Novel strategies for the fight of Alzheimer’s disease targeting amyloid-β protein

Xie, Yang; Wang, Yan; Jiang, Shangfei; Xiang, Xiaohong; Wang, Jianhua; Ning, Linhong

doi:10.1080/1061186x.2021.1973482

Cited by 4 publications

(1 citation statement)

References 116 publications

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“…A comprehensive discussion of amyloid-directed AD therapeutics is beyond the scope of this paper; however, recent reviews have provided thorough coverage of this topic ( Bullain and Doody, 2020 ; Avgerinos et al, 2021 ; Decourt et al, 2021 ; Jeremic et al, 2021 ; Lin et al, 2021 ; Restifo, 2021 ; Sun et al, 2021 ; Van Bokhoven et al, 2021 ; Xie et al, 2021 ; Yu et al, 2021 ). Jeremic et al (2021) summarized the late-stage clinical failures of eight secretase inhibitors, and they report on the clinical status of eight amyloid-directed monoclonal antibodies.…”

Section: The Current Status Of Amyloid-targeting Experimental Therape...mentioning

confidence: 99%

ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects 50 million people worldwide, with 10 million new cases occurring each year. The emotional and economic impacts of AD on patients and families are devastating. Approved treatments confer modest improvement in symptoms, and recently one treatment obtained accelerated approval from the United States Food and Drug Administration (FDA) and may have modest disease modifying benefit. Research over the past three decades has established a clear causal linkage between AD and elevated brain levels of amyloid β (Aβ) peptide, and substantial evidence now implicates soluble, non-fibrillar Aβ oligomers (AβOs) as the molecular assemblies directly responsible for AD-associated memory and cognitive failure and accompanying progressive neurodegeneration. The widely recognized linkage of elevated Aβ and AD spawned a comprehensive 20-year therapeutic campaign that focused primarily on two strategies – inhibition of the secretase enzymes responsible for Aβ production and clearance of Aβ peptide or amyloid plaques with Aβ-directed immunotherapeutics. Unfortunately, all clinical trials of secretase inhibitors were unsuccessful. Of the completed phase 3 immunotherapy programs, bapineuzumab (targeting amyloid plaque) and solanezumab (targeting Aβ monomers) were negative, and the crenezumab program (targeting Aβ monomers and to a small extent oligomers) was stopped for futility. Aducanumab (targeting amyloid plaques), which recently received FDA accelerated approval, had one positive and one negative phase 3 trial. More than 25 negative randomized clinical trials (RCTs) have evaluated Aβ-targeting therapeutics, yet none has directly evaluated whether selective blockage of disease-relevant AβOs can stop or reverse AD-associated cognitive decline. Here, we briefly summarize studies that establish the AD therapeutic rationale to target AβOs selectively, and we describe ACU193, the first AβO-selective immunotherapeutic to enter human clinical trials and the first positioned to test the AβO hypothesis of AD.

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Section: The Current Status Of Amyloid-targeting Experimental Therape...mentioning

confidence: 99%

ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease

et al. 2022

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Single-Cell Cortical Transcriptomics Reveals Common and Distinct Changes in Cell-Cell Communication in Alzheimer’s and Parkinson’s Disease

Le Bars,

Glaab

2024

Mol Neurobiol

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Alzheimer's disease (AD) and Parkinson's disease (PD) cause significant neuronal loss and severely impair daily living. Despite different clinical manifestations, these disorders share common pathological molecular hallmarks, including mitochondrial dysfunction and synaptic degeneration. A detailed comparison of molecular changes at single-cell resolution in the cortex, as one of the main brain regions affected in both disorders, may reveal common susceptibility factors and disease mechanisms. We performed single-cell transcriptomic analyses of post-mortem cortical tissue from AD and PD subjects and controls to identify common and distinct disease-associated changes in individual genes, cellular pathways, molecular networks, and cell-cell communication events, and to investigate common mechanisms. The results revealed significant disease-specific, shared, and opposing gene expression changes, including cell type-specific signatures for both diseases. Hypoxia signaling and lipid metabolism emerged as significantly modulated cellular processes in both AD and PD, with contrasting expression alterations between the two diseases. Furthermore, both pathway and cell-cell communication analyses highlighted shared significant alterations involving the JAK-STAT signaling pathway, which has been implicated in the inflammatory response in several neurodegenerative disorders. Overall, the analyses revealed common and distinct alterations in gene signatures, pathway activities, and gene regulatory subnetworks in AD and PD. The results provide insights into coordinated changes in pathway activity and cell-cell communication that may guide future diagnostics and therapeutics.

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Natural polyphenol: Their pathogenesis-targeting therapeutic potential in Alzheimer's disease

Niu,

Dong,

Niu

2024

European Journal of Medicinal Chemistry

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Novel strategies for the fight of Alzheimer’s disease targeting amyloid-β protein

Cited by 4 publications

References 116 publications

ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease

ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease

Single-Cell Cortical Transcriptomics Reveals Common and Distinct Changes in Cell-Cell Communication in Alzheimer’s and Parkinson’s Disease

Natural polyphenol: Their pathogenesis-targeting therapeutic potential in Alzheimer's disease

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