Overexpression of let-7a increases neurotoxicity in a PC12 cell model of Alzheimer's disease via regulating autophagy

Abstract

Abstract. Increased deposition of β-amyloid (Aβ) protein is one of the typical characteristics of Alzheimer's disease (AD). Recent evidence has demonstrated that the microRNA let-7 family, which is highly expressed in the central nervous system, participates in the regulation of pathologic processes of AD. In the present study, the effect of let-7a overexpression on Aβ1-40-induced neurotoxicity was evaluated in PC12 and SK-N-SH cells. The results indicated that overexpression of let-7a enhanced the neurotoxicity induced by Aβ1-40 in PC12 and SK-N-SH cells. In addition, the apoptosis induced by Aβ1-40 in PC12 and SK-N-SH cells was increased by let-7a overexpression. Furthermore, Aβ1-40 treatment increased the protein levels of microtubule-associated protein 1A/1B-light chain 3 (LC3) and beclin-1 and increased the LC3 II/I ratio. The mRNA expression levels of beclin-1, autophagy protein 5 (Atg-5) and Atg-7 were also increased by Aβ1-40 treatment in PC12 cells. Let-7a overexpression further upregulated the above autophagy-related markers. Furthermore, the protein level of p62 was increased by Aβ1-40 treatment, and this was further enhanced by let-7a overexpression. Finally, the present results demonstrated that the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway was involved in the autophagy regulation by let-7a. In conclusion, the present study demonstrates that the neurotoxicity induced by Aβ1-40 is augmented by let-7a overexpression via regulation of autophagy, and the PI3K/Akt/mTOR signaling pathway also serves a function in this process.

Effect of Letrozole on hippocampal let-7 microRNAs and their correlation with working memory and phosphorylated Tau protein level in an Alzheimer's disease rat model

“…Multiple studies provide evidence of the possible involvement of microRNA (miRNA) Let-7 family members in AD, and their neurotoxicity. These studies include models of Aβ 40 -incduced neurotoxicity in cell lines (Gu et al, 2017), injection of Let-7b into the CSF of wild-type mice (Lehmann et al, 2012), quanti cation of Let-7 miRNAs in the CSF of AD patients (Derkow et al, 2018), miRNA pro ling of the brains of transgenic AD mice (Wang et al, 2009 and, and studying the expression of miRNAs in the brains of a cholesterol-based rabbit model of AD (Liu et al, 2014).…”

“…The Let-7 miRNAs are conserved in multiple species, and are abundantly expressed in the brain (Lee et al, 2016;Derkow et al, 2018). Let-7 miRNAs play roles in cellular differentiation, tumor suppression and neurodegeneration/ neurotoxicity (Lehmann et al, 2012;Shamsuzzama et al, 2016 andGu et al, 2017). Various members of the Let-7 family were found to be differentially expressed in the cerebrospinal uid of AD patients (Derkow et al, 2018).…”

Astrocytic IGF-1 and IGF-1R Orchestrate Mitophagy in Traumatic Brain Injury

“…The control of let-7 family members by the m7G pathway may represent a common mechanism to modulate their expressions and activities. Beyond cancer, let-7 is also implicated in neurodegenerative diseases, such as Alzheimer's disease, in which it is signi cantly upregulated [43].…”

Natural Products Targeting Amyloid Beta in Alzheimer’s Disease

“…Although resveratrol initially accelerates the formation of Aβ fibrils with low toxicity via hydrophobic interaction between its phenolic ring and Aβ hydrophobic domain, these fibrils then undergo conformational changes into unstructured aggregates by the self-stacking of aromatic residues in Aβ core domain, consequently reducing the level of aggregation. Resveratrol is also known to suppress the phosphatidylinositol 3-kinase/protein kinase B signaling pathway in addition to having other effects [ 53 , 54 ] that are closely linked to AD, such as the reduction of the amount of Aβ aggregates or Aβ toxicity. In clinical trials for the treatment of AD, oral administration of low doses resveratrol (5 mg/day) was found safe and well tolerated, but less effective on ameliorating pathology of AD (Clinical trial ID.…”