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Amyloid ? oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.

ABSTRACT: 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.

SUBMITTER: Viola KL

PROVIDER: S-EPMC4390393 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Amyloid β oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.

Viola Kirsten L KL Klein William L WL

Acta neuropathologica 20150122 2

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-defin ...[more]

PMID: 25604547

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Project description:Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-? aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-? in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-? aggregates are the most characteristic feature of Alzheimer's disease. However, the correspondence between the distribution of plaques and the pattern of neurodegeneration is tenuous. This discrepancy has stimulated the investigation of other amyloid-? aggregates, including soluble amyloid-? oligomers. Different soluble amyloid-? oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-? oligomers previously described in mouse models-amyloid-? trimers, A?*56 and amyloid-? dimers-in brain tissue from 75 cognitively intact individuals, ranging from young children to the elderly, and 58 impaired subjects with mild cognitive impairment or probable Alzheimer's disease. As in mouse models, where amyloid-? trimers appear to be the fundamental amyloid-? assembly unit of A?*56 and are present in young mice prior to memory decline, amyloid-? trimers in humans were present in children and adolescents; their levels rose gradually with age and were significantly above baseline in subjects in their 70s. A?*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-? dimers were undetectable until subjects were in their 60s; their levels then increased sharply and correlated with plaque load. Remarkably, in cognitively intact individuals we found strong positive correlations between A?*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between A?*56 and two postsynaptic proteins (drebrin and fyn kinase), but none between amyloid-? dimers or amyloid-? trimers and tau or synaptic proteins. Comparing impaired with age-matched unimpaired subjects, we found the highest levels of amyloid-? dimers, but the lowest levels of A?*56 and amyloid-? trimers, in subjects with probable Alzheimer's disease. In conclusion, in cognitively normal adults A?*56 increased ahead of amyloid-? dimers or amyloid-? trimers, and pathological tau proteins and postsynaptic proteins correlated with A?*56, but not amyloid-? dimers or amyloid-? trimers. We propose that A?*56 may play a pathogenic role very early in the pathogenesis of Alzheimer's disease.

Dataset Information

Amyloid ? oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.

Publications

Amyloid β oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.

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