跨膜蛋白β-淀粉样前体蛋白(APP)在阿尔茨海默病(AD)的病理生理学中起着重要作用。β-淀粉样蛋白假说认为APP的异常加工会形成神经毒性的β-淀粉样蛋白聚集体,这导致在AD中观察到的认知障碍。虽然许多其他因素有助于AD,有必要更好地了解APP的突触功能。我们发现果蝇APP样(APPL)在与Kismet(Kis)的突触中具有共享和非共享的角色,染色质解旋酶结合域(CHD)蛋白。Kis是CHD7和CHD8的同源物,两者都涉及神经发育障碍,包括CHARGE综合征和自闭症谱系障碍,分别。在其中枢神经系统中表达人APP和BACE的kis和动物中功能突变的丧失显示谷氨酸受体亚基的减少,GluRIIC,GTP酶Rab11和骨形态发生蛋白(BMP),pMad,在果蝇幼虫神经肌肉接头(NMJ)。同样,像内吞这样的过程,幼虫运动,这些动物的神经传递是有缺陷的。我们的药理学和上位性实验表明,Kis和APPL之间存在功能关系,但是Kis不调节幼虫NMJ的appl表达。相反,它可能影响APPL的突触定位,可能是通过促进rab11转录。这些数据确定了AD中染色质重塑蛋白与异常突触功能之间的潜在机制联系。
The transmembrane protein β-amyloid precursor protein (APP) is central to the pathophysiology of Alzheimer\'s disease (AD). The β-amyloid hypothesis posits that aberrant processing of APP forms neurotoxic β-amyloid aggregates, which lead to the cognitive impairments observed in AD. Although numerous additional factors contribute to AD, there is a need to better understand the synaptic function of APP. We have found that Drosophila APP-like (APPL) has both shared and non-shared roles at the
synapse with Kismet (Kis), a chromatin helicase binding domain (CHD) protein. Kis is the homolog of CHD7 and CHD8, both of which are implicated in neurodevelopmental disorders including CHARGE Syndrome and autism spectrum disorders, respectively. Loss of function mutations in kis and animals expressing human APP and BACE in their central nervous system show reductions in the glutamate receptor subunit, GluRIIC, the GTPase Rab11, and the bone morphogenetic protein (BMP), pMad, at the Drosophila larval neuromuscular junction (NMJ). Similarly, processes like endocytosis, larval locomotion, and neurotransmission are deficient in these animals. Our pharmacological and epistasis experiments indicate that there is a functional relationship between Kis and APPL, but Kis does not regulate appl expression at the larval NMJ. Instead, Kis likely influences the synaptic localization of APPL, possibly by promoting rab11 transcription. These data identify a potential mechanistic connection between chromatin remodeling proteins and aberrant synaptic function in AD.