Alterations of zinc transporter proteins ZnT-1, ZnT-4 and ZnT-6 in preclinical Alzheimer's disease brain

Our previous studies demonstrate alterations of zinc (Zn) transporter proteins ZnT-1, ZnT-4 and ZnT-6 in vulnerable brain regions of subjects with mild cognitive impairment (MCI), and early and late stage Alzheimer's disease (AD), suggesting disruptions of Zn homeostasis may play a role in the pathogenesis of AD. A preclinical stage of AD (PCAD) has been described in which subjects show no overt clinical manifestations of AD, but demonstrate significant AD pathology at autopsy. To determine if alterations of ZnT proteins occur in PCAD, we measured ZnT-1, ZnT-4 and ZnT-6 in the hippocampus/ parahippocampal gyrus (HPG) and cerebellum (CER) of seven PCAD subjects and seven age-matched normal control (NC) subjects using Western blot analysis and immunohistochemistry. Our results show a significant decrease (P < 0.05) of ZnT-1 in HPG of PCAD subjects, along with an increase of ZnT-4 in PCAD CER and ZnT-6 in PCAD HPG, but a significant decrease in PCAD CER compared to NC subjects. Confocal microscopy of representative sections of HPG shows altered ZnTs are associated with neurons immunopositive for MC-1, a monoclonal antibody that identifies neurons early in formation of neurofibrillary tangles. Overall, our results suggest that alterations in Zn transport proteins may contribute to the pathology observed in PCAD subjects before onset of clinical symptoms.