Knockout of microglial P38A mapk in a mouse model of Alzheimer’s disease

Abstract

AbstractBackgroundThe p38a MAPK signaling pathway is a well‐established regulator of neuroinflammation, and pharmacological inhibitors of this pathway can protect against cognitive impairment in animal models of Alzheimer’s disease (AD). This protection by p38a inhibitors might be mediated via protective effects on neurons, anti‐inflammatory effects on glia, or some combination thereof. To assess whether reduction of p38‐dependent microglial proinflammatory responses is beneficial in this context, we generated AD model mice with microglial knockout (KO) of p38a.MethodThe APPswe/PS1dE9 (MMRRC #34832) mouse AD model was crossed with p38afl/fl mice (Jax #031129) to generate AD model mice homozygous for the floxed p38a allele. These were subsequently crossed with CX3CR1CreERT2 mice (Jax #020940) that express a tamoxifen‐inducible promoter allowing for removal of p38a from microglia. This breeding scheme generated four groups of mice, used in a 2 x 2 study design: WT and AD mice with floxed p38a, with or without a copy of the myeloid‐specific Cre allele. All mice were placed on tamoxifen diet (400 ppm) for 4 weeks beginning at 5 months of age, near the beginning of amyloid plaque deposition in this AD model. After administration of tamoxifen, mice were returned to normal chow for several months, allowing turnover of peripheral myeloid cells. Mice underwent behavioral testing in open field and novel spatial recognition y‐maze (8 months of age), and radial arm water maze (11 months of age). Microglial isolation via fluorescence‐activated cellular sorting and subsequent RNAseq analysis was performed on a subset of 4 mice per group.ResultsMicroglial p38a KO had no effect on the hyperlocomotive phenotype associated with amyloid overexpression in this model; however, p38a KO increased errors in the RAWM test of spatial learning and memory in the AD model but not WT mice.ConclusionsThe p38a signaling pathway in microglia is important in restricting amyloid‐associated cognitive decline. We are currently characterizing the effects of microglial p38 KO on amyloid pathology, neuroinflammation, and microglial gene expression.