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P2–380: Role of PKR in a mouse model of neuronal degeneration linked to oxidative stress
Author(s) -
MoutonLiger François,
Rebillat AnneSophie,
Gourmaud Sarah,
Paquet Claire,
Pradier Laurent,
Rooney Thomas,
Hugon Jacques
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.1029
Subject(s) - thiamine , oxidative stress , protein kinase r , neurodegeneration , inflammation , neuroprotection , kinase , endocrinology , biology , medicine , protein kinase a , microbiology and biotechnology , disease , mitogen activated protein kinase kinase
exposures drive A b lowering more than free brain exposure. This implies that at least a portion of CSF A b is locally derived. To further examine this disconnect, we show evidence that CSF A b is subject to local BACE activity within the ventricular system. Methods: To study this, lentivirus BACE RNAi was injected ICV in mice. After 14 days, CSF and brain samples were taken for A b x-40 ELISA analysis and brain tissue processed histologically to determine the extent of lentiviral infection. Results: CSF A b levels from mice injected with lentivirus had a 36% reduction of CSF A b x-40 and a 13% reduction of brain A b x-40 compared to mice injected with empty vector lentivirus. Immunohistochemistry confirmed the injection within the ventricular system and contained minor spread into the surrounding brain tissue. Conclusions: Data suggest that differential drug exposure and local BACE production within the cerebral ventricles in rodents affect CSF A b lowering following BACE inhibition. Therefore, depending on the compound, CSF A b lowering may not be a good surrogate of brain efficacy.