de Gea Priscille, Benkeder Sarah, Bouvet Pauline, Aimard Mélanie, Chounlamountri Naura, Honnorat Jérôme, Do Le Duy, Meissirel Claire
Laboratory MeLIS, Institut Neuromyogène, Synaptopathies and Autoantibodies, INSERM U1314, CNRS UMR 5284, Université Claude Bernard Lyon 1, Lyon, France.
French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Bron, France.
Front Cell Neurosci. 2023 Dec 15;17:1264402. doi: 10.3389/fncel.2023.1264402. eCollection 2023.
Microglial cells are well known to be implicated in the pathogenesis of Alzheimer's disease (AD), due to the impaired clearance of amyloid-β (Aβ) protein. In AD, Aβ accumulates in the brain parenchyma as soluble oligomers and protofibrils, and its aggregation process further give rise to amyloid plaques. Compelling evidence now indicate that Aβ oligomers (Aβo) are the most toxic forms responsible for neuronal and synaptic alterations. Recently, we showed that the Vascular Endothelial Growth Factor (VEGF) counteracts Aβo-induced synaptic alterations and that a peptide derived from VEGF is able to inhibit Aβ aggregation process. Moreover, VEGF has been reported to promote microglial chemotaxis to Aβ brain deposits. We therefore investigated whether VEGF could influence microglial phagocytic response to Aβ, using and models of amyloid accumulation. We report here that VEGF increases Aβo phagocytosis by microglial cells and further characterized the molecular basis of the VEGF effect. VEGF is able to control α-secretase activity in microglial cells, resulting in the increased cleavage of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2), a major microglial Aβ receptor. Consistently, the soluble form sTREM2 also increases Aβo phagocytosis by microglial cells. Taken together, these findings propose VEGF as a new regulator of Aβ clearance and suggest its potential role in rescuing compromised microglial function in AD.
由于β淀粉样蛋白（Aβ）清除受损，小胶质细胞在阿尔茨海默病（AD）发病机制中的作用广为人知。在AD中，Aβ以可溶性寡聚体和原纤维的形式在脑实质中积累，其聚集过程进一步导致淀粉样斑块的形成。有力证据表明，Aβ寡聚体（Aβo）是导致神经元和突触改变的最具毒性的形式。最近，我们发现血管内皮生长因子（VEGF）可对抗Aβo诱导的突触改变，且一种源自VEGF的肽能够抑制Aβ聚集过程。此外，据报道VEGF可促进小胶质细胞向Aβ脑沉积物的趋化作用。因此，我们使用淀粉样蛋白积累的[具体模型1]和[具体模型2]模型，研究了VEGF是否会影响小胶质细胞对Aβ的吞噬反应。我们在此报告，VEGF可增加小胶质细胞对Aβo的吞噬作用，并进一步阐明了VEGF作用的分子基础。VEGF能够控制小胶质细胞中的α-分泌酶活性，导致髓系细胞2上表达的触发受体（TREM2）的裂解增加，TREM2是小胶质细胞的主要Aβ受体。同样，可溶性形式的sTREM2也可增加小胶质细胞对Aβo的吞噬作用。综上所述，这些发现表明VEGF是Aβ清除的新调节剂，并提示其在挽救AD中受损的小胶质细胞功能方面的潜在作用。
