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

Article type: Research Article

Authors: Mookherjee, Paramita^{a; i} | Green, Pattie S.^{b; c} | Watson, G. Stennis^{b; d; e} | Marques, Marcos A.^e | Tanaka, Kohichi^f | Meeker, Kole D.^{d; h} | Meabon, James S.^{e; d} | Li, Ning^b | Zhu, Ping^b | Olson, Valerie G.^{b; e; g} | Cook, David G.^{b; c; d; h; *}

Affiliations: [a] Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA | [b] Veterans Affairs Puget Sound Health Care System (VAPSHCS) , Seattle, WA, USA | [c] Department of Medicine, University of Washington School of Medicine, Seattle WA, USA | [d] Geriatric Research Education and Clinical Center (GRECC), VAPSHCS, Seattle, WA, USA | [e] Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA | [f] Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan | [g] Mental Illness Research, Education, and Clinical Center (MIRECC), VAPSHCS, Seattle, WA, USA | [h] Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA | [i] Amgen Inc., Seattle, WA, USA

Correspondence: [*] Correspondence to: David G. Cook, Ph.D., VA Medical Center GRECC, 1660 S. Columbian Way, Seattle, WA 98108, USA. Tel.: +206 768 5437; Fax: +206 764 2569; E-mail: dgcook@u.washington.edu.

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.

Keywords: Amyloid-β, dementia, excitatory, excitotoxicity, neurotransmission

DOI: 10.3233/JAD-2011-110503

Journal: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 447-455, 2011