1,2-Dilinoleoyl-sn-glycero-3-phosphoethanolamine ameliorates age-related spatial memory deterioration by preventing neuronal cell death

Takahiro Yaguchi,Tomoyuki Nishizaki,Tetsu Nagata

doi:10.1186/1744-9081-6-52

Abstract

BackgroundAccumulating evidence has pointed that a variety of lipids could exert their beneficial actions against dementia including Alzheimer disease and age-related cognitive decline via diverse signaling pathways. Endoplasmic reticulum (ER) stress-induced neuronal apoptosis, on the other hand, is a critical factor for pathogenesis of neurodegenerative diseases such as Alzheimer disease and Parkinson disease, senile dementia, and ischemic neuronal damage. The present study examined the effects of 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine (DLPhtEtn), a phospholipid, on ER stress-induced neuronal death and age-related cognitive disorders.MethodsPC-12 cell viability was assayed before and after treatment with amyloid-β1-40 peptide or thapsigargin in the presence and absence of DLPhtEtn. A series of behavioral tests were performed for senescence-accelerated mouse-prone 8 (SAMP8) mice after 7-month oral administration with polyethylene glycol (PEG) or DLPhtEtn and then, the number of hippocampal neurons was counted.ResultsAmyloid-β1-40 peptide or thapsigargin is capable of causing ER stress-induced apoptosis. DLPhtEtn (30 μM) significantly inhibited PC-12 cell death induced by amyloid-β1-40 peptide or thapsigargin. In the water maze test, oral administration with DLPhtEtn (1 mg/kg) for 7 months (three times a week) significantly shortened the prolonged retention latency for SAMP8 mice. In contrast, DLPhtEtn had no effect on the acquisition and retention latencies in both the open field test and the passive avoidance test for SAMP8 mice. Oral administration with DLPhtEtn (1 mg/kg) for 7 months prevented a decrease in the number of hippocampal neurons for SAMP8 mice.ConclusionThe results of the present study show that DLPhtEtn ameliorates age-related spatial memory decline without affecting motor activities or fear memory, possibly by protecting hippocampal neuronal death. DLPhtEtn, thus, might exert its beneficial action against senile dementia and neurodegenerative diseases such as Alzheimer disease.

Highlights

Accumulating evidence has pointed that a variety of lipids could exert their beneficial actions against dementia including Alzheimer disease and age-related cognitive decline via diverse signaling pathways
Assay of cell viability PC-12 cells were treated with amyloid-b1-40 peptide (Peptide Institute Inc., Osaka, Japan) or thapsigargin (Wako, Osaka, Japan) in the presence and absence of phospholipids such as DLPhtEtn (Avanti Polar Lipid, Inc., Alabaster, AL, USA), 1-linoleoyl-2-palmitoyl-sn-glycero-3phosphoethanolamine (LPPhtEtn) (Avanti Polar Lipid, Inc.), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPhtEtn) (Avanti Polar Lipid, Inc.), 1,2-dipalmitoyl-snglycero-3-phosphoethanolamine (DPPhtEtn) (Avanti Polar Lipid, Inc.), 1,2-diheptadecanoyl-sn-glycero-3phosphoethanolamine (DHPhtEtn) (Avanti Polar Lipid, Inc.), 1,2-distearoyl -sn-glycero-3-phosphoethanolamine (DSPhtEtn) (Avanti Polar Lipid, Inc.), or DLPhtCho (Avanti Polar Lipid, Inc.), dissolved with polyethylene glycol (PEG), and cell viability was evaluated by a dye staining method using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) (DOJINDO, Kumamoto, Japan) by the method as previously described [41]
DLPhtEtn prevents PC-12 cell death induced by amyloid-b1-40 peptide or thapsigargin Amyloid-b peptide, a neurotoxic factor for Alzheimer disease, mediates Endoplasmic reticulum (ER) stress-induced apoptosis [42]

Summary

Introduction

Accumulating evidence has pointed that a variety of lipids could exert their beneficial actions against dementia including Alzheimer disease and age-related cognitive decline via diverse signaling pathways. Endoplasmic reticulum (ER) stress-induced neuronal apoptosis, on the other hand, is a critical factor for pathogenesis of neurodegenerative diseases such as Alzheimer disease and Parkinson disease, senile dementia, and ischemic neuronal damage. Lines of evidence have pointed to ER stress-induced neuronal apoptosis as a critical factor for pathogenesis of neurodegenerative diseases such as Alzheimer disease and Parkinson disease, senile dementia, and ischemic neuronal damage [4,5,6,7,8,9]. Soluble oligomers of amyloid-b peptide activates cytosolic calcium-dependent phospholipase A2 and sphingomyelinase, causing a ceramide rise to induce neuronal death responsible for Alzheimer disease [12]. Sphingolipids, may be a mediator for progression of Alzheimer disease [13,14,15]

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