Poluektova Larisa, Meyer Vakara, Walters Lisa, Paez Ximena, Gendelman Howard E
Laboratory of Neuroregeneration, Department of Pharmacology and Experimental Neuroscience, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Glia. 2005 Dec;52(4):344-53. doi: 10.1002/glia.20253.
Cognitive, behavioral, and motor impairments, during progressive human immunodeficiency virus type 1 (HIV-1) infection, are linked to activation of brain mononuclear phagocytes (MP; perivascular macrophages and microglia). Activated MPs effect a giant cell encephalitis and neuroinflammatory responses that are mirrored in severe combined immunodeficient (SCID) mice injected with human monocyte-derived macrophages (MDM). Whether activated human MDMs positioned in the basal ganglia affect hippocampal neuronal plasticity, the brain subregion involved in learning and memory, is unknown. Thus, immunohistochemical techniques were used for detection of newborn neurons (polysialylated neuronal cell adhesion molecule [PSA-NCAM]) and cell proliferation (Ki-67) to assay MDM effects on neuronal development in mouse models of HIV-1 encephalitis. Immunodeficient (C.B.-17/SCID and nonobese diabetic/SCID, NOD/SCID) and immune competent (C.B.-17) mice were injected with uninfected or HIV-1-infected MDM. Sham-operated or unmanipulated mice served as controls. Neuronal plasticity was evaluated in the hippocampal dentate gyrus (DG) at days 7 and 28. By day 7, increased numbers of Ki-67+ cells, PSA-NCAM+ cells and dendrites in DG were observed in sham-operated animals. In contrast, significant reductions in neuronal precursors and altered neuronal morphology paralleled increased microglial activation in both HIV-1-infected and uninfected MDM-injected animals. DG cellular composition was restored at day 28. We posit that activated MDM induce inflammation and diminish DG neuronal plasticity. These data provide novel explanations for the cognitive impairments manifested during advanced HIV-1 infection.
在人类1型免疫缺陷病毒（HIV-1）进行性感染期间，认知、行为和运动障碍与脑单核吞噬细胞（MP；血管周围巨噬细胞和小胶质细胞）的激活有关。活化的MP会引发巨细胞性脑炎和神经炎症反应，这在注射了人单核细胞衍生巨噬细胞（MDM）的严重联合免疫缺陷（SCID）小鼠中也有体现。位于基底神经节的活化人MDM是否会影响海马神经元可塑性（参与学习和记忆的脑区）尚不清楚。因此，采用免疫组织化学技术检测新生神经元（多唾液酸神经元细胞粘附分子[PSA-NCAM]）和细胞增殖（Ki-67），以分析MDM对HIV-1脑炎小鼠模型中神经元发育的影响。给免疫缺陷（C.B.-17/SCID和非肥胖糖尿病/SCID，NOD/SCID）和免疫功能正常（C.B.-17）的小鼠注射未感染或感染HIV-1的MDM。假手术或未处理的小鼠作为对照。在第7天和第28天评估海马齿状回（DG）中的神经元可塑性。到第7天，在假手术动物的DG中观察到Ki-67+细胞、PSA-NCAM+细胞和树突数量增加。相比之下，在注射了感染HIV-1和未感染HIV-1的MDM的动物中，神经元前体细胞显著减少且神经元形态改变，同时小胶质细胞活化增加。在第28天，DG的细胞组成恢复。我们认为活化的MDM会诱导炎症并降低DG神经元可塑性。这些数据为晚期HIV-1感染期间出现的认知障碍提供了新的解释。
