Hydroxyl chalcone derivative DK02 as a multi‐target‐directed ligand for Alzheimer's disease: A preclinical study in zebrafish DOI

Balasubramanian Haridevamuthu,

Ankit Kumar Bharti, S.P. Ramya Ranjan Nayak

и другие.

British Journal of Pharmacology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 22, 2024

Background and Purpose Alzheimer's disease (AD) is a widespread neurodegenerative condition characterized by amyloid‐beta (Aβ) plaques tau protein aggregates, leading to significant cognitive decline. Existing treatments primarily offer symptomatic relief, underscoring the urgent need for novel therapies that address multiple AD pathways. This study evaluates efficacy of DK02, hydroxyl chalcone derivative, in scopolamine‐induced dementia model zebrafish, hypothesizing it targets several mechanisms simultaneously. Experimental Approach We employed blend experiments, including silico docking, vitro enzyme inhibition assays vivo zebrafish models, assess therapeutic effects DK02. Methods included molecular docking forecast interaction sites, acetylcholinesterase (AChE) testing, various behavioural histopathological analyses gauge DK02's neuroprotective impacts. Key Results DK02 emerged as potent AChE inhibitor via virtual screening, significantly enhanced functions improving memory retention reducing anxiety‐like behaviours. also displayed strong antioxidant properties, oxidative stress‐induced neuronal damage. Histopathological analysis confirmed its showing decreased amyloid plaque burden mitigated structural brain Conclusion Implications shows promise multi‐target‐directed ligand AD, offering new path simultaneously addressing cholinergic, Its potential enhance curtail neurodegeneration suggests advantages over current treatments. Further research into long‐term impacts essential development therapy.

Язык: Английский

SMOC1 colocalizes with Alzheimer’s disease neuropathology and delays Aβ aggregation DOI Creative Commons

Kaleah Balcomb,

Caitlin Johnston, Tomas Kavanagh

и другие.

Acta Neuropathologica, Год журнала: 2024, Номер 148(1)

Опубликована: Ноя. 25, 2024

Abstract SMOC1 has emerged as one of the most significant and consistent new biomarkers early Alzheimer’s disease (AD). Recent studies show that is earliest changing proteins in AD, with levels cerebrospinal fluid increasing many years before symptom onset. Despite this clear association disease, little known about role AD or its function brain. Therefore, aim study was to examine distribution human brain tissue determine if influenced amyloid beta (Aβ) aggregation. The assessed 3 regions (temporal cortex, hippocampus, frontal cortex) using immunohistochemistry a cohort 73 cases encompassing advanced mild cognitive impairment (MCI), preclinical cognitively normal controls. Aβ- phosphorylated tau-interaction control, MCI, co-immunoprecipitation, influence on Aβ aggregation kinetics Thioflavin-T assays electron microscopy. strongly colocalized subpopulation plaques (43.8 ± 2.4%), MCI (32.8 5.4%), (28.3 6.4%). correlated plaque load, irrespective stage. also tau aggregates (9.6 2.6%). Co-immunoprecipitation showed interacted tissue. significantly delayed dose-dependent manner, microscopy confirmed fibrils generated presence had an altered morphology. Overall, our results emphasize importance onset progression suggest may pathology development AD.

Язык: Английский

Процитировано

2
Sphingosine 1-phosphate receptor subtype 1 (S1P1) activity in the course of Alzheimer's disease DOI Creative Commons
Jonatan Martínez‐Gardeazabal, Gorka Pereira‐Castelo, Marta Moreno‐Rodríguez

и другие.

Neurobiology of Disease, Год журнала: 2024, Номер unknown, С. 106713 - 106713

Опубликована: Окт. 1, 2024

Язык: Английский

Процитировано

1
Evaluating Combined Neurotoxicity of Amyloid Beta and Tau Oligomers in Alzheimer's Disease: A New Criterion DOI Creative Commons
A. V. Kuznetsov

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 3, 2024

Abstract A criterion characterizing the combined neurotoxicity of amyloid beta and tau oligomers is suggested. mathematical model that makes it possible to calculate a value this during senile plaque NFT formation proposed. Computations show for physiologically relevant parameter values, increases approximately linearly as time increases. Once neurofibrillary tangles starts in addition formation, slope rate at which becomes larger. The critical upon reaching neuron dies estimated. predict unless production rates monomers are very large, order accumulated toxicity reach value, degradation machinery responsible must become dysfunctional. after 20 years aggregation process strongly influenced by deposition into plaques NFTs. This suggests NFTs may reduce sequestering more toxic oligomeric species less insoluble aggregates.

Язык: Английский

Процитировано

1
Identification of distinct and shared biomarker panels in different manifestations of cerebral small vessel disease through proteomic profiling DOI Creative Commons
Inès Hristovska, Alexa Pichet Binette, Atul Kumar

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 10, 2024

The pathophysiology underlying various manifestations of cerebral small vessel disease (cSVD) remains obscure. Using cerebrospinal fluid proximity extension assays and co-expression network analysis 2,943 proteins, we found common distinct proteomic signatures between white matter lesions (WML), microbleeds infarcts measured in 856 living patients, validated WML-associated proteins three additional datasets. Proteins indicative extracellular matrix dysregulation vascular remodeling, including ELN, POSTN, CCN2 MMP12 were elevated across all cSVD manifestations, with emerging as an early indicator. cSVD-associated formed a co-abundance linked to metabolism enriched endothelial arterial smooth muscle cells, showing levels at manifestations. Later stages involved changes microglial associated longitudinal WML progression, neuronal mediating cognitive decline. These findings provide atlas novel biomarkers promising roadmap for the next generation therapeutics.

Язык: Английский

Процитировано

0
SMOC1 colocalizes with Alzheimer’s disease neuropathology and delays Aβ aggregation DOI Creative Commons

Kaleah Balcomb,

Caitlin Johnston, Tomas Kavanagh

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Abstract SMOC1 has emerged as one of the most significant and consistent new biomarkers early Alzheimer’s disease (AD). Recent studies show that is earliest changing proteins in AD, with levels cerebrospinal fluid increasing many years before symptom onset. Despite this clear association disease, little known about role AD or its function brain. Therefore, aim study was to examine distribution human brain tissue determine if influenced amyloid beta (Aβ) aggregation. The assessed 3 regions (temporal cortex, hippocampus, frontal cortex) using immunohistochemistry a cohort 73 cases encompassing advanced mild cognitive impairment (MCI), preclinical cognitively normal controls. Aβ- phosphorylated tau-interaction control, MCI co-immunoprecipitation, influence on Aβ aggregation kinetics Thioflavin T assays electron microscopy. strongly colocalized subpopulation plaques (43.8±2.4%), (32.8±5.4%) (28.3±6.4%). correlated plaque load, irrespective stage. also tau aggregates (9.6±2.6%). Co-immunoprecipitation showed interacted tissue. significantly delayed dose-dependent manner, microscopy confirmed fibrils generated presence had an altered morphology. Overall, our results emphasize importance onset progression suggest may pathology development AD.

Язык: Английский

Процитировано

0
Hydroxyl chalcone derivative DK02 as a multi‐target‐directed ligand for Alzheimer's disease: A preclinical study in zebrafish DOI

Balasubramanian Haridevamuthu,

Ankit Kumar Bharti, S.P. Ramya Ranjan Nayak

и другие.

British Journal of Pharmacology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 22, 2024

Background and Purpose Alzheimer's disease (AD) is a widespread neurodegenerative condition characterized by amyloid‐beta (Aβ) plaques tau protein aggregates, leading to significant cognitive decline. Existing treatments primarily offer symptomatic relief, underscoring the urgent need for novel therapies that address multiple AD pathways. This study evaluates efficacy of DK02, hydroxyl chalcone derivative, in scopolamine‐induced dementia model zebrafish, hypothesizing it targets several mechanisms simultaneously. Experimental Approach We employed blend experiments, including silico docking, vitro enzyme inhibition assays vivo zebrafish models, assess therapeutic effects DK02. Methods included molecular docking forecast interaction sites, acetylcholinesterase (AChE) testing, various behavioural histopathological analyses gauge DK02's neuroprotective impacts. Key Results DK02 emerged as potent AChE inhibitor via virtual screening, significantly enhanced functions improving memory retention reducing anxiety‐like behaviours. also displayed strong antioxidant properties, oxidative stress‐induced neuronal damage. Histopathological analysis confirmed its showing decreased amyloid plaque burden mitigated structural brain Conclusion Implications shows promise multi‐target‐directed ligand AD, offering new path simultaneously addressing cholinergic, Its potential enhance curtail neurodegeneration suggests advantages over current treatments. Further research into long‐term impacts essential development therapy.

Язык: Английский

Процитировано

0