Activated CX3CL1/Smad2 signals prevent neuronal loss and Alzheimer's tau pathology-mediated cognitive dysfunction

Neurofibrillary tangles likely cause neurodegeneration in Alzheimer9s disease (AD). We demonstrate that the CX3CL1 C-terminal domain can upregulate neurogenesis, which may ameliorate neurodegeneration. Here we generated transgenic (Tg-CX3CL1) mice by overexpressing CX3CL1 in neurons. Tg-CX3CL1 mice exhibit enhanced neurogenesis in both subgranular and subventricular zones. This enhanced neurogenesis correlates well with elevated expression of TGFβ2, TGFβ3 and activation of their downstream signaling molecule Smad2. Intriguingly, the enhanced adult neurogenesis was mitigated when Smad2 expression was deleted in neurons, supporting a role for the CX3CL1-TGFβ2/3-Smad2 pathway in the control of adult neurogenesis. When Tg-CX3CL1 mice were crossed with Alzheimer9s PS19 mice, which overexpress a tau P301S mutation and exhibit age-dependent neurofibrillary tangles and neurodegeneration, overexpressed CX3CL1 in both male and female mice was sufficient to rescue the neurodegeneration, increase survival time, and improve cognitive function. Hence, we provide in vivo evidence that CX3CL1 is a strong activator of adult neurogenesis, reduces neuronal loss, and improves cognitive function in Alzheimer9s disease. Significance Statement: This study will be the first to demonstrate the enhanced neurogenesis by overexpressed CX3CL1 is mitigated by disruption of Smad2 signaling and independent of its interaction with CX3CR1. Overexpression of CX3CL1 lengthens the lifespan of PS19 tau mice by enhancing adult neurogenesis while having minimal effect on tau pathology. Enhancing neuronal CX3CL1, mainly the C-terminal fragment, is a therapeutic strategy for blocking or reversing neuronal loss in Alzheimer9s or related neurodegenerative disease patients.