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-β protein precursor and presenilin-1 (AβPPswe/PS1ΔE9) and investigated at 6 or 9 months of age. Partial loss of GLT-1 unmasked spatial memory deficits in 6-month-old mice expressing AβPPswe/PS1ΔE9, with these mice also exhibiting an increase in the ratio of detergent-insoluble Aβ42/Aβ40. At 9 months both behavioral performance and insoluble Aβ42/Aβ40 ratios among GLT-1(+/+)/AβPPswe/PS1ΔE9 and GLT-1(+/-)/AβPPswe/PS1ΔE9 mice were comparable. These results suggest that deficits in glutamate transporter function compound the effects of familial AD AβPP/PS1 mutant transgenes in younger animals and thus may contribute to early occurring pathogenic processes associated with AD.

• Authors: Paramita Mookherjee, Pattie S Green, G Stennis Watson, Marcos A Marques, Kohichi Tanaka, Kole D Meeker, James S Meabon, Ning Li, Ping Zhu, Valerie G Olson, David G Cook
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 26 Issue 3 Pg. 447-55 ( 2011) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 21677376 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Excitatory Amino Acid Transporter 2
• Presenilin-1
• Slc1a2 protein, mouse

Topics

• Aging (psychology)
• Alzheimer Disease (genetics, metabolism)
• Amyloid beta-Peptides (genetics, metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Behavior, Animal (physiology)
• Blotting, Western
• Brain Chemistry
• Cognition Disorders (genetics, metabolism)
• Cohort Studies
• Enzyme-Linked Immunosorbent Assay
• Excitatory Amino Acid Transporter 2 (genetics, metabolism)
• Maze Learning
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation
• Presenilin-1 (genetics)