Chittimalli Kishore, Adkins Stephen, Arora Sanjay, Singh Jagdish, Jarajapu Yagna P R
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA.
School of Biomedical Sciences, University of North Dakota, Grand Forks, ND, USA.
J Alzheimers Dis Rep. 2024 Jun 21;8(1):981-998. doi: 10.3233/ADR-240024. eCollection 2024.
The APP/PS1 mouse model recapitulates pathology of human Alzheimer's disease (AD). While amyloid-β peptide deposition and neurodegeneration are features of AD, the pathology may involve inflammation and impaired vascular regeneration.
This study evaluated inflammatory environments in the brain and bone marrow (BM), and the impact on brain microvascular density.
BM and frontal cortex from male nine-month-old APP/PS1 or the control C57Bl6/j mice were studied. Vascular density and inflammatory cells were evaluated in the sections of frontal cortex by immunohistochemistry. Different subsets of hematopoietic stem/progenitor cells (BM) and monocyte-macrophages were characterized by flow cytometry and by clonogenic assays. Myelopoietic or inflammatory factors were evaluated by real-time RT-PCR or by western blotting.
CD34 or CD31 vascular structures were lower ( < 0.01, = 6) in the frontal cortex that was associated with decreased number of LinSca-1cKit vasculogenic progenitor cells in the BM and circulation ( < 0.02, = 6) compared to the control. Multipotent progenitor cells MPP4, common lymphoid, common myeloid and myeloid progenitor cells were higher in the APP/PS1-BM compared to the control, which agreed with increased numbers of monocytes and pro-inflammatory macrophages. The expression of pro-myelopoietic factors and alarmins was higher in the APP/PS1 BM-HSPCs or in the BM-supernatants compared to the control. Frontal cortices of APP/PS1 mice showed higher number of pro-inflammatory macrophages (CD11bF4/80 or CD80) and microglia (OX42Iba1).
These findings show that AD pathology in APP/PS1 mice is associated with upregulated myelopoiesis, which contributes to the brain inflammation and decreased vascularity.
APP/PS1小鼠模型概括了人类阿尔茨海默病（AD）的病理学特征。虽然淀粉样β肽沉积和神经退行性变是AD的特征，但病理学可能涉及炎症和血管再生受损。
本研究评估了大脑和骨髓（BM）中的炎症环境，以及对脑微血管密度的影响。
研究了9月龄雄性APP/PS1小鼠或对照C57Bl6/j小鼠的骨髓和额叶皮质。通过免疫组织化学评估额叶皮质切片中的血管密度和炎症细胞。通过流式细胞术和克隆形成试验对造血干/祖细胞（骨髓）和单核细胞-巨噬细胞的不同亚群进行表征。通过实时RT-PCR或蛋白质免疫印迹法评估骨髓生成或炎症因子。
与对照组相比，额叶皮质中CD34或CD31血管结构较低（<0.01，n = 6），这与骨髓和循环中LinSca-1+cKit血管生成祖细胞数量减少有关（<0.02，n = 6）。与对照组相比，APP/PS1-BM中的多能祖细胞MPP4、常见淋巴祖细胞、常见髓系祖细胞和髓系祖细胞更高，这与单核细胞和促炎巨噬细胞数量增加一致。与对照组相比，APP/PS1骨髓造血干细胞或骨髓上清液中促骨髓生成因子和警戒素的表达更高。APP/PS1小鼠的额叶皮质显示促炎巨噬细胞（CD11b+F4/80或CD80）和小胶质细胞（OX42+Iba1）数量更多。
这些发现表明，APP/PS1小鼠的AD病理学与骨髓生成上调有关，这导致了脑部炎症和血管减少。
