Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA.
Department of Neurology, University of Florida, Gainesville, FL, 32610, USA.
Alzheimers Res Ther. 2022 Jul 27;14(1):104. doi: 10.1186/s13195-022-01044-1.
The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer's disease (AD), but little is known about its function in relation to AD pathogenesis.
Here, we use a mouse model that is deficient in Abi3 locus to study how the loss of function of Abi3 impacts two cardinal neuropathological hallmarks of AD-amyloid β plaques and tau pathology. Our study employs extensive neuropathological and transcriptomic characterization using transgenic mouse models and adeno-associated virus-mediated gene targeting strategies.
Analysis of bulk RNAseq data confirmed age-progressive increase in Abi3 levels in rodent models of AD-type amyloidosis and upregulation in AD patients relative to healthy controls. Using RNAscope in situ hybridization, we localized the cellular distribution of Abi3 in mouse and human brains, finding that Abi3 is expressed in both microglial and non-microglial cells. Next, we evaluated Abi3 mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Using multiple transcriptomic datasets, we show that expression of Abi3 and Gngt2 are tightly correlated in rodent models of AD and human brains, suggesting a tight co-expression relationship. RNAseq of the Abi3-Gngt2 mice revealed upregulation of Trem2, Plcg2, and Tyrobp, concomitant with induction of an AD-associated neurodegenerative signature, even in the absence of AD-typical neuropathology. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in Aβ deposition. Additionally, in Abi3-Gngt2 mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, using in vitro culture assays, we show that the AD-associated S209F mutation alters the extent of ABI3 phosphorylation.
These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function and early inflammatory gliosis in AD. Our studies also demonstrate that inflammatory gliosis could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting immune pathways in AD.
Abelson 相互作用蛋白 3（ABI3）的 S209F 变体增加了阿尔茨海默病（AD）的风险，但对于其与 AD 发病机制的关系知之甚少。
在这里，我们使用缺乏 Abi3 基因座的小鼠模型来研究 Abi3 功能丧失如何影响 AD 的两个主要神经病理学标志——淀粉样β斑块和 tau 病理学。我们的研究采用了广泛的神经病理学和转录组学特征分析，使用转基因小鼠模型和腺相关病毒介导的基因靶向策略。
使用批量 RNAseq 数据分析证实，在 AD 型淀粉样变性的啮齿动物模型中，Abi3 水平随年龄呈进行性增加，并且 AD 患者相对于健康对照上调。使用 RNAscope 原位杂交，我们定位了 Abi3 在小鼠和人大脑中的细胞分布，发现 Abi3 在小胶质细胞和非小胶质细胞中均有表达。接下来，我们评估了 Abi3 小鼠，并证明这些小鼠中 Abi3 和其重叠基因 Gngt2 均被破坏。使用多个转录组数据集，我们表明 Abi3 和 Gngt2 在 AD 啮齿动物模型和人类大脑中的表达紧密相关，表明它们存在紧密的共表达关系。对 Abi3-Gngt2 小鼠的 RNAseq 分析显示，即使在没有 AD 典型神经病理学的情况下，Trem2、Plcg2 和 Tyrobp 也会上调，同时诱导与 AD 相关的神经退行性特征。在 APP 小鼠中，Abi3-Gngt2 的缺失导致 Aβ 沉积的剂量和年龄依赖性减少。此外，在 Abi3-Gngt2 小鼠中，人源 tau 的促聚集形式的表达加剧了 tau 病和星形胶质细胞增生。此外，使用体外培养测定，我们表明 AD 相关的 S209F 突变改变了 ABI3 磷酸化的程度。
这些数据为了解 Abi3-Gngt2 功能和 AD 中的早期炎症性神经胶质细胞在 AD 中的作用提供了重要的实验框架。我们的研究还表明，炎症性神经胶质细胞对淀粉样蛋白和 tau 病理学可能有相反的影响，突出了在 AD 中靶向免疫途径的不可预测性。
