The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the 3rd most costly disease and the leading cause of dementia. It can linger for many years, but ultimately is fatal, the 6th leading cause of death. Alzheimer's disease (AD) is fatal and affected individuals can sometimes linger many years. Current treatments are palliative and transient, not disease modifying. This article reviews progress in the search to identify the primary AD-causing toxins. We summarize the shift from an initial focus on amyloid plaques to the contemporary concept that AD memory failure is caused by small soluble oligomers of the Aβ peptide, toxins that target and disrupt particular synapses. Evidence is presented that links Aβ oligomers to pathogenesis in animal models and humans, with reference to seminal discoveries from cell biology and new ideas concerning pathogenic mechanisms, including relationships to diabetes and Fragile X. These findings have established the oligomer hypothesis as a new molecular basis for the cause, diagnosis, and treatment of AD.

Figure 1. Dendritic oligomer pathology occurs early in disease progression

(Left) Perineuronal localization of oligomers detected using oligomer-specific antibody, enlarged from field at right (box). Stain is associated with dendritic arbor, not somatic cytoplasm. (Right) Low magnification of human brain section stained with anti-oligomer antibody. Pattern indicates association with only scattered individual neurons early in disease, prior to amyloid plaques. Taken from Lacor et al, 2004 (Lacor et al., 2004).

Figure 2

Drug targets emerging from the oligomer hypothesis for Alzheimer' disease.