Cerebral ischemia induces neuronal damage in APP/PS1 double transgenic mice via activation of JNK/P38 pathway

Abstract

Mice expressing human amyloid precursor protein (APP) gene and human mutant presenilin-1 (PS1) gene were more susceptible to photothrombotic stroke than non-transgenic mice with a larger infarct volume plus manifestation of memory impairment. The present study was to investigate the mechanisms. We used Rose Bengal (RB; 1 mg IV for 15 min) to induce photothrombotic stroke in 3-month-old APP/PS1 transgenic and non-transgenic mice which were killed 7 days later, sham stroke groups received RB without illumination. Density of neurons in the hippocampus was counted with Nissl staining, extracellular deposition of beta-amyloid (A-beta) was detected by antibody 6E10 using immunocytochemistry, and mitogen-activated protein kinase (MAPK) pathways and amount of heat shock protein 70 (HSP70) were measured using western blotting. Neuronal density in the hippocampus over the ischemic hemisphere of the stroke group (mean±SEM, 3386?41/mm? n=9) decreased significantly compared with the sham stroke group (4493?03/mm? n=9; P<0.05) of APP/PS1 transgenic mice. No difference of neuronal density over the hippocampus was observed between the stroke and sham stroke groups of non-transgenic mice. Extracellular A-beta deposition was not detected in APP/PS1 transgenic mice or non-transgenic mice. Compared with the sham stroke groups, the MAPK pathways were significantly activated following photothrombotic stroke in APP/PS1 transgenic mice (n=4, P<0.05) but not in non-transgenic mice (n=4, P>0.05). Amount of HSP70 increased over the ischemic hemisphere of non-transgenic mice (n=4, P<0.05) but not APP/PS1 transgenic mice (n=4, P>0.05). In conclusion, post-stroke memory impairment in APP/PS1 transgenic mice is not related to extracellular A-beta deposition. Activation of the MAPK pathways and/or inhibition of HSP70 induction may mediate post-stroke memory impairment in APP/PS1 transgenic mice via increased hippocampal neuronal loss.