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Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer's Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression.

ABSTRACT: A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer's disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling evidence that inhibition of Aβ oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aβ oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aβ oligomers. These trials also show that inhibiting Aβ neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aβ oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aβ oligomers at the clinical dose.

SUBMITTER: Tolar M

PROVIDER: S-EPMC8231952 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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 A? oligomers (A?Os), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic A?Os accumulate in AD brain and constitute long-lived alternatives to the disease-defining A? fibrils deposited in amyloid plaques. Key experiments using fibril-free A?O solutions demonstrated that while A? is essential for memory loss, the fibrillar A? in amyloid deposits is not the agent. The AD-like cellular pathologies induced by A?Os 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 A?Os into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. A?O 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 A?Os 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 A?Os has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic A?Os 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 A?O antibodies. An AD-dependent accumulation of A?Os in CSF suggests their potential use as biomarkers and new A?O probes are opening the door to brain imaging. Overall, current evidence indicates that A? oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer's disease.

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Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer's Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression.

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