Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy

NEUROBIOLOGY OF AGING

卷:34

Article

Nash, Kevin R.¹  Lee, Daniel C.²  Hunt, Jerry B., Jr.²  Morganti, Josh M.³  Selenica, Maj-Linda²  Moran, Peter¹  Reid, Patrick²  Brownlow, Milene¹  Yang, Clement Guang-Yu²  Savalia, Miloni²  Gemma, Carmelina⁴  Bickford, Paula C.^5,6  Gordon, Marcia N.¹  Morgan, David¹ 

[1] Univ S Florida, Byrd Alzheimer Inst, Dept Mol Pharmacol & Physiol, Tampa, FL 33613 USA

[2] USF, Byrd Alzheimer Inst, Coll Pharm, Dept Pharmaceut Sci, Tampa, FL USA

[3] Univ Calif San Francisco, Brain & Spinal Injury Ctr, San Francisco, CA 94143 USA

[4] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA

[5] James A Haley Vet Affairs Hosp, Res Serv, Dept Neurosurg & Brain Repair, Tampa, FL USA

[6] Ctr Excellence Aging & Brain Repair USF, Tampa, FL USA

关键词: Tau;    Neurodegeneration;    Fractalkine;    Alzheimer;   

DOI  :  10.1016/j.neurobiolaging.2012.12.011

来源: Elsevier

【 摘 要 】

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. (C) 2013 Elsevier Inc. All rights reserved.

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