Possible roles ofl-phosphoserine in the pathogenesis of Alzheimer’s disease

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Abstract
L-Phosphoserine is a membrane metabolite that is elevated in Alzheimer’s disease brain. This compound has close structural similarity tol-glutamate. Electrophysiological studies indicate thatl-phosphoserine has an acute inhibitory effect, but a delayed excitatory action. A hypothesis is developed based on pharmacological and electrophysiological studies that suggest that the inhibition may be mediated through presynaptic inhibition ofl-glutamate release or perhaps antagonism of postsynaptic kainic acid receptors. The mechanism of the delayed excitation may lie in the tendency ofl-phosphoserine to mimic the action ofl-2-amino-4-phosphonobutyric acid, a blocker of chloride- and calcium-sensitivel-glutamate transport.l-Phosphoserine has also been found to be a competitive antagonist at theN-methyl-d-aspartate recognition site and an antagonist of metabotropic receptor-mediated hydrolysis of inositol phospholipids. Because of these actions, there are several potentially important implications for the elevation ofl-phosphoserine in Alzheimer’s disease, including production memory impairment through presynaptic inhibition ofl-glutamate release or blockade of postsynapticN-methyl-d-aspartate receptors and/or blockade of certainl-glutamate transport sites resulting in increasedl-glutamate levels in the synaptic cleft.

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