Molecular Pharmacology and Physiology Department, Byrd Alzheimer Institute, University of South Florida, Tampa, FL, USA.
Neurobiol Aging. 2013 Jun;34(6):1540-8. doi: 10.1016/j.neurobiolaging.2012.12.011. Epub 2013 Jan 16.
Alzheimer's disease is characterized by amyloid plaques, neurofibrillary tangles, glial activation, and neurodegeneration. In mouse models, inflammatory activation of microglia accelerates tau pathology. The chemokine fractalkine serves as an endogenous neuronal modulator to quell microglial activation. Experiments with fractalkine receptor null mice suggest that fractalkine signaling diminishes tau pathology, but exacerbates amyloid pathology. Consistent with this outcome, we report here that soluble fractalkine overexpression using adeno-associated viral vectors significantly reduced tau pathology in the rTg4510 mouse model of tau deposition. Furthermore, this treatment reduced microglial activation and appeared to prevent neurodegeneration normally found in this model. However, in contrast to studies with fractalkine receptor null mice, parallel studies in an APP/PS1 model found no effect of increased fractalkine signaling on amyloid deposition. These data argue that agonism at fractalkine receptors might be an excellent target for therapeutic intervention in tauopathies, including those associated with amyloid deposition.
阿尔茨海默病的特征是淀粉样斑块、神经原纤维缠结、神经胶质细胞激活和神经退行性变。在小鼠模型中，小胶质细胞的炎症激活加速了 tau 病理。趋化因子 fractalkine 作为一种内源性神经元调节剂，可抑制小胶质细胞的激活。使用 fractalkine 受体缺失小鼠的实验表明， fractalkine 信号减弱 tau 病理，但加剧淀粉样蛋白病理。与这一结果一致，我们在这里报告，使用腺相关病毒载体过表达可溶性 fractalkine 可显著减少 rTg4510 小鼠 tau 沉积模型中的 tau 病理。此外，这种治疗方法减少了小胶质细胞的激活，并似乎预防了该模型中通常发现的神经退行性变。然而，与 fractalkine 受体缺失小鼠的研究相反，在 APP/PS1 模型中的平行研究发现，增加 fractalkine 信号对淀粉样蛋白沉积没有影响。这些数据表明，fractalkine 受体激动可能是包括与淀粉样蛋白沉积相关的 tau 病治疗干预的一个极好靶点。
