Astroglia cells play versatile function in the central nerve system, which known to release chemokine to induce inflammation reaction but also secret other chemokine and trophic factors to support neurons growth. The type five CC chemokine, CCL5/RANTES, supports neuron function by promoting neuronal neurite out growth, branching, and Ca2+ influx from our previous finding. Reduced dendritic spines numbers was found in CCL5/RANTES knockout mice also. Some finding also indicates CCL5/RANTES and its corresponding receptor CCR5 activity can interfere neuronal stem cell differentiation. Increasing evidences support the protective function of CCL5/RANTES on neurons and neuronal disease such as Huntington’s disease, Alzheimer’s disease, and ischemic stroke in the recent years. CCL5 found in mediating Aβ amyloid clearance in AD mice brain, and increasing BDNF, EGF, and VEGF expression in ischemic regions repairmen. Thus, the supporting role of CCL5/RANTES to neurons is our main interest in this study. The cellular mechanism of CCL5/RANTES activating neurons in axon growth and spine formation or neuron differentiation is first Aim in this proposal. There are two signaling pathways known in neuritis growth regulation. PI3K/Akt/GSK-3β signaling determinates the initiation and elongation of axon. Rho family small GTPase and Par3/Par6/aPKC complex plays as a positive feedback loop signal in axon growth maintenance. Recent study identified phosphorylated AMPKα interrupted the binding of PI3K vesicles to kinesin light chain (KLC) in axongenesis process. Our preliminary results showed increased phosphorylation of AMPK in a CCL5 receptor - CCR5 knockout mice brain and primary cultured cortical neuron, reduced axonogenesis was found in parallel. A reduced phosphorylation of PI3K/Akt/GSK-3β signaling proteins was also found in CCR5-/- primary cortical neurons. These suggest a regulatory role of CCL5/CCR5 in AMPK activity, energy homeostasis, and axonogenesis signaling. A further investigation helps us to reveal the cellular mechanism of CCL5 on axonal function maintenance (Aim-2, 3). To understand the possible physical impact with CCL5 and CCR5, the animals’ neurophysiological tests will perform. Our preliminary found an impaired motor coordination and memory in CCL5 deficiency mice. A time dependent study will presume. CCL5 knockout animals will also employee a rescue experiment to confirm CCL5’s function (Aim-4). With these studies, we hope to find out the contribution of CCL5 in neuron function and the possible treatment to neurodegenerative diseases.
|Effective start/end date||8/1/14 → 7/31/15|
- neurite outgrowth
- neurodegenerative disease