Department of Ophthalmology, Universität of Erlangen-Nürnberg, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.
Department of Neurology, Charite´-Universitätsmedizin Berlin, Berlin, Germany.
PLoS One. 2022 Oct 6;17(10):e0272811. doi: 10.1371/journal.pone.0272811. eCollection 2022.
Glaucoma disease is characterized by an increased intraocular pressure (IOP), glaucomatous alterations of the optic disc and corresponding visual field defects. Even lowering the main risk factor IOP until an individual target level does not prevent this neurodegenerative disorder from proceeding. Several autoimmune mechanisms were discovered, partly showing a functionality. One of these autoimmune phenomena targets the ß2-adrenergic receptor (ß2-AR; i.e. agonistic autoantibodies; ß2-agAAb) and is linked to an elevated IOP and an impaired retinal microcirculation. As neurodegenerative disorder, Alzheimer's Disease (AD) is postulated to share a common molecular mechanism with glaucoma. In the present study we investigated autoimmune phenomena targeting the ß2-AR in patients with AD. Sera of the patients were analyzed in a rat cardiomyocyte bioassay for the presence of functional autoantibodies against ß2-AR. In addition, different species of amyloid beta (Aß) monomers were tested (Aß1-14, Aß10-25, Aβ10-37 Aß1-40, Aß1-42, Aβ28-40, and Aß-[Pyr]3-43). Our results demonstrate that none of the short-chain Aß (Aß1-14, Aß10-25, or Aβ28-40) showed any agonistic or inhibitory effect on ß2-AR. Contrary, long-chain Aß-[Pyr]3-43, representing a major neurogenic plaque component, exerted an activation that after blocking by the ß2-AR antagonist ICI118.551, could be identified as that the effect was realized via the ß2-AR. Moreover, the long chain Aß1-40, Aβ1-42, and Aβ10-37, yet not the short-chain Aß peptides prevented the clenbuterol induced desensitization of the ß2-AR. In addition, we identified functional autoantibodies in the sera of AD patients, activating the ß2-AR, like the ß2-agAAb found in patients with glaucoma. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma and Alzheimer's Disease, we postulate that overstimulation of the ß2-AR pathway can induce an adrenergic overdrive, that may play an important role in the multifactorial interplay of neurodegenerative disorders.
青光眼的特征是眼内压（IOP）升高、视神经盘青光眼改变和相应的视野缺损。即使将主要危险因素 IOP 降低到个体目标水平，也不能阻止这种神经退行性疾病的进展。已经发现了几种自身免疫机制，其中部分具有功能。这些自身免疫现象之一针对β2-肾上腺素能受体（β2-AR；即激动性自身抗体；β2-agAAb），并与升高的 IOP 和受损的视网膜微循环有关。作为神经退行性疾病，阿尔茨海默病（AD）被假定与青光眼具有共同的分子机制。在本研究中，我们研究了 AD 患者针对β2-AR 的自身免疫现象。使用大鼠心肌细胞生物测定法分析患者的血清中是否存在针对β2-AR 的功能性自身抗体。此外，还测试了不同种属的淀粉样β（Aβ）单体（Aβ1-14、Aβ10-25、Aβ10-37、Aβ1-40、Aβ1-42、Aβ28-40 和 Aβ-[Pyr]3-43）。我们的结果表明，短链 Aβ（Aβ1-14、Aβ10-25 或 Aβ28-40）均未显示出对β2-AR 的任何激动或抑制作用。相反，长链 Aβ-[Pyr]3-43，代表主要的神经原性斑块成分，发挥了一种激活作用，这种激活作用在被β2-AR 拮抗剂 ICI118.551 阻断后，可以确定为通过β2-AR 实现的。此外，长链 Aβ1-40、Aβ1-42 和 Aβ10-37，但不是短链 Aβ 肽，可防止克伦特罗诱导的β2-AR 脱敏。此外，我们在 AD 患者的血清中鉴定出了激活β2-AR 的功能性自身抗体，就像在青光眼患者中发现的β2-agAAb 一样。由于自身免疫机制据称参与了青光眼和阿尔茨海默病的发病机制，我们假设β2-AR 途径的过度刺激可能会引起肾上腺素能亢进，这可能在神经退行性疾病的多因素相互作用中发挥重要作用。
