ATG5 (autophagy related 5) in microglia controls hippocampal neurogenesis in Alzheimer disease.
ATG5 (autophagy related 5) in microglia controls hippocampal neurogenesis in Alzheimer disease.
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小胶质细胞中的ATG5（自噬相关5）控制阿尔茨海默病中的海马神经发生。
DOI：
10.1080/15548627.2023.2277634
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发表时间：
2023-11
期刊：
影响因子：
13.3
通讯作者：
Xin Tang;Ellen Walter;Eric S. Wohleb;Yanbo Fan;Chenran Wang
中科院分区：
文献类型：
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作者：
Xin Tang;Ellen Walter;Eric S. Wohleb;Yanbo Fan;Chenran Wang
摘要自噬是细胞内物质和受损细胞器的降解过程。自噬与阿尔茨海默病（AD）的进展密切相关。小胶质细胞是脑内的巨噬细胞，最近的研究表明，小胶质细胞中的自噬保护神经元免于神经变性。出生后的神经发生，从成人神经干细胞（NSC）产生新的神经元，在AD患者以及AD动物模型中受损。然而，在AD动物模型中，小胶质细胞自噬对成体神经干细胞和神经发生的影响程度尚未研究。在这里，我们发现，条件性敲除（cKO）的Atg 5（自噬相关5）的小胶质细胞抑制海马齿状回（DG）的出生后的神经发生，但不是在脑室下区（SVZ）的5×FAD小鼠模型。有趣的是，Atg 5对小胶质细胞神经发生的保护作用仅在雌性AD小鼠中观察到。为了证实自噬在小胶质细胞中对出生后海马神经发生的作用，我们产生了额外的cKO小鼠来删除小胶质细胞中的自噬必需基因Rb 1cc 1或Atg 14。然而，这些rb 1cc 1 cKO和atg 14 cKO小鼠在雌性AD小鼠模型中未表现出神经发生缺陷。最后，我们使用CSF 1 R拮抗剂耗尽ATG 5缺陷的小胶质细胞，这种干预恢复了5×FAD小鼠海马中的神经发生。这些结果表明，小胶质细胞ATG 5是必不可少的，以维持出生后海马神经元的AD小鼠模型。我们的研究结果进一步支持了小胶质细胞中的ATG 5支持NSC健康并可能预防神经变性的观点。缩略语名称：5×FAD：家族性阿尔茨海默病; Aβ：β-淀粉样蛋白;广告：阿尔茨海默病; AIF 1：同种异体移植物炎性因子1; ATG：自噬相关; BrdU：5-溴-2 β-脱氧尿苷; CA：角蛋白; cKO：条件性敲除; CSF 1 R：集落刺激因子1受体; Ctrl：对照; DCX：双皮质素; DG：齿状回; GFAP：胶质细胞酸性蛋白; GZ：颗粒区; H&E：苏木精和伊红; IF：免疫荧光; LD：脂滴; LDAM：脂滴积聚的小胶质细胞; LPS：脂多糖; MAP 1 LC 3B/LC 3：微管相关蛋白1轻链3 β; NSC：神经干细胞; RB 1CC 1：RB 1诱导型卷曲螺旋1; SOX 2：SRY（性别决定区Y）-盒2; SGZ：颗粒下区; SVZ：脑室下区; WT：野生型。
ABSTRACT Macroautophagy/autophagy is the intracellular degradation process of cytoplasmic content and damaged organelles. Autophagy is strongly associated with the progression of Alzheimer disease (AD). Microglia are brain-resident macrophages, and recent studies indicate that autophagy in microglia protects neurons from neurodegeneration. Postnatal neurogenesis, the generation of new neurons from adult neural stem cells (NSCs), is impaired in AD patients as well as in AD animal models. However, the extent to which microglial autophagy influences adult NSCs and neurogenesis in AD animal models has not been studied. Here, we showed that conditional knock out (cKO) of Atg5 (autophagy related 5) in microglia inhibited postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus, but not in the subventricular zone (SVZ) of a 5×FAD mouse model. Interestingly, the protection of neurogenesis by Atg5 in microglia was only observed in female AD mice. To confirm the roles of autophagy in microglia for postnatal hippocampal neurogenesis, we generated additional cKO mice to delete autophagy essential genes Rb1cc1 or Atg14 in microglia. However, these rb1cc1 cKO and atg14 cKO mice did not exhibit neurogenesis defects in the context of a female AD mouse model. Last, we used the CSF1R antagonist to deplete ATG5-deficient microglia and this intervention restored neurogenesis in the hippocampus of 5×FAD mice. These results indicate that microglial ATG5 is essential to maintain postnatal hippocampal neurogenesis in a mouse model of AD. Our findings further support the notion that ATG5 in microglia supports NSC health and may prevent neurodegeneration. Abbreviations: 5×FAD: familial Alzheimer disease; Aβ: β-amyloid; AD: Alzheimer disease; AIF1: allograft inflammatory factor 1; ATG: autophagy related; BrdU: 5-bromo-2ʹ-deoxyuridine; CA: Cornu Ammonis; cKO: conditional knock out; CSF1R: colony stimulating factor 1 receptor; Ctrl: control; DCX: doublecortin; DG: dentate gyrus; GFAP: glial fibrillary acidic protein; GZ: granular zone; H&E: hematoxylin and eosin; IF: immunofluorescence; LD: lipid droplet; LDAM: lipid droplets accumulated microglia; LPS: lipopolysaccharides; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; NSCs: neural stem cells; RB1CC1: RB1-inducible coiled-coil 1; SOX2: SRY (sex determining region Y)-box 2; SGZ: subgranular zone; SVZ: subventricular zone; WT: wild type.