TMCC2 Associates with Alzheimer’s Disease Pathology in the Human Brain

AbstractTransmembrane and Coiled-Coil 2 (TMCC2) is a protein that forms complexes with both apolipoprotein E (apoE) and the amyloid protein precursor (APP), two proteins central to the etiology of Alzheimer’s disease (AD). Here we have carried out the first investigation of TMCC2 expression in the human brain, where TMCC2 immunoreactivity is primarily neuronal. We also examined TMCC2 localization in late onset AD brains,early onset AD cases bearing a mutation in APP, and in Down syndrome cases. TMCC2 immunoreactivity is closely associated with APP immunoreactivity in both control and AD cases. In all AD cases examined, TMCC2 associated with dense core senile plaques and adjacent dystrophic neurites, but not with amyloid surrounding the core, nor with diffuse amyloid plaques or neurofibrillary tangles. In Down syndrome, we found dystrophic neurites in senile plaques that were positive for amyloid and TMCC2, but not for APP, in addition to the APP- and TMCC2-positive dense cores. Western blot analysis revealed TMCC2 exists as at least three protein isoforms. The relative abundance of the isoforms varies in the temporal gyrus and cerebellum, the relative proportions of which were influenced by APOE and/or dementia status.Taken together, these observations are consistent with the evolutionarily conserved interactions between APP and TMCC2 and suggest cooperation betweenTMCC2 and APP in the normal and AD brain. These findings thus support a role for TMCC2 as a mediator of the impact of apoE on AD pathogenesis.