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The-Scientist.com, July 29, 2009, by Jef Akst  —  Researchers report a step forward in understanding the pathology of Alzheimer’s disease. Two genes that are commonly mutated in the early-onset form of Alzheimer’s may cause the disorder by altering how presynaptic neurons release neurotransmitters, according to a study published this week in Nature.

The mechanism may apply to other neurodegenerative disorders as well, the researchers say.

“This is a new concept that’s interesting to know,” said molecular neurobiologist Ilya Bezprozvanny of the Southwestern Medical Center at Dallas, who was not involved in the work.

 

More than 100 different mutations in two genes coding for the proteins presenilin 1 and 2 are associated with early-onset Alzheimer’s disease, but the exact effects of these mutations on neural function is still unclear. “It’s the first [study] suggesting that presenilins play a presynaptic role,” Bezprozvanny said.

In 2007, molecular geneticist and neuroscientist Jie Shen of Harvard Medical School and her colleagues created knockout mice that lacked both presenilin genes and found memory deficits and neurodegeneration in the brain — two key features of Alzheimer’s disease. In the current study, Shen set out to determine on which side of the synapse presenilins exert their effect by creating two strains of knockouts: one that lacked both presinilin genes only in the presynaptic neurons of a synapse in the hippocampus — a brain region that plays an important role in memory — and another where the genes were knocked out just post-synaptically.

Measuring neural activity in dissected brain sections from the two strains of knockout mice, the researchers were able to compare the effects of presenilins on pre- and post-synatpic activity. In presynaptic presenilin knockout mice, the researchers found drastically reduced long-term potentiation (LTP) — a physiological measure of memory formation. In postsynaptic presenilin knockouts, however, LTP was normal.

Knocking out presynaptic presenilins also altered other aspects of neuronal function and reduced the probability of neurotransmitter release. “Our earlier work led us to focus on NMDA receptors, which are postsynaptic receptors,” Shen said. “This [work] led us to see the importance of the presynaptic function.”

Neurotransmitter release depends on increases in calcium levels within the neuron. By blocking the release of calcium from the endoplasmic reticulum — an intracellular source of calcium — the researchers mimicked the effects of the presynaptic presenilin knockouts in control mice. This result points to intracellular calcium release as a possible mechanism by which presenilins regulate neuronal function.

“The main take home message is there is a difference in the way neurons process calcium levels in absence of presenilins, and that has an effect on synaptic [function],” said Bezprozvanny. However, he cautioned, it’s not clear how directly the findings can be applied to Alzheimer’s disease. “This is not an Alzheimer’s mouse model. This is a presenilin knockout.”

Researchers studying neurodegenerative diseases have long debated whether knocking out these genes is a good model for Alzheimer’s because the exact role of the many presenilin mutations associated with the disease is unclear. Some argue that these mutations result in a ‘loss of function,’ in which case a knockout model would appropriately represent the changes that occur in Alzheimer’s patients. Others argue that these mutations result in a ‘gain of function,’ or a change that cannot be replicated by knocking out the genes entirely.

If patients with Alzheimer’s disease do indeed have non-functioning presenilin genes, the results of this study may suggest that presynaptic neurotransmitter release is a more general mechanism of neurodegenerative diseases. For example, Shen and her colleagues found a presynaptic effect in a mouse model of Parkinson’s disease. These changes “might be a precursor to neurodegeneration,” Shen said, and might therefore provide new targets for disease therapies.

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