Homozygous overexpression of ATP6AP2 in female mice and its impact on running-induced modulation of the adult hippocampus.

ATP6AP2 (ATPase H⁺ Transporting Accessory Protein 2) also known as (pro)renin receptor (P)PR is expressed in the central nervous system (CNS). In humans, variants of ATP6AP2 have been linked to neurodegenerative disorders and mental retardation and to changes in the volume of the hippocampus-a limbic brain structure that is capable of adult hippocampal neurogenesis. Cell proliferation in the adult dentate gyrus (DG) can be positively modulated by voluntary exercise. Somewhat surprisingly, we have recently shown that ATP6AP2 overexpression does not show any significant effects on the number of newly generated cells in the DG in transgene-heterozygous mice. Therefore, we now analyzed the effects of voluntary exercise on cell proliferation in the adult hippocampus in female mice overexpressing ATP6AP2 on both alleles. ATP6AP2 mRNA levels in forebrain and hippocampus were increased dose-dependently compared with wild-type mice, with homozygous exhibiting stronger effects than heterozygous mice. Full-length ATP6AP2 protein levels were also increased dose-dependently in forebrain, but the protein fragment representing the soluble prorenin receptor was not. In total hippocampus extracts, no significant differences in ATP6AP2 protein levels were found. However, in the DG, ATP6AP2 immunoreactivity was markedly increased. While the running pattern of mice with access to a running wheel was similar between the groups, cell proliferation, as indicated by BrdU staining, was increased in wild-type mice as expected, but failed to increase in homozygous ATP6AP2 mice. This finding indicates that ATP6AP2 overexpression does not affect basal adult cell proliferation per se but inhibits plastic changes in the rate of cell proliferation. Thus, ATP6AP2 appears to selectively limit exercise-dependent regulation in the hippocampus rather than baseline neurogenic capacity.