Activated microglia proliferate at neurites of mutant huntingtin-expressing neurons

NEUROBIOLOGY OF AGING

卷:33

Article

Kraft, Andrew D.¹  Kaltenbach, Linda S.^2,3  Lo, Donald C.^2,3  Harry, G. Jean¹ 

[1] NIEHS, Neurotoxicol Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA

[2] Duke Univ, Med Ctr, Ctr Drug Discovery, Durham, NC USA

[3] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA

关键词: Huntington's disease;    Microglia;    Huntingtin;    Htt;    Microgliosis;    Neuron-microglia interaction;    Complement;    Interleukin-6;    Neuroinflammation;    Protein aggregation;    Neurite;    Neurodegeneration;    Slice culture;    Neurotoxicity;   

DOI  :  10.1016/j.neurobiolaging.2011.02.015

来源: Elsevier

【 摘 要 】

In Huntington's disease (HD), mutated huntingtin (mhtt) causes striatal neurodegeneration which is paralleled by elevated microglia cell numbers. In vitro corticostriatal slice and primary neuronal culture models, in which neuronal expression of mhtt fragments drives HD-like neurotoxicity, were employed to examine wild type microglia during both the initiation and progression of neuronal pathology. As neuronal pathology progressed, microglia initially localized in the vicinity of neurons expressing mhtt fragments increased in number, demonstrated morphological evidence of activation, and expressed the proliferation marker, Ki67. These microglia were positioned along irregular neurites, but did not localize with mhtt inclusions nor exacerbate mhtt fragment-induced neurotoxicity. Prior to neuronal pathology, microglia upregulated ionized calcium binding adaptor molecule 1 (Iba1), signaling a functional shift. With neurodegeneration, interleukin-6 and complement component 1q were increased. The results suggest a stimulatory, proliferative signal for microglia present at the onset of mhtt fragment-induced neurodegeneration. Thus, microglia effect a localized inflammatory response to neuronal mhtt expression that may serve to direct microglial removal of dysfunctional neurites or aberrant synapses, as is required for reparative actions in vivo. Published by Elsevier Inc.

【 授权许可】

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