title: 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.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Paramita
authors.initials: P
authors.lastname: Mookherjee
authors.forename: Pattie S
authors.initials: PS
authors.lastname: Green
authors.forename: G Stennis
authors.initials: GS
authors.lastname: Watson
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Marques
authors.forename: Kohichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Kole D
authors.initials: KD
authors.lastname: Meeker
authors.forename: James S
authors.initials: JS
authors.lastname: Meabon
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Olson
authors.forename: David G
authors.initials: DG
authors.lastname: Cook
mesh_terms: D000375:Aging / Q000523:psychology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D001923:Brain Chemistry; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D027342:Excitatory Amino Acid Transporter 2; D053764:Presenilin-1; C493396:Slc1a2 protein, mouse