Work

O3‐05‐05: CD45 deficency promotes neurodegeneration in PSAPP mice

Year: 2010

Type: article

Abstract: Deposition of amyloid beta-peptide (Aβ) as Aβ plaques involves activation of microglia-mediated inflammatory responses. However, these activated cells ultimately fail to clear Aβ plaques in the brains of either Alzheimer's disease (AD) patients or AD mouse models. Mounting evidence suggests chronic microglia-mediated immune response during Aβ deposition etiologically contributes to AD pathogenesis by promoting Aβ plaque formation. Past Alzheimer's disease epidemiologic and pathologic studies indicate CD45 dysregulation within the brain and periphery. We bred PSAPP mice with mice homozygously deficient for the CD45. These crosses will yield PSAPP mice that are heterozygously deficient for the CD45. PSAPP mice will also be crossed with mice of identical backgrounds to the CD45 deficient mice to control for a possible alteration in AD-like pathology in these animals simply due to changing their background. Then aged the PSAPP/CD45+/+, PSAPP/CD45, PSAPP /CD45 and PSAPP/CD45 offspring to 4 - 8 months for use in experiments. Given the existence of sex differences in Aβ deposition in this model, we used only females in the present study. We here report transgenic mice overproducing amyloid-beta peptide (Aβ), but CD45 deficient (PSAPP/CD45) closely mimic the neuropathologies of clinical AD. Specifically, we found: (1) increased intra- and extracellular soluble and insoluble Aβ (P < 0.05), (2) decreased plasma soluble Aβ (P < 0.001), (3) alternated microglial phonotype with increased neurotoxic cytokine expression (TNF-α and IL-1β), and most importantly, (5) increased neuronal loss in PSAPP/CD45 mice as compared to PSAPP/CD45 littermates (P < 0.001). This may result from microglial modulation from an Aβ phagocytic to a pro-inflammatory phenotype upon CD45 ablation as observed in vitro and in vivo. These events positively correlated with neuronal loss as revealed by immunohistochemistry, decreased ratio of Bcl-xL to Bax, increased activated caspase-3, and mitochondrial dysfunction. These data suggest that PSAPP/CD45 mice represent a relevant AD model, and specific promotion of CD45-mediated microglial clearance as a novel target for AD treatment.

Source: Alzheimer s & Dementia

DOI: 10.1016/j.jalz.2010.05.423