Impaired neurotransmitter release in Alzheimer's and Parkinson's diseases.

Mutations in several causative genes have been linked to monogenic forms of Alzheimer's disease (AD) or Parkinson's disease (PD). To look for possible common pathogenic mechanisms underlying age-related neurodegeneration in AD and PD, we employed genetic approaches to investigate systematically the roles of these gene products (e.g. presenilins (PS) for AD; Parkin, DJ-1, PINK1 and LRRK2 for PD) in the mouse brain, especially in neural circuits that are particularly vulnerable in AD or PD. Our series of genetic studies revealed that PS play cell type-specific roles in the developing brain with the most prominent function in the maintenance of neural progenitor cells. In the adult cerebral cortex, where the pathogenesis of AD occurs, loss of PS results in progressive memory impairment and age-related neurodegeneration. Specifically, PS are involved in the regulation of long-term potentiation and NMDA receptor functions. Interestingly, our further genetic dissection in the hippocampal Schaeffer collateral pathway highlighted the importance of presynaptic PS in the activity-dependent regulation of glutamate release and long-term potentiation induction via modulation of calcium release from intracellular stores. Intriguingly, our independent genetic analysis of Parkin, DJ-1, PINK1 and LRRK2 showed a common defect in activity-dependent dopamine release caused by PD-linked mutations in these genes. Together, our genetic studies suggest that presynaptic dysfunction might be a converging early pathogenic event before neurodegeneration in AD and PD.