Research into the role of amyloid-β in Alzheimer's disease has shifted somewhat to focus on the surrounding biochemistry rather than the aggregates, now that clearing the aggregates via immunotherapies is an ongoing concern, and has shown less of a benefit to patients than hoped. As researchers note here, there is evidence for specific amyloid-β oligomers to be the most toxic consequence of having too much amyloid-β in general. Researchers have developed a drug that reduces levels of one of the problem oligomers, and this study is one of the early tests of its ability to help in an animal model of Alzheimer's disease.
One possible reason for the failure of early Alzheimer's disease (AD) clinical trials is that treatments were initiated after symptom onset, when pathology is already widespread. Another contributing factor, especially for amyloid-β (Aβ) targeting therapies, is that most treatments have selectively targeted monomeric or fibrillar forms of Aβ, which are not the most toxic species. Soluble amyloid-β oligomers (AβOs), which form prior to plaques, are widely regarded as the most toxic Aβ species.
One proposed mechanism by which early AβOs contribute to AD is by activation of immune cells. AβOs can activate glia in culture and in wild type rodent or primate brain following injection, but their role in initiating gliosis early in AD remains unclear. Since glial activation is among the primary events in AD, identifying molecules that trigger gliosis is critical for diagnostics and therapeutics.
In this study, we investigated early pathology in 5xFAD mice. Results showed distinct AβO subtypes differing in localization, morphology, and association with key AD hallmarks such as degenerating neurons, plaques, phosphorylated TDP-43 (pTDP-43), and activated immune cells. We report an AβO subtype that associates with the earliest degenerating neurons and activated immune cells and provide support for its role in early neuronal degeneration and astrogliosis. Furthermore, we validate the in vivo efficacy of NU-9, a drug-like compound recently shown to inhibit AβO accumulation in cultured hippocampal neurons. Oral NU-9 treatment significantly reduced ACU193+ AβOs on reactive astrocytes and rescued astrocyte glial fibrillary acidic protein (GFAP) levels, suggesting astrocyte-associated AβOs may induce reactive astrogliosis. We predict that neutralization of ACU193+ AβOs early in AD could slow or prevent disease progression.
Link: https://doi.org/10.1002/alz.70968
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