F2‐03‐04: Double‐Immune Challenge with the Viral Mimic Polyi:C Induces Alzheimer's Disease‐Like Neuropathology In Aged Wild‐Type Mice

heimer’s disease (AD) pathoetiology, but the mechanisms for this have become increasingly complex. On the one hand, reactive gliosis is a wellrecognized pathology that accompanies cerebral amyloidosis in human AD and in mouse models. However, generally inhibiting inflammation with non-steroidal anti-inflammatory drugs has not produced a positive signal for primary prevention of AD. One explanation for discrepancy is that brain inflammatory processes are not always deleterious, but rather exist in an imbalanced statewithin theADbrain.Methods:Data from rodentmodels will be presented highlighting early appearance of neuroinflammatory hallmarks and modulation of cerebral amyloidosis by genetic targeting of immune/inflammatory molecules. Particular focus will be placed on mouse models of cerebral amyloid with 1) forced expression of the reactive astroglial product human S100B or 2) deletion of the protein tyrosine phosphatase, CD45 (also known as leukocyte common antigen). Results:Microglia and astrocytes with altered morphology appeared early in rodent models, prior to development of frank amyloid plaques. Expression of the reactive human astrocyte product S100B in the Tg2576 mouse model led to early elevation of pro-inflammatory cytokines and exacerbation of Abeta/beta-amyloid pathology. On the other hand, deletion of the anti-inflammatory CD45 gene resulted in striking accumulation of Abeta oligomers and insoluble Abeta deposits. These pathological changes preceded and likely drove mitochondrial dysfunction and apoptotic loss of neurons in the latter model. Conclusions: When taken together, these data provide an opportunity to re-evaluate the hypothesis that inflammation necessarily plays a damaging role in AD. Rather, it seems at least in principle that ‘re-balancing’ the inflammatory AD brain milieu may provide a better therapeutic approach.