Microglia and Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12990 - 12990

Published: Oct. 27, 2022

There is a huge need for novel therapeutic and preventative approaches to Alzheimer’s disease (AD) neuroinflammation seems be one of the most fascinating solutions. The primary cell type that performs immunosurveillance helps clear out unwanted chemicals from brain microglia. Microglia work reestablish efficiency stop further degeneration in early stages AD but mainly fail illness’s later phases. This may caused by number reasons, e.g., protracted exposure cytokines induce inflammation an inappropriate accumulation amyloid beta (Aβ) peptide. Extracellular and/or intraneuronal phosphorylated tau can both activate activation TLRs scavenger receptors, inducing numerous inflammatory pathways, including NF-kB, JAK-STAT, NLRP3 inflammasome, facilitates microglial phagocytosis response these mediators. Aβ/tau are taken up microglia, their removal extracellular space also have protective effects, if illness worsens, environment constantly inflamed overexposed oxidative might encourage continuous activation, which lead neuroinflammation, stress, iron overload, neurotoxicity. complexity diversity roles microglia play health necessitate urgent development new biomarkers identify activity different It imperative comprehend intricate mechanisms result impairment develop immunomodulating therapies primarily attempt recover physiological role allowing them carry core function protection.

Language: Английский

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The amyloid cascade hypothesis: an updated critical review

Brain, Journal Year: 2023, Volume and Issue: 146(10), P. 3969 - 3990

Published: May 15, 2023

Results from recent clinical trials of antibodies that target amyloid-β (Aβ) for Alzheimer's disease have created excitement and been heralded as corroboration the amyloid cascade hypothesis. However, while Aβ may contribute to disease, genetic, clinical, imaging biochemical data suggest a more complex aetiology. Here we review history weaknesses hypothesis in view new evidence obtained anti-amyloid antibodies. These indicate treatments either no or uncertain effect on cognition. Despite importance definition argue point playing minor aetiological role. We also discuss suggesting concerted activity many pathogenic factors propose evolving multi-factor models will better underpin search effective strategies treat disease.

Language: Английский

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The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Sept. 1, 2022

Currently, there is no disease-modifying treatment available for Alzheimer's and Parkinson's disease (AD PD) that includes the highly controversial approval of Aβ-targeting antibody aducanumab AD. Hence, still an unmet need a neuroprotective drug in both AD PD. Type 2 diabetes risk factor Glucagon-like peptide 1 (GLP-1) hormone growth has shown effects preclinical studies, success GLP-1 mimetics phase II clinical trials PD raised new hope. are currently on market as treatments type diabetes. analogs safe, well tolerated, resistant to desensitization characterized clinic. Herein, we review existing evidence illustrate pathways induced following GLP-1R activation neurons, microglia astrocytes. The latter include synaptic protection, improvements cognition, learning motor function, amyloid pathology-ameliorating properties (Aβ, Tau, α-synuclein), suppression Ca

Language: Английский

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The role of the adaptive immune system and T cell dysfunction in neurodegenerative diseases

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: Oct. 8, 2022

Abstract The adaptive immune system and associated inflammation are vital in surveillance host protection against internal external threats, but can secondarily damage tissues. central nervous is immune-privileged largely protected from the circulating inflammatory pathways. However, T cell involvement disruption of blood–brain barriers have been linked to several neurodegenerative diseases including Parkinson's disease, Alzheimer’s multiple sclerosis. Under normal physiological conditions, regulatory cells (Treg cells) dampen response effector cells. In pathological states many disorders, ability Treg mitigate reduced, a pro-inflammatory environment persists. This perspective review provides current knowledge on roles subsets (e.g., cells, ocular diseases, uveitis, diabetic retinopathy, age-related macular degeneration, glaucoma. Many dysregulation, cellular events molecular mechanisms involved such processes remain unknown. Moreover, role pathologies remains poorly defined limited literature available this area research. Adoptive transfer appears be immunological approach control pathologies. Similarities dysfunction seen among non-ocular suggest that research has great potential develop better therapeutic agents for warrants further studies. Overall, article significant information numerous diseases.

Language: Английский

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Disease-Modifying Therapies for Alzheimer's Disease: More Questions than Answers

Neurotherapeutics, Journal Year: 2022, Volume and Issue: 19(1), P. 209 - 227

Published: Jan. 1, 2022

Scientific advances over the last four decades have steadily infused Alzheimer's disease (AD) field with great optimism that therapies targeting Aβ, amyloid, tau, and innate immune activation states in brain would provide modification. Unfortunately, this optimistic scenario has not yet played out. Though a recent approval of anti-Aβ aggregate binding antibody, Aduhelm (aducanumab), as "disease-modifying therapy for AD" is viewed by some breakthrough, many remain unconvinced data underlying approval. Collectively, we succeeded changing AD from largely untreatable, inevitable, incurable to treatable, preventable, curable one. Here, I will review major foci "disease-modifying" therapeutic pipeline "open questions" terms these approaches. conclude discussing how we, field, might adjust our approach, learning past failures ensure future success.

Language: Английский

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Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 89, P. 101979 - 101979

Published: June 15, 2023

Therapeutic strategies for neurodegenerative disorders have commonly targeted individual aspects of the disease pathogenesis to little success. Neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's (PD), are characterized by several pathological features. In AD PD, there is an abnormal accumulation toxic proteins, increased inflammation, decreased synaptic function, neuronal loss, astrocyte activation, perhaps a state insulin resistance. Epidemiological evidence has revealed link between AD/PD type 2 diabetes mellitus, with these sharing some commonalities. Such opened up promising avenue repurposing antidiabetic agents in treatment disorders. A successful therapeutic strategy would likely require single or which target separate processes disease. Targeting cerebral signalling produces numerous neuroprotective effects preclinical brain models. Clinical trials shown promise approved diabetic compounds improving motor symptoms PD preventing decline, further phase II III underway populations. Alongside signalling, targeting incretin receptors represents one most currently available AD/PD. Most notably, glucagon-like-peptide-1 (GLP-1) receptor agonists displayed impressive clinical potential early studies. GLP-1 agonist, liraglutide, been demonstrated improve glucose metabolism functional connectivity small-scale pilot trials. Whilst agonist exenatide effective restoring function cognition. reduces inhibits apoptosis, prevents protein aggregation, enhances long-term potentiation autophagy as well restores dysfunctional signalling. Support also increasing use additional treatments, intranasal insulin, metformin hydrochloride, peroxisome proliferator-activated nuclear γ agonists, amylin analogs, tyrosine phosphatase 1B inhibitors investigation deployment treatment. As such, we provide comprehensive review anti-diabetic PD.

Language: Английский

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Aducanumab Therapy to Treat Alzheimer’s Disease: A Narrative Review

International Journal of Alzheimer s Disease, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 10

Published: March 9, 2022

Background. Aducanumab, a new monoclonal antibody that targets β-amyloid aggregates, has been granted conditional approval by the U.S. FDA for treatment of mild Alzheimer’s disease (AD). The this drug without confirmed significant clinical impact resulted in several debates. Objective. In narrative review, aducanumab approval-related controversy, drug’s pharmacokinetics and pharmacodynamic characteristics, evidence from efficacy safety trials aducanumab, implications approval, future directions management patients with AD are summarized. Methods. Using relevant keywords, Google Scholar, Web Science, MEDLINE databases manufacturer’s website were searched. Results. Infusion at higher dose modest slowing cognitive decline among impairment or early-onset dementia. however can cause amyloid-related imaging abnormalities. Due to on cognition, use will most likely be limited. manufacturer is required run an extended phase IIIb trial verify benefit drug. Access therapy requires careful selection periodic monitoring ensure optimal Conclusion. Despite limitations, first disease-modifying approved AD. Aducanumab addresses part pathogenesis AD; therefore, drugs act multiple needed. addition, search preventive strategies, validated plasma-based assays, newer AD, which effective, safe, convenient, affordable, vital.

Language: Английский

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Cost-effectiveness of Aducanumab and Donanemab for Early Alzheimer Disease in the US

JAMA Neurology, Journal Year: 2022, Volume and Issue: 79(5), P. 478 - 478

Published: March 28, 2022

Several anti-amyloid monoclonal antibodies have been developed for slowing the progression of Alzheimer disease (AD). Among furthest are aducanumab, which received accelerated approval from US Food and Drug Administration in 2021, donanemab, is currently undergoing phase 3 trials. The cost-effectiveness these treatments has not established.

Language: Английский

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Role of Calcium Homeostasis in Alzheimer’s Disease

Neuropsychiatric Disease and Treatment, Journal Year: 2022, Volume and Issue: Volume 18, P. 487 - 498

Published: March 1, 2022

Abstract: Alzheimer's disease (AD) is a neurodegenerative associated with senile plaques (SP) and neurofibrillary tangles (NFTs) in the brain. With aging of population, AD has become most common form dementia. However, mechanisms leading to are still under investigation, there currently no specific drugs for its treatment. Therefore, further study on pathogenesis develop new treatment remains top priority. Several studies have suggested that intracellular calcium homeostasis dysregulated AD, this been implicated deposition amyloid β (Aβ), hyperphosphorylation tau protein, abnormal synaptic plasticity, apoptosis, all which involved occurrence development AD. In addition, some based pathways linking achieved results This review comprehensively explores relationship between provide theoretical basis future exploration novel therapeutic drugs. Keywords: homeostasis, Aβ, tau, therapy

Language: Английский

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Vascular contributions to Alzheimer's disease

Translational research, Journal Year: 2022, Volume and Issue: 254, P. 41 - 53

Published: Dec. 15, 2022

Language: Английский

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