Reduced early hypoxic/ischemic brain damage is associated with increased GLT-1 levels in mice expressing mutant (P301L) human tau.
Mutations in tau proteins are associated with a group of neurodegenerative diseases, termed tauopathies. To investigate whether over-expressing human tau with P301L mutation also affects stroke-induced brain damage, we performed hypoxia/ischemia (H/I) in young adult P301L tau transgenic mice. Surprisingly, brain infarct volume was significantly smaller in transgenic mice compared to wild-type mice 24 h after H/I induction. TUNEL staining also revealed less brain apoptosis in transgenic mice following H/I. H/I resulted in a significant increase in tau fragments generated by caspase activation and a marked decrease in tau phosphorylation at residue T231 in cortex of wild-type but not transgenic mice. Activation of calpain and caspase-3 following H/I was also reduced in transgenic compared to wild-type mice, as reflected by lower levels of the specific spectrin breakdown products generated by calpain or caspase-3. Finally, basal levels of the glial glutamate transporter, GLT-1, were higher in brains of transgenic as compared to wild-type mice. These results support the idea that enhanced levels of GLT-1 in transgenic mice are responsible for reducing H/I-induced brain damage by decreasing extracellular glutamate accumulation and subsequent calpain and caspase activation.
Liao
Guanghong
G
Department of Basic Medical Sciences, COMP, Western University of Health Sciences, Pomona, CA 91766-1854, USA.
Zhou
Miou
M
Cheung
Simon
S
Galeano
James
J
Nguyen
Nam
N
Baudry
Michel
M
Bi
Xiaoning
X
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020520:Brain Infarction / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D019610:Cytoprotection / Q000235:genetics; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009924:Organ Culture Techniques; D015854:Up-Regulation / Q000235:genetics; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics*
D027342:Excitatory Amino Acid Transporter 2; D016875:tau Proteins; D018698:Glutamic Acid; D002154:Calpain; D053148:Caspase 3