Possible roles of L-phosphoserine in the pathogenesis of Alzheimer's 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.
Klunk
W E
WE
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, PA.
McClure
R J
RJ
Pettegrew
J W
JW
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D006801:Humans; D010768:Phosphoserine / Q000378:metabolism* / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D000613:Aminobutyrates; D016194:Receptors, N-Methyl-D-Aspartate; D010768:Phosphoserine; C012729:2-amino-4-phosphonobutyric acid