POSSIBLE ROLES OF L-PHOSPHOSERINE IN THE PATHOGENESIS OF ALZHEIMERS-DISEASE

L-Phosphoserine is a membrane metabolite that is elevated in Alzheimer's disease brain. This compound has close structural similarity to L-glutamate. Electrophysiological studies indicate that L-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 Of L-glutamate release or perhaps antagonism of postsynaptic kainic acid receptors. The mechanism of the delayed excitation may lie in the tendency of L-phosphoserine to mimic the action Of L-2-amino-4-phosphonobutyric acid, a blocker of chloride- and calcium-sensitive L-glutamate transport. L-Phosphoserine has also been found to be a competitive antagonist at the N-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 Of L-phosphoserine in Alzheimer's disease, including production memory impairment through presynaptic inhibition Of L-glutamate release or blockade of postsynaptic N-methyl-D-aspartate receptors and/or blockade of certain L-glutamate transport sites resulting in increased L-glutamate levels in the synaptic cleft.