Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production.
Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production.
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DOI：
10.1038/s41419-021-04433-w
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发表时间：
2021-12-08
影响因子：
9
通讯作者：
Waites CL
中科院分区：
文献类型：
--
作者：
Zhuravleva V;Vaz-Silva J;Zhu M;Gomes P;Silva JM;Sousa N;Sotiropoulos I;Waites CL
慢性应激和糖皮质激素(GCs)升高是阿尔茨海默病(AD)的危险因素，并促进AD的发病机制，包括毒性淀粉样蛋白(Aβ，Aβ)的过度产生和过度磷酸化的Tau蛋白在神经元内积聚。后者与小GTP酶Rab35的下调有关，该酶通过内溶酶体途径介导牛磺酸的降解。Rab35是否也参与了Aβ的过剩生产仍是一个悬而未决的问题。在这里，我们发现海马区Rab35的水平不仅因应激/GC而降低，而且还因衰老而降低，这是另一个AD危险因素。此外，我们还发现Rab35通过将淀粉样前体蛋白(APP)和β分泌酶(BACE1)从内体网络中分离出来，从而负向调节Aβ的产生，在内体网络中，它们相互作用产生Aβ。有趣的是，Rab35协调BACE1和APP的不同细胞内转运步骤，分别由其效应器OCRL和ACAP2介导。最后，我们证明了Rab35的过表达阻止了高GC水平诱导的APP和BACE1的淀粉样蛋白转运。这些研究确定Rab35是APP加工的关键调节因子，并表明其下调可能有助于应激相关和AD相关的淀粉样蛋白的发生。
Chronic stress and elevated glucocorticoids (GCs), the major stress hormones, are risk factors for Alzheimer’s disease (AD) and promote AD pathomechanisms, including overproduction of toxic amyloid-β (Aβ) peptides and intraneuronal accumulation of hyperphosphorylated Tau protein. The latter is linked to downregulation of the small GTPase Rab35, which mediates Tau degradation via the endolysosomal pathway. Whether Rab35 is also involved in Aβ overproduction remains an open question. Here, we find that hippocampal Rab35 levels are decreased not only by stress/GC but also by aging, another AD risk factor. Moreover, we show that Rab35 negatively regulates Aβ production by sorting amyloid precursor protein (APP) and β-secretase (BACE1) out of the endosomal network, where they interact to produce Aβ. Interestingly, Rab35 coordinates distinct intracellular trafficking steps for BACE1 and APP, mediated by its effectors OCRL and ACAP2, respectively. Finally, we demonstrate that Rab35 overexpression prevents the amyloidogenic trafficking of APP and BACE1 induced by high GC levels. These studies identify Rab35 as a key regulator of APP processing and suggest that its downregulation may contribute to stress-related and AD-related amyloidogenesis.
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