Amyloid β 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 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.

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

“…The topic of amyloidogenesis has been the subject of many scientific endeavors and a great variety of papers have been published, approaching the problem from all possible angles: diagnostics [63][64][65][66], therapeutic [67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] and structural/molecular [82][83][84][85]. Our publication does not, however, discuss amyloidogenesis as such, but rather the molecular processes which lead to the formation of fibrillary aggregates commonly referred to as amyloids.…”

Inhibition of tissue transglutaminase promotes Aβ-induced apoptosis in SH-SY5Y cells

“…Moreover, Aβ was added to mimic an AD pathological condition because it is involved in protein aggregation and neural toxicity in AD pathogenesis [37][38][39] . tTG and its product isopeptide were detected by Western blot analysis at different molecular weights or by in-cell Western assays.…”

Alzheimer’s Disease Pathogenesis: The Denied Access Model

“…Countless articles are published which present new mechanistic hypotheses of AßO toxicity. To briefly summarize, AßOs have been linked to AD in the following ways: Oxidative stress and lipid peroxidation in neurons [33][34][35][36] toxic ion pore formation on the cell membrane [37,38], synaptic plasticity disruption [39][40][41][42], astrocyte and microglia calcium influx [36], selective neuronal degeneration [43], prion-like infectious behavior [34,44,45], binding to numerous membrane proteins [46][47][48][49], insulin resistance [50][51][52] calcium homeostasis disruption [35,53] and tau hyperphosphorylation induction [54]. One of the main issues is that AßOs lack a common description of structural toxicity and are thought of as "an emperor in need of clothes" since they possess numerous conformations ranging from monomers, to trimers, and to eventual fibrils [8].…”