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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-literature | 2011

REPOSITORIES: biostudies-literature

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

Mookherjee Paramita P Green Pattie S PS Watson G Stennis GS Marques Marcos A MA Tanaka Kohichi K Meeker Kole D KD Meabon James S JS Li Ning N Zhu Ping P Olson Valerie G VG Cook David G DG

Journal of Alzheimer's disease : JAD 20110101 3

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(+/-) ...[more]

PMID: 21677376

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Project description:BackgroundAlzheimer's disease (AD) is an unmet medical need worldwide, and physical inactivity is a risk factor for AD. Performing physical exercise is difficult at old age, and thus, decline in physical movement may be a cause of age-associated lowering of the brain function. This study aimed to elucidate the molecular mechanism and onset of the skeletal muscle atrophy-induced acceleration of AD.MethodsPre-symptomatic young 5XFAD or non-transgenic wildtype mice were used. The bilateral hindlimbs were immobilized by placing them in casts for 14 days. Cognitive function was evaluated using the object recognition and spatial memory tests. Further, the hindlimb muscles were isolated for organ culture. Conditioned media (CM) of each muscle was separated by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Protein expressions in the CM were analysed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry analysis. The expression levels of candidate proteins were quantified using ELISA. After continuous intracerebroventricular (i.c.v.) infusion of recombinant hemopexin, cognitive function was evaluated. Gene microarray analysis of the hippocampus was performed to investigate the molecules involved in the accelerated memory deficit. Real-time reverse transcription polymerase chain reaction and histological analysis confirmed the expression.ResultsCasting for 2 weeks reduced skeletal muscle weight. Object recognition memory in the cast-attached 5XFAD mice (n = 7, training vs. test, P = 0.3390) was impaired than that in age-matched wildtype (n = 7, training vs. test, P = 0.0523) and non-cast 5XFAD mice (n = 7, training vs. test, P = 0.0473). On 2D-PAGE, 88 spots were differentially expressed in muscle CM. The most increased spot in the cast-attached 5XFAD CM was hemopexin. Hemopexin levels in the skeletal muscle (n = 3, P = 0.0064), plasma (n = 3, P = 0.0386), and hippocampus (n = 3, P = 0.0164) were increased in cast-attached 5XFAD mice than those in non-cast 5XFAD mice. Continuous i.c.v. infusion of hemopexin for 2 weeks induced memory deficits in young 5XFAD mice (n = 4, training vs. test, P = 0.6764). Lipocalin-2 (Lcn2) messenger RNA (mRNA), neuroinflammation-associated factor, was increased in the hippocampus in hemopexin-infused 5XFAD mice than in control mice. LCN2 protein in the hippocampus was localized in the neurons, but not glial cells. Lcn2 mRNA levels in the hippocampus were also increased by cast-immobilization of the hindlimbs (n = 6, P = 0.0043).ConclusionsThese findings provide new evidence indicating that skeletal muscle atrophy has an unbeneficial impact on the occurrence of memory impairment in young 5XFAD mice, which is mediated by the muscle secreted hemopexin.

Dataset Information

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

Publications

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

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