Semel Institute for Neuroscience and Human Behavior/Neuropsychiatric Institute, Department of Psychiatry, Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, United States of America; Molecular Biology Interdepartmental Program at University of California, Los Angeles, Los Angeles, CA 90095, United States of America.
Semel Institute for Neuroscience and Human Behavior/Neuropsychiatric Institute, Department of Psychiatry, Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, United States of America.
Neurobiol Dis. 2021 Dec;160:105524. doi: 10.1016/j.nbd.2021.105524. Epub 2021 Oct 2.
Chronic inflammation drives synaptic loss in multiple sclerosis (MS) and is also commonly observed in other neurodegenerative diseases. Clinically approved treatments for MS provide symptomatic relief but fail to halt neurodegeneration and neurological decline. Studies in animal disease models have demonstrated that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) exhibits anti-inflammatory, neuroprotective and regenerative properties. Anti-inflammatory actions appear to be mediated primarily by two receptors, VPAC1 and VPAC2, which also bind vasoactive intestinal peptide (VIP). Pharmacological experiments indicate that another receptor, PAC1 (ADCYAP1R1), which is highly selective for PACAP, provides protection to neurons, although genetic evidence and other mechanistic information is lacking. To determine if PAC1 receptors protect neurons in a cell-autonomous manner, we used adeno-associated virus (AAV2) to deliver Cre recombinase to the retina of mice harboring floxed PAC1 alleles. Mice were then subjected to chronic experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates major clinical and pathological features of MS and associated optic neuritis. Unexpectedly, deletion of PAC1 in naïve mice resulted in a deficit of retinal ganglionic neurons (RGNs) and their dendrites, suggesting a homeostatic role of PAC1. Moreover, deletion of PAC1 resulted in increased EAE-induced loss of a subpopulation of RGNs purported to be vulnerable in animal models of glaucoma. Increased axonal pathology and increased secondary presence of microglia/macrophages was also prominently seen in the optic nerve. These findings demonstrate that neuronal PAC1 receptors play a homeostatic role in protecting RGNs and directly protects neurons and their axons against neuroinflammatory challenge. SIGNIFICANCE STATEMENT: Chronic inflammation is a major component of neurodegenerative diseases and plays a central role in multiple sclerosis (MS). Current treatments for MS do not prevent neurodegeneration and/or neurological decline. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to have anti-inflammatory, neuroprotective and regenerative properties but the cell type- and receptor-specific mechanisms are not clear. To test whether the protective effects of PACAP are direct on the PAC1 receptor subtype on neurons, we delete PAC1 receptors from neurons and investigate neuropathologigical changes in an animal model of MS. The findings demonstrate that PAC1 receptors on neurons play a homeostatic role in maintaining neuron health and can directly protect neurons and their axons during neuroinflammatory disease.
慢性炎症会导致多发性硬化症（MS）中的突触损失，这种情况在其他神经退行性疾病中也很常见。目前已被临床批准用于 MS 的治疗方法只能缓解症状，但无法阻止神经退行性病变和神经功能衰退。动物疾病模型的研究表明，神经肽垂体腺苷酸环化酶激活肽（PACAP，ADCYAP1）具有抗炎、神经保护和再生特性。抗炎作用似乎主要通过两种受体，即 VPAC1 和 VPAC2，这两种受体也结合血管活性肠肽（VIP）而起作用。药理学实验表明，另一种受体 PAC1（ADCYAP1R1）对 PACAP 具有高度选择性，可为神经元提供保护，尽管缺乏遗传证据和其他机制信息。为了确定 PAC1 受体是否以细胞自主的方式保护神经元，我们使用腺相关病毒（AAV2）将 Cre 重组酶递送至携带 floxed PAC1 等位基因的小鼠视网膜。然后，将这些小鼠暴露于慢性实验性自身免疫性脑脊髓炎（EAE）中，该疾病模型可重现 MS 和相关视神经炎的主要临床和病理特征。出乎意料的是，在未受刺激的小鼠中敲除 PAC1 会导致视网膜神经节细胞（RGNs）及其树突减少，这表明 PAC1 具有维持内稳态的作用。此外，PAC1 的缺失导致 EAE 诱导的 RGN 亚群丢失增加，而在动物模型中，这些亚群被认为易受青光眼的影响。在视神经中也明显观察到轴突病变增加和继发性小胶质细胞/巨噬细胞增多。这些发现表明，神经元 PAC1 受体在保护 RGNs 方面发挥着维持内稳态的作用，并直接保护神经元及其轴突免受神经炎症的挑战。意义声明：慢性炎症是神经退行性疾病的主要组成部分，在多发性硬化症（MS）中起着核心作用。目前用于 MS 的治疗方法并不能预防神经退行性病变和/或神经功能衰退。神经肽垂体腺苷酸环化酶激活肽（PACAP）已被证明具有抗炎、神经保护和再生特性，但细胞类型和受体特异性机制尚不清楚。为了测试 PACAP 的保护作用是否直接作用于神经元上的 PAC1 受体亚型，我们从神经元中敲除 PAC1 受体，并在 MS 的动物模型中研究神经病理学变化。研究结果表明，神经元上的 PAC1 受体在维持神经元健康方面发挥着维持内稳态的作用，并且在神经炎症性疾病期间可以直接保护神经元及其轴突。
