Investigations on the Cellular Mechanisms of Ccl5 in Memory Formation and Its Role in Alzheimer’S Disease

Alzheimer’s disease (AD) is the most common cause of dementia. There are 240,000 AD patients in Taiwan currently. How to improve the therapy for AD and studies on AD are critical. Hallmarks of Alzheimer’s disease is amyloidogenesis - amyloid beta (Aβ) deposition and tauopathy – hyperphosphorylated tau protein in neurons. Cellular energy impairment facilitates disease progression. The energy sensor AMPKα, is a tau kinase, and is robustly up regulated in postmortem AD brains. It is thought to promote the pathogenesis in AD. Aβ inhibits mitochondria enzyme generation and p-Tau disturbs mitochondrial transport; both are also implicated in the pathogenesis of Alzheimer's disease. Reducing Aβ accumulation, Tau pathology and improving cellular energy and mitochondrial function are important therapeutic targets in Alzheimer’s disease. CCL5/RANTES derived from astrocytes and contributing to neuronal activity and neuritic growth in Huntington’s disease, is also highly correlated with AD. AD patients have lower CCL5/RANTES in serum; CCL5/RANTES can enhance Aβ clearance and prevent neuron death from Aβ neuronal toxicity in animal models and cellular studies. The role and importance of CCL5/RANTES in AD remains unclear. CCL5/RANTES has many positive effects on neurons. We found that CCL5/RANTES induces GLUT4 membrane translocation and reduces cellular AMPKα activation. CCL5/RANTES administration improves neuritic outgrowth and axon genesis inhibited by activating AMPKα. CCL5-knockout (KO) mice have impaired memory formation in our preliminary study. Reintroducing recombinant CCR5/RANTES into KO mice hippocampus improved memory performance and increased synaptic plasticity-related molecules expression in our preliminary work. Thus, CCL5/RANTES could be a plausible treatment for AD and the cellular mechanisms of CCL5/RANTES role in AD and memory formation is investigated in this current proposal. We propose to evaluate CCL5 effects on memory formation and cognition in animals and investigate the possible cellular mechanisms of CCL5/RANTES effects in memory formation, such as on mitochondrial function and synaptogenesis related mechanisms. Finally, we will investigate the role of CCL5 in Alzheimer's disease. We will investigate the protective effects of CCL5/RANTES on Aβ toxicity in mouse hippocampal-neurons in vitro and the effects of CCL5/RANTES in AD memory and Aβ deposit-induced toxicity in a transgenic AD mouse model.