alzheimer é um tema de elevada relevância na prática clínica contemporânea, dada a crescente incidência desta condição neurodegenerativa. Os recentes avanços neste campo têm introduzido uma variedade estratégias terapêuticas que não apenas visam aliviar os sintomas, mas também prometem substanciais melhorias qualidade vida dos pacientes acometidos por esta doença. O propósito deste estudo conduzir análise exaustiva e profunda das inovações terapêuticas, com o intuito alcançar entendimento minucioso cada intervenção avaliar sua viabilidade contexto clínico. Este processo envolveu busca criteriosa artigos científicos em bases dados devidamente indexadas. seleção referências pautou-se pela avaliação da pertinência atualidade, priorizando estudos exploraram eficácia diversas abordagens se destacaram pelo caráter inovador âmbito Alzheimer. organização seguiu as diretrizes estritas estilo Vancouver, garantindo, dessa forma, acurácia integridade revisão. No Alzheimer, destaca-se série intervenções cruciais demonstrado promissores avanços. Entre elas, merece destaque terapia icariina, destaca seu mecanismo ação nível molecular potencial impacto modulação microbioma intestinal. Além disso, significativos sido observados aplicação baseadas nanocarregadores para mitigação efeitos patológicos proteínas beta-amiloide tau doença Alzheimer. Esta revisão integrativa diversidade farmacológicas disponíveis enfatiza importância personalizada multidisciplinar. consideração particularidades clínicas características únicas paciente emerge como pilar essencial otimização resultados terapêuticos. vigilância constante segurança longo prazo apresenta responsabilidade inalienável cuidado desses pacientes.
Процитировано
1
International Journal of Neuroscience, Год журнала: 2023, Номер 134(12), С. 1663 - 1673
Опубликована: Дек. 15, 2023
Background Diabetes-associated cognitive dysfunction (DACD) is a chronic ailment that exerts substantial influence on the overall well-being of individuals. The hippocampus assumes pivotal role in progression and sustenance impairment. identification differentially expressed proteins (DEPs) crucial for understanding mechanisms DACD.
Язык: Английский
Процитировано
1