Accumulation of Abeta oligomers in Alzheimer's disease is associated with cognitive impairment by disrupting scaffold dendritic spine proteins: Effects of immunotherapy

Abstract

The cognitive impairment in patients with Alzheimer's disease (AD) is closely associated with synaptic loss in the neocortex and limbic system. Recent studies in slices and in animal models shown that Abeta protein oligomers ranging in size between 2-12 subunits might be responsible for the damage to the synapses and memory deficits. Although the neurotoxic effects of the oligomers have been widely studied in experimental models, less is known about the mechanisms through which oligomers might damage synaptic terminals in AD. We hypothesized, Abeta oligomers secreted at the presynaptic site might cross into the dendritic spines disturbing scaffold molecules such as PSD95 and Shank and antibodies might block this defect. Immunoblot in AD patient and APP transgenic for the levels of oligomers with antibodies A11, 82E1 and for postsynaptic proteins with PSD95, Shank1 and 3. Co-immunoprecipitation assays with frontal cortex from well characterized control and AD patients from the AD Research Center and mThy1-APP transgenic mice were performed. Primary neuronal cultures treated with conditioned media containing Abeta oligomers or pretreatment with anti-Abeta antibodies were analyzed by immunoblot and immunohistochemistry. Levels of oligomers detected with the A11 and 82E1 antibodies were correlated with the severity of the cognitive impairment (Blessed score and minimental) and with decrease in synaptic markers. Moreover, co-immunoprecipitation assays with frontal cortex of control and AD patients and mThy1-APP transgenic mice shows that compared to other synaptic proteins, an oligomerized recognizing antibody Abeta (82E1) interacts selectively with PSD95. Immunoblot, shows a reduction in the levels of the postsynaptic protein Shank1 and 3. In contrast, homogenates of AD patients or APP tg mice that were immunized with Abeta these effects were attenuated. Primary neuronal cultures were treated with conditioned media containing Abeta oligomers, in these preparations synaptic and dendritic spines were reduced, this was accompanied by a reduction in Shank3 levels. These effects can be blocked by pre-treatment with anti-Abeta antibodies. In conclusion, this study showed that the presence of a subpopulation of Abeta oligomers in the brains of patients with AD is predicts alterations in selected synaptic proteins and cognitive impairment and that this can be reversed by specific antibodies.