Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 72, P. 101496 - 101496

Published: Oct. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Language: Английский

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Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12841 - 12841

Published: Oct. 25, 2022

Alzheimer’s disease (AD) is the leading cause of dementia in elderly people. Amyloid beta (Aβ) deposits and neurofibrillary tangles are major pathological features an brain. These proteins highly expressed nerve cells found most tissues. Tau primarily provides stabilization to microtubules part axons dendrites. However, tau a state becomes hyperphosphorylated, causing dysfunction synaptic impairment degeneration neurons. This article presents summary role tau, phosphorylated (p-tau) AD, other tauopathies. Tauopathies, including Pick’s disease, frontotemporal dementia, corticobasal degeneration, argyrophilic grain progressive supranuclear palsy, Huntington’s result misprocessing accumulation within neuronal glial cells. also focuses on current research post-translational modifications genetics pathology, tauopathies development new drugs targeting p-tau, therapeutics for treating possibly preventing

Language: Английский

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APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

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

Published: Sept. 24, 2022

Abstract ApoE is the major lipid and cholesterol carrier in CNS. There are three human polymorphisms, apoE2, apoE3, apoE4, genetic expression of APOE4 one most influential risk factors for development late-onset Alzheimer's disease (AD). Neuroinflammation has become third hallmark AD, together with Amyloid-β plaques neurofibrillary tangles hyperphosphorylated aggregated tau protein. This review aims to broadly extensively describe differential aspects concerning apoE. Starting from evolution apoE how APOE's single-nucleotide polymorphisms affect its structure, function, involvement during health disease. reflects on impact critical AD pathology, such as neuroinflammatory response, particularly effect APOE astrocytic microglial function dynamics, synaptic amyloid-β load, autophagy, cell–cell communication. We discuss affecting pathology combined genotype, sex, age, diet, physical exercise, current therapies clinical trials field. The genotype other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, multiple also addressed. Therefore, this gathers relevant findings related up date implications CNS pathologies provide a deeper understanding knowledge

Language: Английский

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Insulin action in the brain: cell types, circuits, and diseases

Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 45(5), P. 384 - 400

Published: March 28, 2022

Language: Английский

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Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 144(5), P. 821 - 842

Published: Sept. 6, 2022

Abstract Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by European Alzheimer & Dementia Biobank (EADB), largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total 13,116 individuals (discovery n = 8074; replication 5042 individuals). Besides APOE locus, novel associations two other well-established AD risk loci were observed; CR1 shown locus for Aβ42 BIN1 pTau. GMNC C16orf95 further identified as pTau, which latter is novel. Clustering methods exploring influence all known protein levels, revealed 4 biological categories suggesting multiple pTau related pathways involved etiology AD. In functional follow-up analyses, both associated lateral ventricular volume, implying an overlap genetic brain volume.

Language: Английский

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Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: March 9, 2022

After advanced age, female sex is the major risk factor for late-onset Alzheimer's disease (AD), most common cause of dementia affecting over 24 million people worldwide. The prevalence AD higher in women than men, with postmenopausal accounting 60% all those affected. While research has focused on gender-combined risk, emerging data indicate and gender differences pathophysiology, onset, progression, which may help account women. Notably, AD-related brain changes develop during a 10-20 year prodromal phase originating midlife, thus proximate hormonal transitions endocrine aging characteristic menopause transition Preclinical evidence neuroprotective effects gonadal steroid hormones, especially 17β-estradiol, strongly argue associations between fertility, reproductive history, risk. level hormones to exposed considerably across lifespan, relevance However, neurobiological consequences fluctuations, as well that hormone therapies, are yet be fully understood. Epidemiological studies have yielded contrasting results protective, deleterious null estrogen exposure In contrast, imaging provide encouraging positive greater cumulative lifetime lower women, whereas deprivation associated negative structure, function, biochemistry. Herein, we review existing literature evaluate strength observed female-specific health factors focus role endogenous exogenous exposures key underlying mechanism. Chief among these variables status, type (spontaneous vs. induced), number pregnancies, therapy, including contraceptives, therapy menopause, anti-estrogen treatment. As greatest followed by sex, understanding sex-specific biological pathways through history modulates crucial inform preventative therapeutic strategies AD.

Language: Английский

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Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(1), P. 778 - 778

Published: Jan. 1, 2023

APOE ε4 allele (ApoE4) is the primary genetic risk factor for sporadic Alzheimer’s disease (AD), expressed in 40–65% of all AD patients. ApoE4 has been associated to many pathological processes possibly linked cognitive impairment, such as amyloid-β (Aβ) and tau pathologies. However, exact mechanism underlying impact on progression unclear, while no effective therapies are available this highly debilitating neurodegenerative disorder. This review describes current knowledge interaction with mitochondria, causing mitochondrial dysfunction neurotoxicity, increased Ca2+ reactive oxygen species (ROS) levels, it effects dynamics, namely fusion fission, mitophagy. Moreover, translocates nucleus, regulating expression genes involved aging, Aβ production, inflammation apoptosis, potentially pathogenesis. Thus, novel therapeutical targets can be envisaged counteract induced by brain.

Language: Английский

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Multifaceted roles of APOE in Alzheimer disease

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(8), P. 457 - 474

Published: June 21, 2024

Language: Английский

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Phytoconstituents as modulators of NF-κB signalling: Investigating therapeutic potential for diabetic wound healing

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 177, P. 117058 - 117058

Published: July 4, 2024

The NF-κB pathway plays a pivotal role in impeding the diabetic wound healing process, contributing to prolonged inflammation, diminished angiogenesis, and reduced proliferation. In contrast modern synthetic therapies, naturally occurring phytoconstituents are well-studied inhibitors of that now attracting increased attention context because lower toxicity, better safety efficacy, cost-effectiveness. This study explores recent research on phytoconstituent-based therapies delve into their action mechanisms targeting potential for assisting effective wounds. For this purpose, we have carried out surveys literature analyzed studies from prominent databases such as Science Direct, Scopus, PubMed, Google Scholar, EMBASE, Web Science. classification various categorie as: alkaloids, triterpenoids, phenolics, polyphenols, flavonoids, monoterpene glycosides, naphthoquinones tocopherols. Noteworthy phytoconstituents, including Neferine, Plumbagin, Boswellic acid, Genistein, Luteolin, Kirenol, Rutin, Vicenin-2, Gamma-tocopherol, Icariin, Resveratrol, Mangiferin, Betulinic Berberine, Syringic Gallocatechin, Curcumin, Loureirin-A, Loureirin-B, Lupeol, Paeoniflorin, Puerarin emerge these promising agents through inhibition pathway. Extensive has revealed how they modulate signalling pathways, NF-κB, demonstrate development therapeutic assist chronic

Language: Английский

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Exercise mimetics: a novel strategy to combat neuroinflammation and Alzheimer’s disease

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Feb. 2, 2024

Abstract Neuroinflammation is a pathological hallmark of Alzheimer’s disease (AD), characterized by the stimulation resident immune cells brain and penetration peripheral cells. These inflammatory processes facilitate deposition amyloid-beta (Aβ) plaques abnormal hyperphosphorylation tau protein. Managing neuroinflammation to restore homeostasis decrease neuronal damage therapeutic approach for AD. One way achieve this through exercise, which can improve function protect against neuroinflammation, oxidative stress, synaptic dysfunction in AD models. The neuroprotective impact exercise regulated various molecular factors that be activated same as administration their mimetics. Recent evidence has proven some mimetics effective alleviating AD, and, additionally, they are helpful alternative option patients who unable perform regular physical manage neurodegenerative disorders. This review focuses on current state knowledge mimetics, including efficacy, regulatory mechanisms, progress, challenges, limitations, future guidance application therapy.

Language: Английский

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