Impaired glutamate transport in a mouse model of tau pathology in astrocytes.
Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of tauopathies. The discovery of microtubule-associated protein tau gene mutations that are pathogenic for a heterogenous group of neurodegenerative disorders, called frontotemporal dementia and parkinsonism linked to chromosome-17 (FTDP-17), directly implicate tau abnormalities in the onset/progression of disease. Although the role of tau pathology in neurons in disease pathogenesis is well accepted, the contribution of glial pathology is essentially unknown. We recently generated a transgenic (Tg) mouse model of tau pathology in astrocytes by expressing the human tau protein under the control of the glial fibrillary acidic protein (GFAP) promoter. Both wild-type and FTDP-17 mutant GFAP/tau Tg animals manifest an age-dependent accumulation of tau inclusions in astrocytes that resembles the pathology observed in human tauopathies. We further demonstrate that both strains of Tg mice manifest compromised motor function that correlates with altered expression of the glial glutamate-aspartate transporter and occurs before the development of tau pathology. Subsequently, the Tg mice manifest additional deficits in neuromuscular strength that correlates with reduced expression of glutamate transporter-1 (GLT-1) and occurs concurrent with tau inclusion pathology. Reduced GLT-1 expression was associated with a progressive decrease in sodium-dependent glutamate transport capacity. Reductions in GLT-1 expression were also observed in corticobasal degeneration, a tauopathy with prominent pathology in astrocytes. Less robust changes were observed in Alzheimer's disease in which neuronal tau pathology predominates. Thus, these Tg mice recapitulate features of astrocytic pathology observed in tauopathies and implicate a role for altered astrocyte function in the pathogenesis of these disorders.
Dabir
Deepa V
DV
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Robinson
Michael B
MB
Swanson
Eric
E
Zhang
Bin
B
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
Forman
Mark S
MS
D019943:Amino Acid Substitution; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism; D004195:Disease Models, Animal; D027341:Excitatory Amino Acid Transporter 1 / Q000172:deficiency / Q000502:physiology; D027342:Excitatory Amino Acid Transporter 2 / Q000172:deficiency / Q000502:physiology*; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018908:Muscle Weakness / Q000235:genetics / Q000503:physiopathology; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D024801:Tauopathies / Q000378:metabolism*; D016875:tau Proteins
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C493393:Slc1a3 protein, mouse; D016875:tau Proteins