Deficient glutamate transport is associated with neurodegeneration in Alzheimer's disease.
The mechanisms of synapse damage in Alzheimer's disease (AD) are not fully understood. Deficient functioning of glutamate transporters might be involved in synaptic pathology and neurodegeneration by failing to clear excess glutamate at the synaptic cleft. In AD, glutamate transporter activity as assessed by D-[3H]aspartate binding is decreased; however, it is not clear to what extent it is associated with the neurodegenerative process and cognitive alterations. For this purpose, levels of D- and L-[3H]aspartate binding in midfrontal cortex were correlated with synaptophysin levels, brain spectrin degradation product levels, and clinical and neuropathological indicators of AD. Compared to control brains, AD brains displayed a 34% decrease in levels of D-[3H]aspartate binding, a 30% decrease in L-[3H]aspartate binding, and a 48% loss of synaptophysin immunoreactivity. Increased levels of brain spectrin degradation products correlated with a decrease in levels of D-[3H] and L-[3H]aspartate binding, and decreased levels of synaptophysin immunoreactivity. Levels of L-[3H]aspartate binding correlated with levels of synaptophysin immunoreactivity. These results suggest that decreased glutamate transporter activity in AD is associated with increased excitotoxicity and neurodegeneration, supporting the possibility that abnormal functioning of this system might be involved in the pathogenesis of synaptic damage in AD.
Masliah
E
E
Department of Neurosciences, University of California San Diego, La Jolla 92093-0624, USA.
Alford
M
M
DeTeresa
R
R
Mallory
M
M
Hansen
L
L
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000368:Aged; D027322:Amino Acid Transport System X-AG; D001224:Aspartic Acid / Q000378:metabolism*; D001344:Autopsy; D001692:Biological Transport; D015415:Biomarkers; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D009410:Nerve Degeneration; D016874:Neurofibrillary Tangles / Q000473:pathology; D009928:Organ Specificity; D012016:Reference Values; D012044:Regression Analysis; D013049:Spectrin / Q000032:analysis; D016708:Synaptophysin / Q000032:analysis
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D015415:Biomarkers; D016708:Synaptophysin; D013049:Spectrin; D001224:Aspartic Acid