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, Год журнала: 2023, Номер 24(2), С. 1659 - 1659

Опубликована: Янв. 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

Язык: Английский

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Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer’s disease

Cell Reports, Год журнала: 2025, Номер unknown, С. 115109 - 115109

Опубликована: Янв. 1, 2025

Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies infectious agents, with herpes simplex virus 1 (HSV-1) being leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples. Expression herpesvirus protein ICP27 increases severity strongly colocalizes p-tau but not Aβ. Modeling organoids shows that HSV-1 infection elevates phosphorylation. Notably, reduces expression markedly decreases post-infection neuronal death from 64% to 7%. This modeling prompts investigation into cGAS-STING-TBK1 pathway products, nuclear factor (NF)-κB IRF-3, which AD. Furthermore, experimental activation STING enhances phosphorylation, while TBK1 inhibition prevents it. Together, these findings suggest phosphorylation acts as an innate immune response AD, driven by cGAS-STING.

Язык: Английский

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Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model

Science Signaling, Год журнала: 2025, Номер 18(868)

Опубликована: Янв. 7, 2025

Infection with herpes simplex virus type 1 (HSV-1) in the brains of APOE4 carriers increases risk Alzheimer’s disease (AD). We previously found that latent HSV-1 a three-dimensional vitro model -heterozygous human brain tissue was reactivated response to neuroinflammation caused by exposure other pathogens. Because traumatic injury also causes neuroinflammation, we surmised might similarly reactivate HSV-1. Here, examined effects one or more controlled blows our absence presence infection. After repeated, mild blows, latently infected tissues showed reactivation HSV-1; production and accumulation β amyloid phosphorylated tau (which promotes synaptic dysfunction neurodegeneration); activated gliosis, which is associated destructive neuroinflammation. These are collectively AD, dementia, chronic encephalopathy (CTE) were increased additional but absent mock-infected tissue. Blocking cytokine IL-1β prevented induction gliosis monolayer cultures after scratch wounding. thus propose repeated mechanical injuries brain, such as from direct head jarring motions head, resulting may contribute development AD related diseases some individuals.

Язык: Английский

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Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer’s disease

Research Square (Research Square), Год журнала: 2023, Номер unknown

Опубликована: Июнь 9, 2023

The integration of quantitative trait loci (QTL) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes disease-associated loci. QTL mapping mainly been focused on multi-tissue expression or plasma protein (pQTL). Here we generated the largest-to-date cerebrospinal fluid (CSF) pQTL atlas by analyzing 7,028 proteins in 3,107 samples. We identified 3,373 independent study-wide associations for 1,961 proteins, including 2,448 novel pQTLs which 1,585 are unique to CSF, demonstrating genetic regulation CSF proteome. In addition established chr6p22.2-21.32 HLA region, pleiotropic regions chr3q28 near

Язык: Английский

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Alzheimer’s Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3892 - 3892

Опубликована: Март 31, 2024

The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that protein amyloid-beta cause of disease. Two antibodies, aducanumab and lecanemab, have been approved by U.S. Food Drug Administration, while a third, donanemab, under review. main argument FDA approvals presumed therapy-induced removal cerebral deposits. Lecanemab donanemab are also thought to some statistical delay in determination cognitive decline. However, clinical efficacy less than with conventional treatment, selection amyloid-positive trial patients non-specific amyloid-PET imaging, uncertain amyloids trials cast doubt on this anti-Alzheimer's antibody therapy hence hypothesis, calling more thorough investigation negative impact type brain.

Язык: Английский

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Viral Infections, Are They a Trigger and Risk Factor of Alzheimer’s Disease?

Pathogens, Год журнала: 2024, Номер 13(3), С. 240 - 240

Опубликована: Март 8, 2024

Alzheimer’s Disease (AD), a progressive and debilitating condition, is reported to be the most common type of dementia, with at least 55 million people believed currently affected. Many causation hypotheses AD exist, yet intriguing link between viral infection its possible contribution known etiology has become an attractive focal point research for field challenging study task. In this review, we will explore historical perspective milestones that led investigate connection AD. Specifically, several viruses such as Herpes Simplex Virus 1 (HSV-1), Zika virus (ZIKV), severe cute respiratory syndrome coronavirus 2 (SARS-CoV-2), along others mentioned, include various presently considered within field. We delve into strong evidence implicating these in development lytic replication axonal transport HSV-1, mechanisms ZIKV neurotropism through human protein Musashi-1 (MSI1), spread SARS-CoV-2 transfer BBB endothelial cells glial then neurons via transsynaptic transfer. also beyond mere associations by carefully analyzing potential which may contribute pathology. This includes but not limited direct neuronal infections, dysregulation immune responses, impact on processing (Aβ42 hyperphosphorylated tau). Controversies challenges virus–AD relationship emerge tease out mechanisms. Looking forward, emphasize future directions, distinct questions proposed experimentations explore, should take tackle remaining unanswered glaring gaps persist. Overall, review aims provide comprehensive survey past, present, infections their association while encouraging further discussion.

Язык: Английский

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Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Май 25, 2023

The root causes of dementia are still largely unclear, and the medical community lacks highly effective preventive therapeutic pharmaceutical agents for despite large investments into their development. There is growing interest in question if infectious play a role development dementia, with herpesviruses attracting particular attention. To provide causal as opposed to merely correlational evidence on this question, we take advantage fact that Wales eligibility herpes zoster vaccine (Zostavax) shingles prevention was determined based an individual's exact date birth. Those born before September 2 1933 were ineligible remained life, while those or after eligible receive vaccine. By using country-wide data all vaccinations received, primary secondary care encounters, death certificates, patients' birth weeks, first show percentage adults who received increased from 0.01% among patients one week too old be eligible, 47.2% just younger. Apart difference probability ever receiving vaccine, there no plausible reason why prior should differ systematically later. We demonstrate empirically by showing systematic differences (e.g., pre-existing conditions uptake other interventions) between across date-of-birth cutoff, interventions used same cutoff program. This unique natural randomization, thus, allows robust causal, rather than correlational, effect estimation. replicate vaccine's known clinical trials reducing occurrence shingles. then reduced new diagnosis over follow-up period seven years 3.5 points (95% CI: 0.6 - 7.1, p=0.019), corresponding 19.9% relative reduction dementia. Besides preventing had effects any common morbidity mortality. In exploratory analyses, find protective far stronger women men. Randomized needed determine optimal population groups time interval administration prevent delay well quantify magnitude when more precise measures cognition used. Our findings strongly suggest important varicella virus etiology

Язык: Английский

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Dendrimers in Alzheimer’s Disease: Recent Approaches in Multi-Targeting Strategies

Pharmaceutics, Год журнала: 2023, Номер 15(3), С. 898 - 898

Опубликована: Март 10, 2023

Nanomaterials play an increasingly important role in current medicinal practice. As one of the most significant causes human mortality, and that is increasing year by year, Alzheimer's disease (AD) has been subject a very great body research area which nanomedicinal approaches show promise. Dendrimers are class multivalent nanomaterials can accommodate wide range modifications enable them to be used as drug delivery systems. By means suitable design, they incorporate multiple functionalities transport across blood-brain barrier subsequently target diseased areas brain. In addition, number dendrimers themselves often display therapeutic potential for AD. this review, various hypotheses relating development AD proposed interventions involving dendrimer-base systems outlined. Special attention focused on more recent results importance aspects such oxidative stress, neuroinflammation mitochondrial dysfunction design new treatments.

Язык: Английский

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Pathways to healing: Plants with therapeutic potential for neurodegenerative diseases

IBRO Neuroscience Reports, Год журнала: 2023, Номер 14, С. 210 - 234

Опубликована: Фев. 10, 2023

Some of the greatest challenges in medicine are neurodegenerative diseases (NDs), which remain without a cure and mostly progress to death. A companion study employed toolkit methodology document 2001 plant species with ethnomedicinal uses for alleviating pathologies relevant NDs, focusing on its relevance Alzheimer's disease (AD). This aimed find plants therapeutic bioactivities range NDs. 1339 were found have bioactivity from literature NDs such as Parkinson's disease, Huntington's AD, motor neurone diseases, multiple sclerosis, prion Neimann-Pick glaucoma, Friedreich's ataxia Batten disease. 43 types found, reducing protein misfolding, neuroinflammation, oxidative stress cell death, promoting neurogenesis, mitochondrial biogenesis, autophagy, longevity, anti-microbial activity. Ethno-led selection was more effective than random species. Our findings indicate that provide large resource ND potential. The extensive validate usefulness mining this data. We number documented able modulate molecular mechanisms underlying various key pathologies, revealing promising even profound capacity halt reverse processes neurodegeneration.

Язык: Английский

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Herpes Simplex Viral Infection Doubles the Risk of Dementia in a Contemporary Cohort of Older Adults: A Prospective Study

Journal of Alzheimer s Disease, Год журнала: 2024, Номер 97(4), С. 1841 - 1850

Опубликована: Фев. 2, 2024

Evidence indicates that herpes simplex virus (HSV) participates in the pathogenesis of Alzheimer's disease (AD).

Язык: Английский

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