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Papers of the Week

Papers: 14 Sep 2019 - 20 Sep 2019

Animal Studies

2019 Jan-Dec

Mol Pain


mTOR activation due to APPL1 deficiency exacerbates hyperalgesia via Rab5/Akt and AMPK signaling pathway in STZ-induced diabetic rats.


He W-Y, Zhang B, Zhao W-C, He J, Wang Y, Zhang L, Xiong Q-M, Wang H-B
Mol Pain. 2019 Jan-Dec; 15:1744806919880643.
PMID: 31530215.


Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus with obscure underlying mechanisms. The adaptor protein APPL1 is critical in mediating the insulin sensitizing and insulin signaling. In neurons, APPL1 reportedly affects synaptic plasticity, while its role in the pathogenesis of PDN is masked. Our western blotting revealed significantly decreased APPL1 expression in the dorsal horn in streptozocin (STZ)-induced rats versus the control rats, coupled with concomitant mechanical and thermal hyperalgesia. Afterwards, the determination of exact localization of APPL1 in spinal cord by immunofluorescent staining assay revealed highly expressed APPL1 in the lamina of spinal dorsal horn in control rats, with the overexpression in neurons, microglia and underexpression in astrocytes. The APPL1 expression in laminae I and II was significantly downregulated in PDN rats. Additionally, APPL1 deficiency or overexpression contributed to the increase or decrease of Map and Bassoon, respectively. The localization and immunoactivity of APPL1 and mammalian target of rapamycin (mTOR) were determined in spinal dorsal horn in PDN rats and control rats by immunohistochemistry, suggesting pronounced decrease in APPL1 expression in the superficial layer of the spinal cord in PDN rats, with p-mTOR expression markedly augmented. APPL1 knockdown by infection with lentiviral vector facilitated the activation of mTOR and abrogated mechanical withdrawal threshold (MWT) values in PDN rats. Genetically overexpressed APPL1 significantly eliminated the activation of mTOR and resulted in the augmented MWT values and thermal withdrawal latency (TWL) values. Further, the APPL1 levels affect phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), and Akt, the phosphorylation of AMPK and Akt as well as the small GTPase, Rab5 expression in PDN rats. Our results uncovered a novel mechanism by which APPL1 deficiency facilitates the mTOR activation, and thus exacerbates the hyperalgesia in STZ-induced diabetic rats, presumably via the regulation of Rab5/Akt and AMPK signaling pathway.