BACKGROUND Multiomic studies by several groups in the NIH Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) identified VGF as a major driver of Alzheimer's disease (AD), also finding that reduced VGF levels correlate with mean amyloid plaque density, Clinical Dementia Rating (CDR) and Braak scores. VGF-derived peptide TLQP-21 activates the complement C3a receptor-1 (C3aR1), predominantly expressed in the brain on microglia. However, it is unclear how mouse or human TLQP-21, which are not identical, modulate microglial function and/or AD progression. METHODS We performed phagocytic/migration assays and RNA sequencing on BV2 microglial cells and primary microglia isolated from wild-type or C3aR1-null mice following treatment with TLQP-21 or C3a super agonist (C3aSA). Effects of intracerebroventricular TLQP-21 delivery were evaluated in 5xFAD mice, a mouse amyloidosis model of AD. Finally, the human HMC3 microglial cell line was treated with human TLQP-21 to determine whether specific peptide functions are conserved from mouse to human. RESULTS We demonstrate that TLQP-21 increases motility and phagocytic capacity in murine BV2 microglial cells, and in primary wild-type but not in C3aR1-null murine microglia, which under basal conditions have impaired phagocytic function compared to wild-type. RNA sequencing of primary microglia revealed overlapping transcriptomic changes induced by treatment with TLQP-21 or C3a super agonist (C3aSA). There were no transcriptomic changes in C3aR1-null or wild-type microglia exposed to the mutant peptide TLQP-R21A, which does not activate C3aR1. Most of the C3aSA- and TLQP-21-induced differentially expressed genes were linked to cell migration and proliferation. Intracerebroventricular TLQP-21 administration for 28 days via implanted osmotic pump resulted in a reduction of amyloid plaques and associated dystrophic neurites and restored expression of subsets of Alzheimer-associated microglial genes. Finally, we found that human TLQP-21 activates human microglia in a fashion similar to activation of murine microglia by mouse TLQP-21. CONCLUSIONS These data provide molecular and functional evidence suggesting that mouse and human TLQP-21 modulate microglial function, with potential implications for the progression of AD-related neuropathology.

中文翻译：

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VGF 衍生肽 TLQP-21 通过 C3aR1 信号通路调节小胶质细胞功能，并减少 5xFAD 小鼠的神经病理学。

背景 NIH 阿尔茨海默病加速药物合作伙伴关系 (AMP-AD) 的多个小组进行的多组学研究确定 VGF 是阿尔茨海默病 (AD) 的主要驱动因素，还发现 VGF 水平降低与平均淀粉样斑块密度、临床痴呆评级相关。 CDR）和 Braak 分数。VGF 衍生肽 TLQP-21 可激活补体 C3a 受体 1 (C3aR1)，该受体主要在大脑中的小胶质细胞上表达。然而，目前尚不清楚小鼠或人类 TLQP-21（它们不相同）如何调节小胶质细胞功能和/或 AD 进展。方法 我们对用 TLQP-21 或 C3a 超级激动剂 (C3aSA) 治疗后从野生型或 C3aR1 缺失小鼠中分离的 BV2 小胶质细胞和原代小胶质细胞进行吞噬/迁移测定和 RNA 测序。在 5xFAD 小鼠（AD 小鼠淀粉样变性模型）中评估了脑室内 TLQP-21 递送的效果。最后，用人 TLQP-21 处理人 HMC3 小胶质细胞系，以确定特定肽功能在小鼠和人之间是否保守。结果我们证明，TLQP-21 增加了小鼠 BV2 小胶质细胞和原代野生型小鼠小胶质细胞的运动性和吞噬能力，​​但不增加 C3aR1 缺失小鼠小胶质细胞的活力和吞噬能力，​​与野生型相比，C3aR1 缺失的小鼠小胶质细胞在基础条件下吞噬功能受损。原代小胶质细胞的 RNA 测序揭示了 TLQP-21 或 C3a 超级激动剂 (C3aSA) 治疗诱导的重叠转录组变化。暴露于突变肽TLQP-R21A（不会激活C3aR1）的C3aR1缺失或野生型小胶质细胞中没有转录组变化。大多数 C3aSA 和 TLQP-21 诱导的差异表达基因与细胞迁移和增殖有关。通过植入渗透泵脑室内给予 TLQP-21 28 天，导致淀粉样斑块和相关营养不良性神经突减少，并恢复阿尔茨海默病相关小胶质细胞基因子集的表达。最后，我们发现人类 TLQP-21 激活人类小胶质细胞的方式类似于小鼠 TLQP-21 激活小鼠小胶质细胞。结论 这些数据提供了分子和功能证据，表明小鼠和人类 TLQP-21 调节小胶质细胞功能，对 AD 相关神经病理学的进展具有潜在影响。