GSK-3β, a pivotal kinase in Alzheimer disease

Frontiers in Molecular Neuroscience, Journal Year: 2014, Volume and Issue: 7

Published: May 21, 2014

Alzheimer disease (AD) is the most common form of age-related dementia. The etiology AD considered to be multifactorial as only a negligible percentage cases have familial or genetic origin. Glycogen synthase kinase-3 (GSK-3) regarded critical molecular link between two histopathological hallmarks disease, namely senile plaques and neurofibrillary tangles. In this review, we summarize current data regarding involvement kinase in several aspects development progression, well key observations highlighting GSK-3 one relevant targets for treatment.

Language: Английский

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Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: June 30, 2023

Abstract Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as molecular driver pathogenesis progression. Aβ prime target for development AD therapy. However, repeated failures Aβ-targeted clinical trials have cast considerable doubt on amyloid cascade hypothesis whether drug followed correct course. recent successes targeted assuaged those doubts. In this review, we discussed evolution over last 30 years summarized application diagnosis modification. particular, extensively pitfalls, promises important unanswered questions regarding current anti-Aβ therapy, well strategies further study more feasible approaches optimization prevention treatment.

Language: Английский

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Common pathological processes in Alzheimer disease and type 2 diabetes: A review

Brain Research Reviews, Journal Year: 2007, Volume and Issue: 56(2), P. 384 - 402

Published: Sept. 12, 2007

Language: Английский

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GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Frontiers in Molecular Neuroscience, Journal Year: 2011, Volume and Issue: 4

Published: Jan. 1, 2011

Inhibiting glycogen synthase kinase-3 (GSK-3) activity via pharmacological intervention has become an important strategy for treating neurodegenerative and psychiatric disorders. The known GSK-3 inhibitors are of diverse chemotypes mechanisms action include compounds isolated from natural sources, cations, synthetic small-molecule ATP-competitive inhibitors, non-ATP-competitive substrate-competitive inhibitors. Here we describe the variety with a specific emphasis on their biological activities in neurons neurological We further highlight our current progress development GSK-3. available data raise hope that one or more these drug design approaches will prove successful at stabilizing even reversing aberrant neuropathology cognitive deficits certain central nervous system

Language: Английский

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Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set

Physiological Genomics, Journal Year: 2008, Volume and Issue: 33(2), P. 240 - 256

Published: Feb. 13, 2008

Alzheimer's Disease (AD) is the most widespread form of dementia during later stages life. If improved therapeutics are not developed, prevalence AD will drastically increase in coming years as world's population ages. By identifying differences neuronal gene expression profiles between healthy elderly persons and individuals diagnosed with AD, we may be able to better understand molecular mechanisms that drive pathogenesis, including formation amyloid plaques neurofibrillary tangles. In this study, profiled histopathologically normal cortical neurons collected laser capture microdissection (LCM) from six anatomically functionally discrete postmortem brain regions 34 AD-afflicted individuals, using Affymetrix Human Genome U133 Plus 2.0 microarrays. These include entorhinal cortex, hippocampus, middle temporal gyrus, posterior cingulate superior frontal primary visual cortex. This study predicated on previous parallel research brains same 14 for which LCM were similarly processed analysis. We identified significant regional differential compared control changes genes previously implicated particularly regard tangle plaque formation. Pinpointing factors play a role pathogenesis provides foundation future identification new targets therapeutics. provide carefully phenotyped, microdissected intraindividual region data set community public resource.

Language: Английский

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Protein phosphatase 2A dysfunction in Alzheimer’s disease

Frontiers in Molecular Neuroscience, Journal Year: 2014, Volume and Issue: 7

Published: March 11, 2014

Protein Phosphatase 2A (PP2A) is a large family of enzymes that account for the majority brain Ser/Thr phosphatase activity. While PP2A collectively modulate most cellular processes, sophisticated regulatory mechanisms are ultimately responsible ensuring isoform-specific substrate specificity. Of particular interest to Alzheimer’s disease (AD) field, alterations in regulators and catalytic activity, subunit expression, methylation and/or phosphorylation, have been reported AD-affected regions. “PP2A” dysfunction has linked Tau hyperphosphorylation, amyloidogenesis synaptic deficits pathological hallmarks this neurodegenerative disorder. Deregulation also affects activity many protein kinases implicated AD. This review will more specifically discuss role PP2A/B holoenzyme AD pathogenesis. The isoform binds tau primary phosphatase. Its deregulation correlates with increased phosphorylation vivo Disruption PP2A/B-Tau interactions likely contribute Significantly, one-carbon metabolism impair associated risk sporadic AD, enhanced AD-like pathology animal models. Experimental studies down-regulation PP2A/B, amyloid precursor protein, mislocalization, microtubule destabilization neuritic defects. it remains unclear what events underlie definitely key players pathogenic process. As such, there growing developing PP2A-centric therapies but may be daunting task without better understanding regulation function specific enzymes.

Language: Английский

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Physiological and pathological phosphorylation of tau by Cdk5

Frontiers in Molecular Neuroscience, Journal Year: 2014, Volume and Issue: 7

Published: July 15, 2014

Hyperphosphorylation of microtubule-associated protein tau is one the major pathological events in Alzheimer's disease (AD) and other related neurodegenerative diseases, including Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Mutations gene MAPT are a cause FTDP-17, mutated proteins hyperphosphorylated patient brains. Thus, it important determine molecular mechanism hyperphosphorylation understand pathology these diseases collectively called tauopathy. Tau phosphorylated at many sites via several kinases, characteristic phosphorylation Ser/Thr residues Ser/Thr-Pro sequences, which targeted by proline-directed kinases such as ERK, GSK3β Cdk5. Among Cdk5 particularly interesting because could be abnormally activated AD. member cyclin-dependent (Cdks), but contrast Cdks, promote cell cycle progression proliferating cells, post-mitotic neurons neuron-specific activator p35. Cdk5-p35 plays critical role brain development physiological synaptic activity. In contrast, brains, thought hyperactivated p25, N-terminal truncated form p35 generated cleavage calpain. Several reports have indicated that Cdk5-p25. However, normal abnormal still not completely understood. this article, we summarise

Language: Английский

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Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer’s Disease

BioMed Research International, Journal Year: 2016, Volume and Issue: 2016, P. 1 - 15

Published: Jan. 1, 2016

The failure of several Phase II/III clinical trials in Alzheimer’s disease (AD) with drugs targeting β -amyloid accumulation the brain fuelled an increasing interest alternative treatments against tau pathology, including approaches phosphatases/kinases, active and passive immunization, anti-tau aggregation. most advanced aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing equilibrium between reduced (leuco-methylthioninium) oxidized form (MT + ). MT chloride (methylene blue) was investigated 24-week II trial 321 patients mild to moderate AD that failed show significant positive effects patients, although long-term observations (50 weeks) biomarker studies suggested possible benefit. dose 138 mg/day showed potential benefits on cognitive performance moderately affected cerebral blood flow mildly patients. Further evidence will come from large ongoing III for treatment behavioral variant frontotemporal dementia new this TAI, more bioavailable less toxic at higher doses, called TRx0237. More recently, inhibitors acetylation are being actively pursued based impressive results animal obtained by salsalate, clinically used derivative salicylic acid.

Language: Английский

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Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease

Nature Aging, Journal Year: 2021, Volume and Issue: 1(12), P. 1175 - 1188

Published: Dec. 6, 2021

Language: Английский

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Brain-targeted Tet-1 peptide-PLGA nanoparticles for berberine delivery against STZ-induced Alzheimer’s disease in a rat model: Alleviation of hippocampal synaptic dysfunction, Tau pathology, and amyloidogenesis

International Journal of Pharmaceutics, Journal Year: 2024, Volume and Issue: 658, P. 124218 - 124218

Published: May 9, 2024

Language: Английский

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