Electronegative Low-Density Lipoprotein L5 Impairs Viability and NGF-Induced Neuronal Differentiation of PC12 Cells via LOX-1

Abstract

Abstract:There have been striking associations of cardiovascular diseases (e.g., atherosclerosis) and hypercholesterolemia with increased risk of neurodegeneration including Alzheimer's disease (AD). Low-density lipoprotein (LDL), a cardiovascular risk factor, plays a crucial role in AD pathogenesis; further, L5, a human plasma LDL fraction with high electronegativity, may be a factor contributing to AD-type dementia. Although L5 contributing to atherosclerosis progression has been studied, its role in inducing neurodegeneration remains unclear. Here, PC12 cell culture was used for treatments with human LDLs (L1, L5, or oxLDL), and subsequently cell viability and nerve growth factor (NGF)-induced neuronal differentiation were assessed. We identified L5 as a neurotoxic LDL, as demonstrated by decreased cell viability in a time-and concentration-dependent manner. Contrarily, L1 had no such effect. L5 caused cell damage by inducing ATM/H2AX-associated DNA breakage as well as by activating apoptosis via lectin-like oxidized LDL receptor-1 (LOX-1) signaling to p53 and ensuring cleavage of caspase-3. Additionally, sublethal L5 long-termly inhibited neurite outgrowth in NGF-treated PC12 cells, as evidenced by downregulation of early growth response factor-1 and neurofilament-M. This inhibitory effect was mediated via an interaction between L5 and LOX-1 to suppress NGF-induced activation of PI3k/Akt cascade, but not NGF receptor TrkA and downstream MAPK pathways. Together, our data suggest that L5 creates a neurotoxic stress via LOX-1 in PC12 cells, thereby leading to impairment of viability and NGF-induced differentiation. Atherogenic L5 likely contributes to neurodegenerative disorders.

The Association between Electronegative Low-Density Lipoprotein Cholesterol L5 and Cognitive Functions in Patients with Mild Cognitive Impairment

“…Therefore, L5 contributes to cognitive impairment by causing cerebrovascular dysfunction [ 36 ]. In addition, L5 creates neuroinflammatory and neurotoxic stress, impairs neuronal viability and differentiation, and contributes to neurodegenerative diseases [ 21 , 22 ]. Instead of TC or LDL-C, L5 could play a key role in the pathogenesis of cognitive impairment due to neurodegeneration.…”

“…L5 causes microglial activation and produces neuroinflammatory stress [ 21 ]. Furthermore, L5 induces neurotoxic stress and impairs neuronal differentiation [ 22 ]. Therefore, we hypothesized that L5 probably contributes to neurodegenerative disorders by enhancing neuroinflammation and producing neurotoxic effects.…”

Physiological and pathogenic role of scavenger receptors in humans

“…Напротив, задействование SR-B2 (CD36), и SR-J1 (RAGE) приводит к патологической активации микроглии, а SR-J1 -непосредственно нейронов [28,129,230] [225]. Возможно и острое развитие нейродегенерации.…”

Molecular and Cellular Mechanisms of Electronegative Lipoproteins in Cardiovascular Diseases

“…LDL(−) is highly atherogenic and pro-apoptotic to the vascular system, including the endothelium of the blood-brain barrier (BBB). Wang et al in 2017 explored the role of LDL(−) in pheochromocytoma-derived cell line (PC12) cells, where deliberate dosages of LDL(−) induced neurotoxic stress in a LOX-1-dependent manner [125].…”