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Presenilins are a family of membrane proteins that were linked to hereditary Alzheimer's disease more than a decade ago. Although presenilin inactivation was known to lead to impaired memory and neurodegeneration, two key features of Alzheimer's disease, how it did this was not clear. Now Jie Shen at Harvard Medical School and her colleagues have shed new light on the functions of presenilins by showing that they regulate neurotransmitter release at synapses — the specialized connections between neurons — in the mouse hippocampus (see page 632). Shen tells Nature more.

Why did you focus on the hippocampus?

Because this region is essential to learning and memory, and is particularly vulnerable in Alzheimer's disease. In addition, the synaptic mechanisms that underlie memory have been best studied in the hippocampus. Synapses pass information chemically from a presynaptic cell to a postsynaptic cell. We were able to genetically inactivate presenilins in mice in either pre- or postsynaptic hippocampal neurons.

Did presenilin inactivation have different effects on pre- and postsynaptic neurons?

Yes. Synaptic transmission and plasticity — the ability of the synapse to change in strength — were normal when presenilins were inactivated in postsynaptic neurons. By contrast, when we inactivated presenilins in presynaptic neurons, we observed an impairment in the induction of long-term potentiation, a form of synaptic plasticity that is thought to underlie memory formation.

What causes the impairment?

All presynaptic neurons contain neurotransmitters enclosed in small, membrane-bound vesicles. We determined that presenilins are required in presynaptic neurons for regulating the release of the neurotransmitter glutamate, which is essential to synaptic transmission and plasticity. If we depleted intracellular stores of calcium, or blocked intracellular calcium release, we could mimic the effects of presenilin inactivation in presynaptic neurons. This suggests that presenilins control neurotransmitter release by regulating the release of calcium from intracellular stores.

What are the implications for human health?

There is increasing evidence that loss of presenilin function may have an important role in the development of Alzheimer's disease. We identified the earliest pathogenic changes caused by loss of presenilin function: impaired neurotransmitter release and impaired calcium homeostasis. These might provide new therapeutic targets.