THE PHOSPHORYLATION STATE OF AMYLOID PRECURSOR PROTEIN IS ASSOCIATED WITH INCREASED AMYLOIDOGENIC PROCESSING IN ISCHEMIC STROKE
Document Type
Presentation
Start Date
22-10-2010 3:00 PM
End Date
22-10-2010 4:30 PM
Description
There is clinical and experimental evidence that stroke plays an important role in the occurrence and severity of sporadic Alzheimer's disease (AD). Although the cause of AD is still unknown, abnormal accumulation of amyloid 13 peptide (Al3) aggregates is believed to be the causative of the neuronal loss and inflammation typically associated to the disease. The production of A13 is mediated by the sequential cleavage of amyloid precursor protein (APP) through the amyloidogenic pathway. Using an in vivo model of ischemic stroke, we tested the hypothesis that ischemia directly alters APP metabolism and promotes Al3 accumulation. Sprague-Dawley rats were subjected to 2h of middle cerebral artery occlusion and after 3 days of reperfusion, brain samples from ischemic and contralateral (control) regions were collected. Western blot analysis of brain homogenates demonstrated that in ischemic tissue, APP is more abundantly glycosylated as compared to control brain extracts. The increase in APP maturation (glycosylation) was accompanied by significant increase in Al3 levels, as measured by ELISA, and increased sAPPl3 and CTF-13 immunoreactivity, diagnostic of APP entering the amyloidogenic route. We also found that increased glycosylation of APP correlated with a loss of phosphorylation state at the Threonine-688 residue, which has been shown to control APP trafficking. Our finding proposes a new mechanism to explain Al3 accumulation upon ischemic stroke and may help develop new therapeutic approaches.
Recommended Citation
Pacheco-Quinto, Javier; Belayev, L.; Khoutorova, L.; and Atkins, K. D., "THE PHOSPHORYLATION STATE OF AMYLOID PRECURSOR PROTEIN IS ASSOCIATED WITH INCREASED AMYLOIDOGENIC PROCESSING IN ISCHEMIC STROKE" (2010). Dr. Joseph M. Moerschbaecher, III Graduate Research Day. 15.
https://digitalscholar.lsuhsc.edu/grad_rs/2010/poster2/15
THE PHOSPHORYLATION STATE OF AMYLOID PRECURSOR PROTEIN IS ASSOCIATED WITH INCREASED AMYLOIDOGENIC PROCESSING IN ISCHEMIC STROKE
There is clinical and experimental evidence that stroke plays an important role in the occurrence and severity of sporadic Alzheimer's disease (AD). Although the cause of AD is still unknown, abnormal accumulation of amyloid 13 peptide (Al3) aggregates is believed to be the causative of the neuronal loss and inflammation typically associated to the disease. The production of A13 is mediated by the sequential cleavage of amyloid precursor protein (APP) through the amyloidogenic pathway. Using an in vivo model of ischemic stroke, we tested the hypothesis that ischemia directly alters APP metabolism and promotes Al3 accumulation. Sprague-Dawley rats were subjected to 2h of middle cerebral artery occlusion and after 3 days of reperfusion, brain samples from ischemic and contralateral (control) regions were collected. Western blot analysis of brain homogenates demonstrated that in ischemic tissue, APP is more abundantly glycosylated as compared to control brain extracts. The increase in APP maturation (glycosylation) was accompanied by significant increase in Al3 levels, as measured by ELISA, and increased sAPPl3 and CTF-13 immunoreactivity, diagnostic of APP entering the amyloidogenic route. We also found that increased glycosylation of APP correlated with a loss of phosphorylation state at the Threonine-688 residue, which has been shown to control APP trafficking. Our finding proposes a new mechanism to explain Al3 accumulation upon ischemic stroke and may help develop new therapeutic approaches.
Comments
See abstract book page 59