CSF transthyretin neuroprotection in a mouse model of brain ischemia.
Brain injury caused by ischemia is a major cause of human mortality and physical/cognitive disability worldwide. Experimentally, brain ischemia can be induced surgically by permanent middle cerebral artery occlusion. Using this model, we studied the influence of transthyretin in ischemic stroke. Transthyretin (TTR) is normally responsible for the transport of thyroid hormones and retinol in the blood and CSF. We found that TTR null mice (TTR(-/-) ) did not show significant differences in cortical infarction 24 h after permanent middle cerebral artery occlusion compared with TTR(+/+) control littermates. However, TTR null mice, heterozygous for the heat-shock transcription factor 1 (TTR(-/-) HSF1(+/-) mice), which compromised the stress response, showed a significant increase in cortical infarction, cerebral edema and the microglial-leukocyte response compared with TTR(+/+) HSF1(+/-) mice. Unexpectedly, we observed novel TTR distribution throughout the infarct, localized to disintegrated β-tubulin III(+) neurons and cell debris. Specific elimination of TTR synthesis in the liver by RNAi had no effect on TTR distribution in the infarct, indicating that the observed TTR infiltration derived from CSF and not from the serum. This finding is corroborated by results from 'in situ' hybridization and real time PCR that excluded the presence of transthyretin mRNA in the infarct and peri-infarct areas. Our data suggest that in conditions of a compromised heat-shock response, CSF TTR contributes to control neuronal cell death, edema and inflammation, thereby influencing the survival of endangered neurons in cerebral ischemia.
Molecular Neurobiology Unit, Institute for Molecular and Cell Biology - IBMC, Porto, Portugal.
Sofia Duque
SD
Santos
Kate Lykke
KL
Lambertsen
Bettina Hjelm
BH
Clausen
Akin
A
Akinc
Rene
R
Alvarez
Bente
B
Finsen
Maria João
MJ
Saraiva
D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002545:Brain Ischemia / Q000134:cerebrospinal fluid / Q000473:pathology* / Q000517:prevention & control*; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000134:cerebrospinal fluid*; D011228:Prealbumin / Q000134:cerebrospinal fluid*
D015415:Biomarkers; D018696:Neuroprotective Agents; D011228:Prealbumin