G-quadruplex DNA in senescence of the neurovascular unit

项目摘要 神经血管单位(NVU)是一种功能结构，由内皮细胞组成，周围有一个 细胞外基质、神经元、星形胶质细胞和周细胞。NVU能够调节局部脑血液 向脑组织流动和输送营养物质。随着年龄的增长，NVU的结构性减弱，这也是 与炎性信号和运输缺陷有关。关键是，目前还不清楚神经元是如何， 星形胶质细胞、周细胞和内皮细胞在NVU中经历衰老，以及是否有差异 在健康的NVU老化和阿尔茨海默病(AD)的NVU之间的衰老途径中。 G-四链(G4)是一种非规范的DNA二级结构，由四条DNA链组成，其中包括 多次使用鸟嘌呤。G4S在DNA重组、复制和调控中发挥重要作用 抄写。在我们的数据中，我们证明了来自老年小鼠的大脑样本比 幼小的老鼠。我们发现，用小分子G4稳定剂治疗的小鼠会出现认知障碍和 加速大脑老化。使用异慢性异种异生小鼠模型，我们还发现G4S水平 与年龄匹配的同种异生小鼠相比，老年同种异生小鼠大脑中的蛋白质减少，这意味着 年轻因子的存在可以逆转G4S随年龄增长而升高的趋势。旧帕拉比翁的作用 对年轻伴侣的影响更明显(年轻人更多的是G4S)，暗示着 老化因素。重要的是，在AD的小鼠模型中，我们证明了G4S在大脑中稳定存在， 在淀粉样蛋白沉积之前。我们假设这些汇聚的证据指向а 衰老的机制。因此，拟议研究的主要目标是调查与G4有关的 NVU、衰老和AD中的细胞衰老。在目标1中，我们将比较NVU中不同细胞类型的G4S。 在目标2中，我们将确定G4S是否优先积聚在最脆弱的大脑区域的NVU中 神经退行性变。在目标3中，我们将研究外周因子CXCL10是如何影响NVU的G4的 衰老。G4S可能是一种新的途径，可以靶向减轻细胞的有害影响 大脑中的衰老。

Project Summary The neurovascular unit (NVU) is a functional structure that consists of endothelial cells, surrounded by an extracellular matrix, neurons, astrocytes, and pericytes. The NVU enables regulation of regional cerebral blood flow and nutrient delivery to the brain tissue. With aging, a structural weakening of the NVU occurs, which is also associated with inflammatory signaling and transport deficiencies. Critically, it is not clear how neurons, astrocytes, pericytes, and endothelial cells undergo senescence in the NVU, and whether there are differences in senescence pathways between healthy NVU aging and NVU in Alzheimer's diseases (AD). The G-quadruplex (G4) is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G4s play important roles in DNA recombination, replication, and regulation of transcription. In our data, we demonstrated that brain samples from aged mice contain more G4s than that of young mice. We showed that mice treated with a small-molecule G4 stabilizer develop cognitive impairment and accelerated brain aging. Using a heterochronic parabiosis mouse model, we also showed that the levels of G4s are decreased in the brain of old parabiont, compared to the age-matched iso-parabiotic mice, implicating presence of rejuvenating factors that can reverse the elevation of G4s with aging. The effect of the old parabiont on the young partner is more pronounced (more G4s in the young), suggesting a strong negative influence of aging factors. Importantly, in a mouse model of AD, we demonstrated that G4s are stabilized in the brains, well before the deposition of amyloid occurs. We hypothesize that these converging lines of evidence point at а mechanism of senescence. Thus, the primary objective of the proposed studies is to investigate G4-associated cellular senescence in the NVU, in aging and AD. In Aim 1, we will compare G4s across cell types in the NVU. In Aim 2, we will determine whether G4s preferentially accumulate in the NVUs of brain regions most vulnerable to neurodegeneration. In Aim 3, we will investigate how a peripheral factor, CXCL10, contributes to NVU's G4 senescence. G4s might be a novel pathway that can be targeted to mitigate the detrimental effects of cellular senescence in the brain.