科研之友
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摘要
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 beta oligomers (A beta Os), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic A beta Os accumulate in AD brain and constitute long-lived alternatives to the disease-defining A beta fibrils deposited in amyloid plaques. Key experiments using fibril-free A beta O solutions demonstrated that while A beta is essential for memory loss, the fibrillar A beta in amyloid deposits is not the agent. The AD-like cellular pathologies induced by A beta 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 beta Os into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. A beta O binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca2+ overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of A beta 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 beta 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 beta 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 beta O antibodies. An AD-dependent accumulation of A beta Os in CSF suggests their potential use as biomarkers and new A beta O probes are opening the door to brain imaging. Overall, current evidence indicates that A beta oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer's disease.
- 出版日期2015-2
- 单位西北大学
