Acta Neuropathologica

, Volume 129, Issue 2, pp 183–206 | Cite as

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

Review

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 Ca2+ 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.

Keywords

ADDLs Antibodies Diagnostics Etiology Immunotherapy Signaling Structure Synapses Therapeutics 

Abbreviations

Amyloid beta

AβO

Amyloid beta oligomer

AD

Alzheimer’s disease

AFM

Atomic force microscopy

CNS

Central nervous system

CSF

Cerebrospinal fluid

FAD

Familial Alzheimer’s disease

HMW

High molecular weight

IDP

Intrinsically disordered proteins

LMW

Low molecular weight

LTP

Long-term potentiation

MAb

Monoclonal antibody

MCI

Mild cognitive impairment

MRI

Magnetic resonance imaging

MW

Molecular weight

PET

Positron emission tomography

PrP

Prion protein

scFv

Single chain variable fragment

Supplementary material

401_2015_1386_MOESM1_ESM.pdf (360 kb)
Supplementary material 1 (PDF 360 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.NeurobiologyNorthwestern UniversityEvanstonUSA
  2. 2.Cognitive Neurology and Alzheimer’s Disease CenterNorthwestern UniversityChicagoUSA
  3. 3.Chemistry of Life Processes InstituteNorthwestern UniversityEvanstonUSA

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