Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo

Fibrillar amyloid beta (fA beta) peptide is the major component of A beta plaques in the brains of Alzheimer's disease (AD) patients. Inflammatory mediators have previously been proposed to be drivers of A beta pathology in AD patients by increasing amyloidogenic processing of APP and promoting A beta accumulation, but recent data have shown that expression of various inflammatory cytokines attenuates A beta pathology in mouse models. In an effort to further study the role of different inflammatory cytokines on A beta pathology in vivo, we explored the effect of murine Tumor Necrosis Factor alpha (mTNF alpha) in regulating A beta accumulation. Recombinant adeno-associated virus serotype 1 (AAV2/1) mediated expression of mTNF alpha in the hippocampus of 4 month old APP transgenic TgCRND8 mice resulted in significant reduction in hippocampal A beta burden. No changes in APP levels or APP processing were observed in either mTNF alpha expressing APP transgenic mice or in non-transgenic littermates. Analysis of A beta plaque burden in mTNF alpha expressing mice showed that even after substantial reduction compared to EGFP expressing age-matched controls, the A beta plaque burden levels of the former do not decrease to the levels of 4 month old unmanipulated mice. Taken together, our data suggests that proinflammatory cytokine expression induced robust glial activation can attenuate plaque deposition. Whether such an enhanced microglial response actually clears preexisting deposits without causing bystander neurotoxicity remains an open question.