GLT-1 Loss Accelerates Cognitive Deficit Onset in an Alzheimer's Disease Animal Model

Glutamate transporters regulate normal synaptic network interactions and prevent neurotoxicity by rapidly clearing extracellular glutamate. GLT-1, the dominant glutamate transporter in the cerebral cortex and hippocampus, is significantly reduced in Alzheimer's disease (AD). However, the role GLT-1 loss plays in the cognitive dysfunction and pathology of AD is unknown. To determine the significance of GLT-1 dysfunction on AD-related pathological processes, mice lacking one allele for GLT-1(+/-) were crossed with transgenic mice expressing mutations of the amyloid-beta protein precursor and presenilin-1 (A beta PPswe/PS1 Delta E9) and investigated at 6 or 9 months of age. Partial loss of GLT-1 unmasked spatial memory deficits in 6-month-old mice expressing A beta PPswe/PS1 Delta E9, with these mice also exhibiting an increase in the ratio of detergent-insoluble A beta(42)/A beta(40). At 9 months both behavioral performance and insoluble A beta(42)/A beta(40) ratios among GLT-1(+/+)/A beta PPswe/PS1 Delta E9 and GLT-1(+/-)/A beta PPswe/PS1 Delta E9 mice were comparable. These results suggest that deficits in glutamate transporter function compound the effects of familial AD A beta PP/PS1 mutant transgenes in younger animals and thus may contribute to early occurring pathogenic processes associated with AD.