Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease.
Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease.
复制标题
DOI：
10.1016/j.nbd.2020.105089
复制
发表时间：
2020-12
影响因子：
6.1
通讯作者：
Shamloo M
中科院分区：
文献类型：
--
作者：
Evans AK;Ardestani PM;Yi B;Park HH;Lam RK;Shamloo M
肾上腺素能系统调节认知功能和免疫功能。脑中肾上腺素能信号的主要来源是蓝斑（LC）的去甲肾上腺素（NE）神经元，其易受年龄相关性变性的影响，并且是神经变性疾病如阿尔茨海默病（AD）中最早的病理和变性部位之一。在衰老和神经退行性疾病中，肾上腺素能张力的丧失可能会加剧神经炎症。重要的是，β-受体阻滞剂（β-肾上腺素能拮抗剂）是高血压的常用治疗方法，与衰老共病，并可能进一步加剧与中枢神经系统（CNS）中肾上腺素能张力丧失相关的神经炎症。本研究旨在检测急性脂多糖（LPS）模型中β受体阻滞剂给药的促炎性后果，以及在淀粉样β蛋白前体（APP）AD小鼠模型中β受体阻滞剂给药对神经炎症和行为的慢性影响。我们提供了在LPS急性模型中使用4种不同的β受体阻滞剂对外周炎症的强有力的增强作用的证据。然而，β-受体阻滞剂在该模型中没有增强CNS炎症。值得注意的是，在相同的模型中，小胶质细胞中β 1或β 2肾上腺素能受体的基因敲除确实增强了CNS炎症。此外，在淀粉样蛋白病理学的APP小鼠模型中，长期β受体阻滞剂给药确实增强了CNS炎症。β受体阻滞剂美托洛尔也诱导了野生型和APP小鼠的吞噬作用和认知行为受损的标志物。考虑到体内吞噬标志物的诱导作用，我们在体外原代小胶质细胞培养物中检测了突触体的吞噬作用，结果显示β受体阻滞剂增强了突触体的吞噬作用，而β肾上腺素能激动剂抑制了突触体的吞噬作用。总之，β受体阻滞剂在全身炎症模型中外周增强炎症，在神经炎症的淀粉样变性模型中中枢增强炎症。此外，β-受体阻滞剂损害学习和记忆，并调节突触吞噬作用，暗示突触变性。这些发现需要进一步考虑长期β受体阻滞剂给药的促炎性后果，这不仅限于神经退行性疾病患者的外周。
Adrenergic systems regulate both cognitive function and immune function. The primary source of adrenergic signaling in the brain is norepinephrine (NE) neurons of the locus coeruleus (LC), which are vulnerable to age-related degeneration and are one of the earliest sites of pathology and degeneration in neurodegenerative disorders such as Alzheimer’s Disease (AD). Loss of adrenergic tone may potentiate neuroinflammation both in aging and neurodegenerative conditions. Importantly, beta-blockers (beta-adrenergic antagonists) are a common treatment for hypertension, co-morbid with aging, and may further exacerbate neuroinflammation associated with loss of adrenergic tone in the central nervous system (CNS). The present studies were designed to both examine proinflammatory consequences of beta-blocker administration in an acute lipopolysaccharide (LPS) model as well as to examine chronic effects of beta-blocker administration on neuroinflammation and behavior in an amyloid-beta protein precursor (APP) mouse model of AD. We provide evidence for robust potentiation of peripheral inflammation with 4 different beta-blockers in an acute model of LPS. However, beta-blockers did not potentiate CNS inflammation in this model. Notably, in this same model, the genetic knockdown of either beta1- or beta2-adrenergic receptors in microglia did potentiate CNS inflammation. Furthermore, in an APP mouse model of amyloid pathology, chronic beta-blocker administration did potentiate CNS inflammation. The beta-blocker, metoprolol, also induced markers of phagocytosis and impaired cognitive behavior in both wild-type and APP mice. Given the induction of markers of phagocytosis in vivo, we examined phagocytosis of synaptosomes in an in vitro primary microglia culture and showed that beta-blockers enhanced whereas beta-adrenergic agonists inhibited phagocytosis of synaptosomes. In conclusion, beta-blockers potentiated inflammation peripherally in a systemic model of inflammation and centrally in an amyloidosis model of neuroinflammation. Additionally, beta-blockers impaired learning and memory and modulated synaptic phagocytosis with implications for synaptic degeneration. These findings warrant further consideration of the proinflammatory consequences of chronic beta-blocker administration, which are not restricted to the periphery in patients with neurodegenerative disorders.
登录
查看更多内容
DOI：
10.3233/jad-140036
发表时间：
2014
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Nguyen TV;Shen L;Vander Griend L;Quach LN;Belichenko NP;Saw N;Yang T;Shamloo M;Wyss-Coray T;Massa SM;Longo FM
通讯作者：
Longo FM
影响因子：
4.2
作者：
Kalinin, Sergey;Gavrilyuk, Vitaliy;Feinstein, Douglas L.
通讯作者：
Feinstein, Douglas L.
影响因子：
4.7
作者：
Feinstein, Douglas L.;Kalinin, Sergey;Braun, David
通讯作者：
Braun, David
影响因子：
15.1
作者：
Johnson, JD;O'Connor, KA;Maier, SF
通讯作者：
Maier, SF
DOI：
10.1016/0169-328x(95)00242-k
发表时间：
1996-02-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Goujon, E;Parnet, P;Dantzer, R
通讯作者：
Dantzer, R