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Current Anti-Amyloid-β Therapy for Alzheimer's Disease Treatment: From Clinical Research to Nanomedicine.

ABSTRACT: Recent successive approval of anti-amyloid-β (Aβ) monoclonal antibodies as disease-modifying therapies against Alzheimer's disease (AD) has raised great confidence in the development of anti-AD therapies; however, the current therapies still face the dilemma of significant adverse reactions and limited effects. In this review, we summarized the therapeutic characteristics of the approved anti-Aβ immunotherapies and dialectically analyzed the gains and losses from clinical trials. The review further proposed the reasonable selection of animal models in preclinical studies from the perspective of different animal models of Aβ deposition and deals in-depth with the recent advances of exploring preclinical nanomedical application in Aβ targeted therapy, aiming to provide a reliable systematic summary for the development of novel anti-Aβ therapies. Collectively, this review comprehensively dissects the pioneering work of Aβ-targeted therapies and proposed perspective insight into AD-modified therapies.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC10749171 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Current Anti-Amyloid-β Therapy for Alzheimer's Disease Treatment: From Clinical Research to Nanomedicine.

Zhao Zixuan Z Liu Yun Y Ruan Shirong S Hu Yixuan Y

International journal of nanomedicine 20231220

Recent successive approval of anti-amyloid-β (Aβ) monoclonal antibodies as disease-modifying therapies against Alzheimer's disease (AD) has raised great confidence in the development of anti-AD therapies; however, the current therapies still face the dilemma of significant adverse reactions and limited effects. In this review, we summarized the therapeutic characteristics of the approved anti-Aβ immunotherapies and dialectically analyzed the gains and losses from clinical trials. The review furt ...[more]

PMID: 38144511

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Project description:Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson's and Alzheimer's. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca(2+) overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific AβO antibodies. An AD-dependent accumulation of AβOs in CSF suggests their potential use as biomarkers and new AβO probes are opening the door to brain imaging. Overall, current evidence indicates that Aβ oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer's disease.

Dataset Information

Current Anti-Amyloid-β Therapy for Alzheimer's Disease Treatment: From Clinical Research to Nanomedicine.

Publications

Current Anti-Amyloid-β Therapy for Alzheimer's Disease Treatment: From Clinical Research to Nanomedicine.

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