Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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Ultrasound as a versatile tool for short- and long-term improvement and monitoring of brain function

Neuron, Journal Year: 2023, Volume and Issue: 111(8), P. 1174 - 1190

Published: March 13, 2023

Language: Английский

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Focused ultrasound-assisted delivery of immunomodulating agents in brain cancer

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 367, P. 283 - 299

Published: Jan. 29, 2024

Language: Английский

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BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

Science Advances, Journal Year: 2023, Volume and Issue: 9(16)

Published: April 19, 2023

Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal of adeno-associated virus serotype 9 vectors into brain regions involved Parkinson’s disease using low-intensity focus ultrasound adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically confirmed opening. Similar openings safely demonstrated three patients disease. In these one monkey, followed by 18 F-Choline uptake the putamen midbrain based on positron emission tomography. This indicates cellular binding molecules that otherwise would not enter parenchyma. The less-invasive nature this methodology could facilitate viral for gene therapy might allow early repeated interventions to treat neurodegenerative disorders.

Language: Английский

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Optical and Photoacoustic Imaging In Vivo: Opportunities and Challenges

Chemical & Biomedical Imaging, Journal Year: 2023, Volume and Issue: 1(2), P. 99 - 109

Published: March 20, 2023

Optical and photoacoustic imaging plays an important role in biomedical applications owing to its noninvasiveness high resolution. Fluorescence emerge as powerful tools deconstruct molecular information investigate biological processes vivo. Despite great progress has been achieved chemical probe synthesis, how design probes with optimal fluorescence or performance dynamically visualize the process vivo still faces challenges. From this perspective, we will focus on advanced development of Furthermore, concerns prospects for future be demonstrated.

Language: Английский

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Transcranial blood-brain barrier opening in Alzheimer's disease patients using a portable focused ultrasound system with real-time 2-D cavitation mapping

Theranostics, Journal Year: 2024, Volume and Issue: 14(11), P. 4519 - 4535

Published: Jan. 1, 2024

: Focused ultrasound (FUS) in combination with microbubbles has recently shown great promise facilitating blood-brain barrier (BBB) opening for drug delivery and immunotherapy Alzheimer's disease (AD). However, it is currently limited to systems integrated within the MRI suites or requiring post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we investigate safety feasibility of a portable, non-invasive neuronavigation-guided FUS (NgFUS) system real-time 2-D microbubble cavitation mapping.

Language: Английский

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A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

Theranostics, Journal Year: 2022, Volume and Issue: 12(16), P. 6826 - 6847

Published: Jan. 1, 2022

Rationale:The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD).Focused ultrasound applied together with microbubbles (FUS +MB ) novel technique transiently open BBB and increase delivery.Evidence suggests that FUS safe, however, effects on human cells, especially in context AD, remain sparsely investigated.In addition, there currently are no cell platforms test -mediated delivery.Methods: Here we generated cells (induced brain endothelial-like (iBECs) astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 (APOE4, high sporadic AD risk) E3 (APOE3, lower carrying patient-derived induced pluripotent stem (iPSCs).We established mono-and co-culture models control investigate phenotype screen two potentially antibodies, an Aducanumab-analogue (Aduhelm TM ; anti-amyloid-β) anti-Tau antibody, RNF5.We then developed hydrogel-based 2.5D model as step towards more physiologically relevant platform.Results: When compared untreated RNF5 was significantly increased (up 1.73 fold), across Transwell-based following treatment.Our results also demonstrated safety indicated by minimal changes iBEC transcriptome well little or iAstrocyte viability inflammatory responses within first 24 h post .Furthermore, successful formation our (1.4 fold) .Conclusion: Our demonstrate robust reproducible approach utilize patient screening vitro.With such platform research previously not reported, it has potential identify -deliverable drugs cell-and patient-specific , accelerating use modality AD.

Language: Английский

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Alzheimer’s disease and immunotherapy

Current Medicine, Journal Year: 2024, Volume and Issue: 3(1)

Published: Aug. 23, 2024

Abstract Alzheimer's disease (AD) is the leading cause of dementia, characterized by neuropathological features such as amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration. Immunotherapy offers a promising potentially disease-modifying treatment for AD. We review recent advances in AD immunotherapy, specifically focusing on Aβ, tau, neuroinflammation-targeted approaches, gain insights from randomized controlled trials to propose directions.

Language: Английский

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Shedding light on ultrasound in action: Optical and optoacoustic monitoring of ultrasound brain interventions

Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: 205, P. 115177 - 115177

Published: Jan. 5, 2024

Monitoring brain responses to ultrasonic interventions is becoming an important pillar of a growing number applications employing acoustic waves actuate and cure the brain. Optical interrogation living tissues provides unique means for retrieving functional molecular information related activity disease-specific biomarkers. The hybrid optoacoustic imaging methods have further enabled deep-tissue with optical contrast at high spatial temporal resolution. marriage between light sound thus brings together highly complementary advantages both modalities toward precision interrogation, stimulation, therapy strong impact in fields ultrasound neuromodulation, gene drug delivery, or noninvasive treatments neurological neurodegenerative disorders. In this review, we elaborate on current advances monitoring interventions. We describe main principles mechanisms underlying each method before diving into corresponding biomedical applications. identify areas improvement as well promising approaches clinical translation potential.

Language: Английский

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CD31 as a probable responding and gate-keeping protein of the blood-brain barrier and the risk of Alzheimer’s disease

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2023, Volume and Issue: 43(7), P. 1027 - 1041

Published: April 12, 2023

Several studies have shown that an abnormal vascular-immunity link could increase Alzheimer’s disease (AD) risk; however, the mechanism is unclear. CD31, also named platelet endothelial cell adhesion molecule (PECAM), a surface membrane protein of both and immune cells plays important roles in interaction between vascular systems. In this review, we focus on research regarding CD31 biological actions pathological process may contribute to AD based following rationales. First, endothelial, leukocyte soluble forms play multi-roles regulating transendothelial migration, increasing blood–brain barrier (BBB) permeability resulting neuroinflammation. Second, expressed by dynamically modulates numbers signaling pathways, including Src family kinases, selected G proteins, β-catenin which turn affect cell-matrix cell–cell attachment, activation, permeability, survival, ultimately neuronal injury. endothelia cells, these diverse CD31-mediated pathways act as critical regulator immunity-endothelia-brain axis, thereby mediating pathogenesis ApoE4 carriers, major genetic risk factor for AD. This evidence suggests novel potential drug target background vulnerabilities peripheral inflammation development progression.

Language: Английский

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