Phospholipase D1 Mediated Early Events Affecting Synaptic Dysfunction in Alzheimer's Disease and Related Dementia

项目总结/文摘

PROJECT SUMMARY/ABSTRACT In the pursuit of our therapeutic/mechanistic study to address our hypothesis that inducible phospholipase D (PLD1) overexpression contributes to the progressive detrimental impact on AD-cog- nitive deficits, we have published two papers that highlights how attenuating PLD1 levels contributes to synaptic resilience by preserving dendritic spines that is observed at the synaptic level and measur- able using two different kind of memory tests affected in dementia. Moreover, using the 3xTg-AD model, we assessed a sex-specific and a temporally designed approach of chronic attenuation that confirmed our hypothesis that inhibiting the recruitment of PLD1 by Aβ and tau both at early stages and late stages remains efficacious in promoting synaptic preservation. Surprisingly, when using immunofluorescence to confirm the reduced co-localization of PLD1 and these amyloidogenic threats, we also observed a reduction in the Aβ levels in specific hippocampal subregions. Moreover, this reduction was also ob- served in altered morphology of the plaques. As a result, we propose to investigate this mechanism of action, which extends the field ahead in terms of what outcomes the PLD1 attenuation has on amyloid protein chemistry in diseased states. Under the premise of this supplement, we are requesting addi- tional funds that would increasing the resolving power of our already existing microscopy resource at the Mitchell Center and allow us to dissect the mechanism in a better qualitative and quantitative man- ner leading to increased confidence in the therapeutic abilities associated with our approach.