An early pathological process that leads to synaptic loss and decline of cognitive ability in a mouse model of Alzheimer's disease is unraveled in a paper online this week in Nature Neuroscience. This early pathology could be inhibited by a small molecule drug.
Francesco Cecconi and colleagues studied mice that carry a mutated gene known to cause a hereditary form of Alzheimer's disease in people. At the age of three months, these mice lose the ability to remember a threatening environment. The group found that at the same age, the enzyme caspase-3 was activated in the mice's hippocampus ― a brain structure crucial to memory. Caspase-3 is a trigger of nerve cell death, however in this case no hippocampal neurons died. Instead, caspase-3 activity, via activation of a second enzyme, caused the removal of crucial receptor molecules from hippocampal synapses, thereby impairing synapse function. They show that inhibitor of caspase-3 prevented receptor loss from the synapses, and conserved the mice's ability to remember a cage where they had received painful electric shocks.
It remains to be tested, however, whether a caspase-3-dependent mechanism is also responsible for memory decline in early stage Alzheimer's patients, and whether inhibitors of caspase-3 might slow progress of the disease in people.
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