Brain oligomeric ß-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice.

It has long been assumed that ß-amyloid (Aß) had to assemble into fibrillar amyloid plaques to exert its neurotoxic effects in Alzheimer disease. An alternative hypothesis is that soluble oligomers ofAß play a much larger role in neuronal damage than the insoluble component. We have tested these competing hypotheses in vivo by studying the clinicopathologic correlates of oligomeric Aß species and classic fibrillar amyloid plaques in the brains of double-transgenic APP-tau mice up to 17 months of age. Biochemical and immunohistochemical measures of brain oligomeric Aß exponentially increased with age. Oligomeric Aß load correlated with morphological markers of fibrillar Aß deposition. In contrast to total amyloid plaque burden, the amount of oligomeric Aß deposits labeled by the conformational epitope-specific antibody Nab61 closely correlated with neuronal loss and numbers of astrocytes in the entorhinal cortex and the CA1 hippocampal subfield. However, like other morphological Aß measurements, brain oligomeric Aß burden did not correlate well with memory deficits in these mice. The number of glial fibrillary acidic protein-positive astrocytes in entorhinal cortex and CA1 most tightly correlated with memory impairment and neuronal cell loss. Based on these findings, we hypothesize that the astrocyte response, which is likely triggered by brain oligomeric Aß accumulation, adversely affects cognition and might also contribute to neuronal cell death in this model.