Role of Mast cells in Alzheimer's Disease

肥大细胞(MC)在变态反应中起着重要作用。最近的研究表明，MC也是 通过释放炎性细胞因子、趋化因子和MC，对其他炎症性疾病至关重要。 脱粒后的特定蛋白水解酶、凝乳酶和类胰蛋白酶。MC的药理灭活可防止或 延缓疾病的发展。阿尔茨海默病(AD)是导致痴呆症和残疾的最常见原因 老年人。它是美国第六大死因，仅影响500多万美国人， 根据阿尔茨海默氏症协会的说法。AD的一个明确诊断是基于存在 神经毒性β-淀粉样蛋白(A-β)在衰老斑块中的细胞外沉积人类阿尔茨海默病的大脑已经升高 蛋白水解酶表达、神经元死亡和突触丢失、血脑屏障(BBB)渗漏和激活 炎性细胞，如小胶质细胞、星形胶质细胞和T细胞。MCS也存在于人的AD脑中，主要是在 海马体、大脑皮层和丘脑，但研究尚未测试这些细胞是否参与 直接在发病机制中或仅作为另一个炎症性标志。我们的初步数据 证明血浆MC激活剂IgE水平和MC颗粒含量、类胰蛋白酶和组胺 在早期AD患者中升高，表明全身性MC激活增强。抗类胰蛋白酶和 CD117抗体检测到人和小鼠AD患者大脑皮质和海马区MC积聚 大脑。使用MC缺陷的KitW-sh/W-sh小鼠和非处方药(OTC)MC抑制剂酮替芬，我们 MCs的缺失或药物抑制可减少Aβ沉积和老年斑块 并减少Iba-1总阳性小胶质细胞的数量 APPsWE-PS1∆E9/-(APP-PS1)小鼠上述区域的吞噬小胶质细胞 大脑淀粉样变性。脑组织提取液ELISA法显示，MCs的缺失减少了 病理性Aβ物种(Aβ1-40和Aβ1-42)。体外制备的MC过继转移入KitW-sh/W-Shapp-PS1- 受体小鼠大脑皮质和海马区Aβ沉积、小胶质细胞浸润和激活以及AD 大脑皮层Aβ1-40和Aβ1-42含量。初步的水T迷宫行为测试表明MC耗尽 改善APP-PS1小鼠的认知能力下降。我们推测MC通过以下途径在AD中起致病作用 释放促炎细胞因子和蛋白水解酶，并与抗过敏药物一起抑制MC 人类阿尔茨海默病的一种新疗法。我们提出了三个目标来检验MC耗尽或抑制是否具有保护作用 阿尔茨海默病小鼠；检测Fc-εR1基因缺陷或抗-Ig E抗体治疗 保护小鼠免受阿尔茨海默氏病的影响，并建立肥大细胞激活和 小鼠阿尔茨海默氏症。

Mast cells (MCs) play important roles in allergic responses. Recent studies suggest that MCs are also essential to other inflammatory diseases by releasing inflammatory cytokines, chemokines, and the MC- specific proteases chymase and tryptase after degranulation. Pharmacological inactivation of MCs prevents or slows disease progression. Alzheimer’s disease (AD) is the most common cause of dementia and disability in the elderly. It is the sixth leading cause of death in the U.S., affecting more than 5 million Americans alone, according to the Alzheimer’s Association. One definitive diagnosis of AD is based on the presence of extracellular deposition of neurotoxic β-amyloid (Aβ) into senile plaques. Human AD brains have elevated protease expression, neuronal death and synapse loss, blood-brain barrier (BBB) leakage, and activation of inflammatory cells such as microglia, astrocytes, and T cells. MCs also present in human AD brains, mainly in the hippocampus, cerebral cortex, and thalamus, but studies have yet to test whether these cells participate directly in the pathogenesis or serve merely as another inflammatory hallmark. Our preliminary data demonstrated that the plasma levels of MC activator IgE and MC granular contents tryptase and histamine were elevated in patients with early stage AD, indicating enhanced systemic MC activation. Anti-tryptase and CD117 antibodies detected MC accumulation in the cortex and hippocampus from human and murine AD brains. Using MC-deficient KitW-sh/W-sh mice and over-the-counter (OTC) MC inhibitor ketotifen, we demonstrated that the absence or pharmacological inhibition of MCs reduced Aβ deposition and senile plaque formation in the hippocampus and cerebral cortex, and reduced the numbers of total Iba-1-positive microglia and CD68-positive phagocytic microglia in these regions in APPSWE-PS1∆e9+/– (APP-PS1) mice that develop cerebral amyloidosis. Brain tissue extract ELISA showed that the absence of MCs reduced the production of pathological Aβ species (Aβ1-40 and Aβ1-42). Adoptive transfer of in vitro-prepared MCs into KitW-sh/W-shAPP-PS1- recipient mice restored cortical and hippocampal Aβ deposition, microglia infiltration and activation, and AD brain cortex Aβ1-40 and Aβ1-42 contents. A preliminary water T-maze behavior test suggested that MC depletion improved cognitive decline in APP-PS1 mice. We hypothesize that MCs play a pathogenic role in AD by releasing pro-inflammatory cytokines and proteases, and MC inhibition with the anti-allergy drugs may become a novel therapy of human AD. We propose three aims to examine whether MC depletion or inhibition protects mice from Alzheimer’s disease; to examine whether genetic deficiency of FcεR1 or anti-IgE antibody therapy protects mice from Alzheimer’s disease and, to establish the mechanistic link between mast cell activation and mouse Alzheimer’s disease.