Cited by 635Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Viola, Kirsten L., Klein, William L.·2015·Acta Neuropathologica

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

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  • Because pathogenic soluble aggregates of Aβ appear early in the sequence of Alzheimer's disease, they can represent interesting targets for therapeutics and diagnostics.

    “Because pathogenic soluble aggregates of Aβ appear early in the sequence of AD, they can represent interesting targets for therapeutics and diagnostics [51].”
  • Oligomers are suggested to be the most neurotoxic species in AD because their levels correlate better with cognitive symptoms than presence of plaques or NFTs.

    “It is suggested that oligomers are the most neurotoxic species in AD as levels of these species correlate much better with cognitive symptoms than presence of plaques or NFTs [166].”

    From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [166]

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  1. [128]Nigh AB Vahedi S Davis EG Weintraub S Bigio EH Klein WL Geula C Intracellular Amyloid-beta in cholinergic neurons Brain J Neurol 2014 In Press

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Authors
Viola, K. L., & Klein, W. L.
Affiliations
Northwestern University (US)
Corresponding author
Klein, William L.
Venue
Acta Neuropathologica
Published
2015-01-22
Volume
129
Issue
2
Pages
183-206
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
OpenAlex
W2055775253
Cited by
628
References
198
Citations by year
2026: 42 · 2025: 45 · 2024: 55 · 2023: 51 · 2022: 75 · 2021: 69 · 2020: 66 · 2019: 58 · 2018: 60 · 2017: 53 · 2016: 42 · 2015: 10
FWCI
6.76
Type
journal article
Language
en
Open access
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (AG045637, AG029460, R01AG022547, AG022547, R01AG029460, R21AG045637)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid-beta oligomers, Alzheimer's disease pathogenesis, protein aggregation, neurotoxicity, synaptic dysfunction, glutamate receptors, calcium overload, tau hyperphosphorylation, insulin resistance, oxidative stress, synaptic loss, cerebrospinal fluid biomarkers, diabetes comorbidity, hypercholesterolemia, Alzheimer's disease therapeutics
MeSH terms
Alzheimer Disease, Animals, Humans, Neurons, Amyloid beta-Peptides

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