Function and dysfunction of presenilin.

The presenilin(PS) genes harbor approximately 90% of the identified mutations linked to familial forms of Alzheimer's disease, and the presenilin (PS) proteins are essential components of the γ-secretase complex involved in the proteolytic cleavage of type I receptors, such as Notch and the amyloid precursor protein. Genetic analysis employing cell type-specific conditional knockout technology highlighted the importance of PS in the adult brain, including learning and memory, synaptic function and age-dependent neuronal survival. In the central synapse, PS regulates neurotransmitter release, short- and long-term synaptic plasticity and calcium homeostasis. However, the molecular mechanisms by which PS maintains these essential functions are less clear. Although many γ-secretase substrates have been identified, their physiological relevance is often unclear. The findings that nicastrin and PS conditional knockout mice exhibit similar deficits in memory and age-dependent neurodegeneration are consistent with the notion that γ-secretase-dependent activities of PS are required for the maintenance of memory and neuronal survival, though the γ-secretase physiological substrates, Notch receptors, are not targets of PS in the adult brain. Thus, despite of the intense interest in PS since its identification in 1995, more work is needed to define the molecular and cellular mechanisms by which PS controls brain functions and the dysfunction conferred by disease-causing mutations.