This revised proposal (R21 AG025496) aims to develop new mouse models to understand the neurobiology and neuropathology of C-reactive protein (CRP). Blood CRP, the major acute phase reactant detected during an inflammatory response, is a robust risk predictor for first-ever or recurrent coronary events. CRP elevation is also associated with cerebral ischaemia and may be a contributing factor in Alzheimer disease (AD) and vascular dementia. Because inflammatory processes are active in aging, AD, in vascular disease, we hypothesize that CRP elevations will accelerate glial activation during normal brain aging and will intensify AD-like changes. This hypothesis will be evaluated with transgenic mouse models which have chronic CRP elevations, either systemically or specifically in neurons. We propose four aims:
Aim 1 : Determine effects of chronically elevated blood human CRP (huCRP) on glial activation during normal brain aging, using existing CRP overexpressing mice (huCRPtg).
Aim 2 : Construct mice with neuron-specific expression of transgenic huCRP (neuron-huCRPtg) Aim 3: Study contribution of huCRP elevations to brain lesions in young neuron-huCRPtg mice.
Aim 4 : Study contribution of hu CRP elevations in existing AD transgenic mice (APPswe/ind) that rapidly accumulate deposits of Abeta-amyloid. F1 hybrids will be made with APPswe/ind and the existing systemic huCRPtg (Y1) and with the neuron-specific huCRPtg (when available). The F1 hybrids will be examined for changes in deposits of Abeta-amyloid.
