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GLT-1 loss accelerates cognitive deficit onset in an Alzheimer's disease animal model.


ABSTRACT: 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-? protein precursor and presenilin-1 (A?PPswe/PS1?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?PPswe/PS1?E9, with these mice also exhibiting an increase in the ratio of detergent-insoluble A?42/A?40. At 9 months both behavioral performance and insoluble A?42/A?40 ratios among GLT-1(+/+)/A?PPswe/PS1?E9 and GLT-1(+/-)/A?PPswe/PS1?E9 mice were comparable. These results suggest that deficits in glutamate transporter function compound the effects of familial AD A?PP/PS1 mutant transgenes in younger animals and thus may contribute to early occurring pathogenic processes associated with AD.

SUBMITTER: Mookherjee P 

PROVIDER: S-EPMC3256092 | BioStudies | 2011-01-01

REPOSITORIES: biostudies

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