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.
Highlights
Dementia is the most common neurodegenerative disorder afflicting the aged
Epidemiological studies have established a strong relation between cardiovascular disease (CVD) and Alzheimer’s disease (AD), but it remains unclear whether this relation is due to shared risk factors that independently influence disease progression, or if certain CVD risk factors contribute to AD pathogenesis by inducing neuronal damage or promoting the accumulation of plaques and tangles
To our knowledge, the role of L5 in neurodegenerative pathogenesis remains uncharacterized. It remains uncertain whether L5 leakage into brain tissue under the situations of aberrant cerebrovasculature caused by cerebral amyloid angiopathy or increased blood-brain barrier (BBB) permeability induced by CVD-related vascular factors can directly induce neuronal dysfunction or death
Summary
Dementia is the most common neurodegenerative disorder afflicting the aged. Growing evidence suggests a strong and likely causal association of cardiovascular disease (CVD) with cognitive decline and Alzheimer’s disease (AD) [1]. Among CVD risk factors, elevated low-density lipoprotein (LDL) is reported to reduce cerebral perfusion, increase oxidative stress, and activate neuroinflammatory responses, all of which promote AD progression [3,4]. To our knowledge, the role of L5 in neurodegenerative pathogenesis remains uncharacterized It remains uncertain whether L5 leakage into brain tissue under the situations of aberrant cerebrovasculature caused by cerebral amyloid angiopathy or increased blood-brain barrier (BBB) permeability induced by CVD-related vascular factors can directly induce neuronal dysfunction or death. We found that L5 induces ataxia-telangiectasia mutated (ATM) protein/H2AX-associated DNA damage, causes cell apoptosis via lectin-like oxidized LDL receptor-1 (LOX-1)/p53/caspase-3, and inhibits neurite outgrowth by interacting with LOX-1 and reducing NGF-stimulated Akt activation. We present novel findings showing that L5 induces neurotoxicity directly, thereby identifying elevated plasma L5 as a possible causal link between hypercholesterolemia-related CVD and neurodegeneration, such as AD
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call