在阿尔茨海默病小鼠模型中检测基因多样性对大脑组成的影响。

Detecting the effect of genetic diversity on brain composition in an Alzheimer's disease mouse model.

作者信息

Gurdon Brianna, Yates Sharon C, Csucs Gergely, Groeneboom Nicolaas E, Hadad Niran, Telpoukhovskaia Maria, Ouellette Andrew, Ouellette Tionna, O'Connell Kristen, Singh Surjeet, Murdy Tom, Merchant Erin, Bjerke Ingvild, Kleven Heidi, Schlegel Ulrike, Leergaard Trygve B, Puchades Maja A, Bjaalie Jan G, Kaczorowski Catherine C

机构信息

The Jackson Laboratory, Bar Harbor, ME.

The University of Maine Graduate School of Biomedical Sciences and Engineering, Orono, ME.

出版信息

bioRxiv. 2023 Feb 28:2023.02.27.530226. doi: 10.1101/2023.02.27.530226.

DOI:10.1101/2023.02.27.530226

PMID:36909528

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10002670/

Abstract

Alzheimer's disease (AD) is characterized by neurodegeneration, pathology accumulation, and progressive cognitive decline. There is significant variation in age at onset and severity of symptoms highlighting the importance of genetic diversity in the study of AD. To address this, we analyzed cell and pathology composition of 6- and 14-month-old AD-BXD mouse brains using the semi-automated workflow (QUINT); which we expanded to allow for nonlinear refinement of brain atlas-registration, and quality control assessment of atlas-registration and brain section integrity. Near global age-related increases in microglia, astrocyte, and amyloid-beta accumulation were measured, while regional variation in neuron load existed among strains. Furthermore, hippocampal immunohistochemistry analyses were combined with bulk RNA-sequencing results to demonstrate the relationship between cell composition and gene expression. Overall, the additional functionality of the QUINT workflow delivers a highly effective method for registering and quantifying cell and pathology changes in diverse disease models.

摘要

阿尔茨海默病（AD）的特征是神经退行性变、病理积累和进行性认知衰退。发病年龄和症状严重程度存在显著差异，这突出了基因多样性在AD研究中的重要性。为了解决这个问题，我们使用半自动工作流程（QUINT）分析了6个月和14个月大的AD-BXD小鼠大脑的细胞和病理组成；我们对该流程进行了扩展，以允许对脑图谱配准进行非线性优化，以及对图谱配准和脑切片完整性进行质量控制评估。我们检测到小胶质细胞、星形胶质细胞和淀粉样β蛋白积累几乎在整体上随年龄增加，而不同品系之间神经元负荷存在区域差异。此外，海马免疫组织化学分析与大量RNA测序结果相结合，以证明细胞组成与基因表达之间的关系。总体而言，QUINT工作流程的附加功能提供了一种高效的方法，用于在各种疾病模型中对细胞和病理变化进行配准和量化。