Neuronal dysfunction and degeneration in Alzheimer's disease and brain trauma

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by significant loss of neuronal function associated with learning and memory. The memory loss in AD has been linked to cholinergic hypoactivity. Mutations in presenilin-1 (PS-1) are responsible for majority of familial AD cases. PS-1 mutations may alter cholinergic signaling, although their precise roles in dementia are unsettled. Neuronal uptake of choline via the high affinity choline transporter (CHT1) is essential for cholinergic neurotransmission. CHT1 is a Na +-dependent, hemicholinium-3 (HC-3) sensitive choline transporter. It is unclear whether cortical neurons exhibit intrinsic CHT1 activity that is altered in AD. We now report that primary cortical neurons express intrinsic and biologically active CHT1, and CHT1-mediated choline uptake activity is significantly reduced in PS-1 M146V mutant knock-in mice. Further kinetic studies using HC-3 binding and cell surface biotinylation assays showed that the PS-1 mutation inhibits CHT1 mediated choline uptake by reducing the ligand binding affinity of CHT1 without significantly altering levels of CHT1 expression in the plasma membrane. These results indicate that alterations in CHT1-mediated high affinity choline uptake in cortical neurons may contribute to Alzheimer's dementia. Traumatic brain injury (TBI) is a significant clinical problem in which patients are left with significant cognitive, behavioral, and communicative disabilities. Prostate Apoptosis Response-4 (Par-4) is a death domain-containing protein characterized as a critical regulator of apoptosis in Alzheimer's disease. Whether Par-4 is involved in neuronal cell death in TBI is unknown. We have generated and characterized mice transgenic for Par-4 under the control of neuron-specific enclose promoter. We found that Par-4 overexpression in cortical neurons drastically increased apoptotic cell death following TBI. Cortical neurons from Par-4 transgenic mice showed a sharper decrease in mitochondrial transmembrane potential, a higher degree of free radical accumulation, and earlier activation of caspase-3 than those from wild-type animals did. A significantly increased volume of cortical injury and exacerbated activation of caspase-3 were observed in Par-4 transgenic mice when compared to wild-type mice in vivo using a weight drop TBI model. Collectively, these data suggest that aberrant Par-4 expression may exacerbate neuronal cell death following TBI by altering mitochondrial function, enhancing oxidative damage, and execution of apoptosis via caspase activation. We provide plausible explanations of how Par-4 may participate in the pathologies surrounding both AD and TBI. Finding a way to restore a properly functioning choline uptake mediated by CHT1 and to prevent aberrant upregulation of Par-4 may prove to be essential for normal neuronal function and survival.