P3‐375: Phenotypic and functional switch in microglial cells correlates with neurodegeneration in the hippocampus of aged PS1xAPP transgenic model of Alzheimer's disease

Microglial activation by beta-amyloid is a key feature in Alzheimer's disease (AD), however it is not clear whether inflammation represents a protective reaction to neurodegeneration or it is rather a destructive process that contributes to further loss of brain function. Here, we have evaluated by molecular (RT-PCR) and cellular (immunohistochemistry) approaches the inflammatory response in the hippocampus of PS1(M146L)xAPP(751SL) transgenic mice from 2 to 18 months of age. The expression of Iba1 and CD11b (microglial markers) as well as GFAP (astroglial marker) were significantly increased as early as 4 month of age. The activated microglial and astroglial cells concentrated around the amyloid plaques. However, the expression of putative cytotoxic factors was not upregulated, instead there was an induction in the expression of neuroprotective factors such as IGF1. In this AD model during the first year of life, even in the presence of abundant Abeta plaques and microglial activation, neuronal death is restricted to specific interneuron subpopulations and no pyramidal cell loss is detected. Then, the early in vivo inflammation triggered by Abeta may play a beneficial role that explains the limited neuronal degeneration at these ages. However, at 18 months of age a large activation in the expression of potentially cytotoxic factors (TNF-alpha, NO, FASL, Trail, Cox2, Nox1) was detected, coincident with a 33% decrease in the number of total pyramidal cells in CA1. Taken together, these data demonstrated the existence of a phenotypic/functional switch in the activated microglial cells from potentially beneficial (early ages) to detrimental (late ages) stage. Soluble oligomeric Abeta acting through, probably, toll-like receptor 2 might be the factor implicated in this microglia phenotypic change at late ages. These findings support the potential of suppressing the activation of microglia neurotoxic phenotype for the development of novel therapeutic approaches in AD.