Porcine liver decomposition product-derived lysophospholipids promote microglial activation in vitro

Abstract

cognitive impairments such as dementia are common in later life, and have been suggested to occur via a range of mechanisms, including oxidative stress, age-related changes to cellular metabolism, and a loss of phospholipids (pLs) from neuronal membranes. pLs are a class of amphipathic lipids that form plasma membrane lipid bilayers, and that occur at high concentrations in neuronal membranes. our previous study suggested that a porcine liver decomposition product (pLDp) produced via protease treatment may improve cognitive function at older ages, by acting as a rich source of pLs and lysophospholipids (LPLs); however, its specific composition remains unclear. Thus, the present study used a novel liquid chromatography electrospray ionization tandem mass spectrometric (Lc-MS/MS) protocol to identify the major PLs and LPLs in PLDP. Furthermore, it assessed the effect of identified LPLs on microglial activation in vitro, including cell shape, proliferation, and cell morphology. the results of the conducted analyses showed that pLDp and pLDp-derived LpLs concentrationdependently modulate microglial activation in vitro. in particular, lysophosphatidylcholine (Lpc) concentration-dependently promotes cell morphology, likely via effects mediated by the enzyme autotaxin (AtX), since inhibiting AtX also promoted cell morphology, while conversely, increasing AtX production (via treatment with high levels of LPC) abolished this effect. These findings suggest that Lpc is likely neuroprotective, and thus, support the importance of further research to assess its use as a therapeutic target to treat age-related cognitive impairments, including dementia.Rapid population aging and age-related disease represent an increasing global health-care burden. Dementias are the most common cause of significant late-onset cognitive decline, and affect approximately 50 million people worldwide, with nearly 10 million new cases diagnosed annually 1 . There are many different forms of dementia; for example, Alzheimer's disease is the most common form, and contributes to 60-70% of cases. Other major forms include vascular and Lewy body dementia, and a group of diseases that together comprise frontotemporal dementia 2 . Patients with mild cognitive impairment (MCI) are at risk of developing dementia; however, in some individuals, MCI reverts to normal cognition or remains stable. While clinical studies are currently being conducted to identify novel treatments to improve symptoms and/or prevent or delay the progression of MCI to dementia, no drugs or other treatments have yet been specifically approved for MCI. Lipids are increasingly recognized for their roles in neuronal function in the brain 3,4 ; for example, the lipid fraction of mammalian membranes consists of glycerophospholipids, sphingolipids, and cholesterol 4 . We previously reported that a porcine liver decomposition product (PLDP) induces a significant increase in the Hasegawa's Dementia Scale-Revised (HDS-R) score in a randomized, double-blind, placebo-controlled study in healthy hu...

Therapeutic Potential of Porcine Liver Decomposition Product: New Insights and Perspectives for Microglia-Mediated Neuroinflammation in Neurodegenerative Diseases

“…We showed that media conditioned via exposure to LPE-treated microglia promoted morphological changes in a dose-dependent manner. Our study also indicated that LPC and LPE synergistically suppressed LPS-stimulated ROS production [ 39 ]. This finding is important given that microglia-mediated neuroinflammation is regarded as a pathological mechanism in many neurodegenerative diseases, such as dementia and Alzheimer’s disease, and a key event in accelerating cognitive or functional decline.…”

“…The most abundant LPE was LPE (18:0), while the most abundant LPI detected was LPI (18:0). The most abundant LPS detected was LPS (18:0), and the most abundant LPA detected was LPA (18:0) [ 39 ]. PLDP primarily includes phospholipids [ 29 ].…”

“…With growing interest in the involvement of extracellular lysophospholipids in both normal physiology and pathology, it has become increasingly evident that these small mediators may have therapeutic potential for anti-neurodegenerative indications. It has been demonstrated that the lipopolysaccharide (LPS)-mediated inflammatory response, including increased microglial cytokine production, is significantly suppressed by LPC or LPE exposure [ 39 , 61 ]. Microglial activation leads to the production of pro-inflammatory cytokines, including IL-1, IL-6, and TNF-α [ 25 ].…”

The Combined Effects of Lysophospholipids against Lipopolysaccharide-induced Inflammation and Oxidative Stress in Microglial Cells

“…Although the exact mechanism of this phenomenon remains unclear, we have conducted investigations on functional phospholipids. A recent report also indicated that LPC in PLDP inhibited microglia activation 5 . We aimed to identify a functional phospholipid contained within PLDP that has been confirmed to have clinical effects and to develop a new drug for treating neurodegenerative disease.…”

“…Microglia activation is a hallmark of brain pathology 3 . We reported that a porcine liver decomposition product PLDP improves cognitive function at old age 4 , and composition of this PLDP has been well characterized 5 . The PLDP is a rich source of phospholipids, but the specific mechanism through which it affects cognitive function remains unclear.…”