Solving neurodegeneration: common mechanisms and strategies for new treatments

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: March 21, 2022

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology site disease pathology. To address these and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus the Melza M. Frank Theodore Barr Foundation collaborated to bring together key opinion leaders experts field for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style focused uncovering mechanistic roots promising new catalyzed by goal finding treatments glaucoma, world's leading cause irreversible blindness interest three hosting foundations. Glaucoma, which causes vision loss through degeneration optic nerve, likely shares early cellular molecular events with other diseases central nervous system. Here we major areas overlap between system: neuroinflammation, bioenergetics metabolism, genetic contributions, neurovascular interactions. We summarize important discussion points emphasis research that are most innovative treatment neurodegeneration yet require further development. The is highlighted provides unique opportunities collaboration will lead efforts preventing ultimately loss.

Language: Английский

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Cognitive Aging and the Promise of Physical Activity

Annual Review of Clinical Psychology, Journal Year: 2022, Volume and Issue: 18(1), P. 417 - 442

Published: Jan. 19, 2022

Is the field of cognitive aging irretrievably concerned with decline and deficits, or is it shifting to emphasize hope preservation enhancement function in late life? A fragment an answer comes from research attempting understand reasons for individual variability extent rate decline. This body work has created a sense optimism based on evidence that there are some health behaviors amplify performance mitigate age-related In this context, we discuss role physical activity neurocognitive adulthood summarize how can be conceptualized as constructive approach both maintenance therapeutic enhancing optimizing life. way, used shape perceptions aging.

Language: Английский

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Inhibitory potential of nitrogen, oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase

RSC Advances, Journal Year: 2022, Volume and Issue: 12(31), P. 19764 - 19855

Published: Jan. 1, 2022

The present review focuses on various heterocyclic scaffolds and their role in designing developing new potential AChE BChE inhibitors to treat AD.

Language: Английский

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Pharmacological significance of nitrogen-containing five and six-membered heterocyclic scaffolds as potent cholinesterase inhibitors for drug discovery

Process Biochemistry, Journal Year: 2022, Volume and Issue: 120, P. 250 - 259

Published: June 11, 2022

Language: Английский

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Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer’s Disease and MCI: A Review

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1659 - 1659

Published: Jan. 14, 2023

Alzheimer's disease (AD) is a multifactorial, progressive, neurodegenerative typically characterized by memory loss, personality changes, and decline in overall cognitive function. Usually manifesting individuals over the age of 60, this most prevalent type dementia remains fifth leading cause death among Americans aged 65 older. While development effective treatment prevention for AD major healthcare goal, unfortunately, therapeutic approaches to date have yet find plan that produces long-term improvement. Drugs may be able slow down progression rate are being introduced market; however, there has been no previous solution preventing or reversing disease-associated decline. Recent studies identified several factors contribute severity disease: diet, lifestyle, stress, sleep, nutrient deficiencies, mental health, socialization, toxins. Thus, increasing evidence supports dietary other lifestyle changes as potentially ways prevent, slow, reverse progression. Studies also demonstrated personalized, multi-therapeutic approach needed improve metabolic abnormalities AD-associated These suggest effects abnormalities, such insulin resistance, chronic inflammation, hypovitaminosis D, hormonal hyperhomocysteinemia, process. Therefore program based on an individual's genetics biochemistry preferable single-drug/mono-therapeutic approach. This article reviews these strategies identify attenuate all risk specific each affected individual. systematically incorporated multiple target numerous simultaneously treat We included high-quality clinical trials observational focused programs comprising physical, activity, well nutritional aspects. Articles from PubMed Central, Scopus, Google Scholar databases were collected, abstracts reviewed relevance subject matter. Epidemiological, pathological, toxicological, genetic, biochemical concluded represents complex network insufficiency. The research explored manuscript confirm need multifactorial various AD. A single-drug delay loss but, date, not prevented reversed it. Diet, physical environment disease, and, therefore, multi-factorial optimization support function offers rational strategy. targets underlying more than mono-therapeutic

Language: Английский

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Aducanumab—Hope or Disappointment for Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4367 - 4367

Published: Feb. 22, 2023

In June 2021, the world was informed about a new drug for Alzheimer’s disease approved by FDA. Aducanumab (BIIB037, ADU), being monoclonal antibody IgG1, is newest AD treatment. The activity of targeted towards amyloid β, which considered one main causes disease. Clinical trials have revealed time- and dose-dependent Aβ reduction, as well cognition improvement. Biogen, company responsible conducting research introducing to market, presents solution cognitive impairment, but its limitations, costs, side effects are controversial. framework paper focuses on mechanism aducanumab’s action along with positive negative sides therapy. review basis hypothesis that cornerstone therapy, latest information aducanumab, action, possibility use drug.

Language: Английский

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Sex and gender differences in cognitive resilience to aging and Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5695 - 5719

Published: July 5, 2024

Abstract Sex and gender—biological social constructs—significantly impact the prevalence of protective risk factors, influencing burden Alzheimer's disease (AD; amyloid beta tau) other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding interplay these factors is central to understanding resilience resistance mechanisms explaining maintained function reduced pathology accumulation in aging AD. In this narrative review, ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach provide foundations recommendations for future research into sex‐ gender‐specific drivers resilience, including sex/gender‐oriented review genetics, AD non‐AD pathologies, brain structure function, animal research. We urge field adopt sex/gender‐aware advance our intricate biological determinants consider sex/gender‐specific throughout stages. Highlights differences decline vary by age status. Initial evidence supports sex‐specific distinctions pathology. Findings suggest sex on cognition. There change transition clinical Gender warrant study: modifiable, immune, inflammatory, vascular.

Language: Английский

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Mitochondrial complex I as a therapeutic target for Alzheimer's disease

Acta Pharmaceutica Sinica B, Journal Year: 2021, Volume and Issue: 12(2), P. 483 - 495

Published: Nov. 9, 2021

Alzheimer's disease (AD), the most prominent form of dementia in elderly, has no cure. Strategies focused on reduction amyloid beta or hyperphosphorylated Tau protein have largely failed clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that response to environmental stress, mitochondria initiate an integrated stress (ISR) shown be beneficial for healthy aging neuroprotection. Here, we review implicate mitochondrial electron transport complexes involved oxidative phosphorylation as a hub small molecule-targeted therapeutics could induce ISR. Specifically, partial inhibition complex I been exploited novel strategy multiple human conditions, including AD, with several molecules being tested We discuss current understanding molecular mechanisms this counterintuitive approach. Since also enhance health life span, development safe efficacious inhibitors promote aging, delaying onset age-related neurodegenerative diseases.

Language: Английский

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Alzheimer’s disease – the journey of a healthy brain into organ failure

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: March 5, 2022

As the most common dementia, Alzheimer's disease (AD) exacts an immense personal, societal, and economic toll. AD was first described at neuropathological level in early 1900s. Today, we have mechanistic insight into select aspects of pathogenesis ability to clinically detect diagnose underlying pathologies living patients. These insights demonstrate that is a complex, insidious, degenerative proteinopathy triggered by Aβ aggregate formation. Over time pathology drives neurofibrillary tangle (NFT) pathology, dysfunction virtually all cell types brain, ultimately, overt neurodegeneration. Yet, large gaps our knowledge pathophysiology huge unmet medical need remain. Though largely conceptualize as aging, heritable non-heritable factors impact brain physiology, either continuously or specific points during lifespan, thereby alter risk for devolvement AD. Herein, I describe lifelong journey healthy from birth death with AD, while acknowledging many remain regarding understanding pathogenesis. To ensure current lexicon surrounding changes inevitable, incurable, poorly manageable preventable, curable, must address these gaps, develop therapies bigger on clinical symptoms progression use interventions appropriate stage disease.

Language: Английский

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Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Nov. 23, 2022

Abstract Background Abnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases. Microglia play essential roles the clearance lipid-rich cellular debris upon myelin damage or demyelination, common pathogenic event neuronal disorders. Apolipoprotein E (apoE) plays pivotal role brain homeostasis; however, apoE isoform-dependent mechanisms regulating microglial response demyelination remain unclear. Methods To determine how isoforms impact damage, 2-month-old apoE2-, apoE3-, and apoE4-targeted replacement (TR) mice were fed with normal diet (CTL) 0.2% cuprizone (CPZ) for four weeks induce brain. examine effects on subsequent remyelination, was switched back regular chow an additional two weeks. After treatment, brains collected subjected immunohistochemical biochemical analyses assess myelination status, responses, their capacity clearance. Bulk RNA sequencing performed corpus callosum (CC) address molecular underpinning apoE-mediated activation demyelination. Results We demonstrate dramatic differences function cuprizone-induced ApoE2 hyperactive more efficient clearing debris, whereas apoE4 displayed less activated phenotype reduced efficiency, compared apoE3 microglia. Transcriptomic profiling revealed that molecules known modulate functions had differential expression patterns manner. Importantly, excessive buildup droplets, consistent impairment metabolism, apoE2 superior ability metabolize enriched lipids. Further, apoE2-TR greater extent remyelination; remyelination compromised apoE4-TR mice. Conclusions Our findings provide critical mechanistic insights into differentially regulate maintenance dynamics, which may inform novel therapeutic avenues targeting dysfunctions

Language: Английский

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