Effects of PARP-1 gene deletion in a mouse model of Alzheimer's disease

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DESCRIPTION (provided by applicant): Poly(ADP-ribose) polymerase-1 (abbreviated as PARP-1) is a nuclear enzyme that is activated by genotoxic stress. PARP-1 activation can 1) facilitate DNA repair; 2) induce cell death, or 3) promote inflammation, each of which may contribute to the pathogenesis of Alzheimer's disease. Here we will investigate the role of PARP-1 in Alzheimer's disease by generating a double transgenic mouse, mAPPJ20 x PARP-1-/-. Mice of the mAPPJ20 strain express a mutant human amyloid precursor protein (mAPP) associated with familial Alzheimer's disease. These mice develop amyloid plaques, microglial activation, and cognitive impairment. Mice deficient in PARP-1 show reduced neuronal death under conditions of oxidative stress and attenuated microglial response to many stimuli, including ¿-amyloid aggregates. The mAPPJ20 x PARP-1-/- genotype mice will be compared to control mice and mice from the two parental strain genotypes using behavioral and histological outcome measures. The specific aims are as follows: Aim 1: Cross the existing mAPPJ20 and PARP-1-/- mouse strains to generate a new, double transgenic, mAPPJ20 / PARP1-/- mouse line Aim 2: Quantify age-dependent behavioral changes in these mice. Aim 3: Quantify age-dependent histological changes in these mice: plaque deposition, microglial activation, synapse and neuronal loss, and neuronal DNA damage. Our working hypothesis is that the mAPPJ20 x PARP-1-/- mice will exhibit reduced microglial activation and slowed cognitive impairment relative to the mAPPJ20 parental strain. However, it is possible that the behavioral and histological changes may be exacerbated, rather than attenuated, in the PARP-1-/- x mAPPJ20 mice. This result would suggest that microglial activation, or at least those aspects of microglial activation regulated by PARP-1, is a net beneficial event in AD. Alternatively, an observed deleterious effect of PARP-1 gene deletion could uncover a role for PARP-1 in the neuronal response to amyloid deposition, because PARP-1 is also important in neuronal responses to DNA damage and stress. The study is designed to evaluate each of these potential effects of PARP-1 gene deletion on the pathogenesis of Alzheimer's disease. Effects of PARP-1 gene deletion in a mouse model of Alzheimer's disease. Alzheimer's disease is the major cause of cognitive impairment in elderly adults. Microglia are the resident inflammatory cells in brain. Some studies have suggested that microglia contribute to the progression of Alzheimer's disease, whereas other studies suggest that microglia have a beneficial effect. We will address this controversy by breeding mice with an Alzheimer's disease protein with mice that have impaired microglia activation, and examining disease progression in the offspring. The results of these studies will help establish the role of inflammation in Alzheimer's disease and the potential for anti-inflammatory drugs to modify the course of this disease.