Lipidomic analysis of brain tissues and plasma in a mouse model expressing mutated human amyloid precursor protein/tau for Alzheimer’s disease

Yoko Tajima,Mayumi Murayama,Yuya Senoo,Keiko Maekawa,Osamu Takikawa,Ryuta Mikawa,Yoshiro Saito,Alato Okuno,Hiroki Nakanishi,Ryo Taguchi,Kazutaka Ikeda,Shumpei Niida,Makoto Arita,Tomoko Nishimaki-Mogami,Masaki Ishikawa

doi:10.1186/1476-511x-12-68

Abstract

BackgroundAlzheimer’s disease (AD), the most common cause of dementia among neurodegenerative diseases, afflicts millions of elderly people worldwide. In addition to amyloid-beta (Aβ) peptide and phosphorylated tau, lipid dysregulation is suggested to participate in AD pathogenesis. However, alterations in individual lipid species and their role in AD disease progression remain unclear.MethodsWe performed a lipidomic analysis using brain tissues and plasma obtained from mice expressing mutated human amyloid precursor protein (APP) and tau protein (Tg2576×JNPL3) (APP/tau mice) at 4 (pre-symptomatic phase), 10 (early symptomatic) and 15 months (late symptomatic).ResultsLevels of docosahexaenoyl (22:6) cholesterol ester (ChE) were markedly increased in APP/tau mice compared to controls at all stages examined. Several species of ethanolamine plasmalogens (pPEs) and sphingomyelins (SMs) showed different levels between brains from APP/tau and control mice at various stages of AD. Increased levels of 12-hydroxyeicosatetraenoic acid (12-HETE) during the early symptomatic phase were consistent with previous reports using human AD brain tissue. In addition, 19,20-dihydroxy-docosapentaenoic acid (19,20-diHDoPE) and 17,18-dihydroxy-eicosatetraenoic acid (17,18-diHETE), which are produced from docosahexaenoic acid and eicosapentaenoic acid via 19,20-epoxy-docosapentaenoic acid (19,20-EpDPE) and 17,18-epoxy-eicosatetraenoic acid (17,18-EpETE), respectively, were significantly increased in APP/tau brains during the pre-symptomatic phase, and concomitant increases occurred in plasma. Several arachidonic acid metabolites such as prostaglandin D2 (PGD2) and 15-hydroxyeicosatetraenoic acid (15-HETE), which have potential deteriorating and protective actions, respectively, were decreased in the early symptomatic phase of APP/tau mice. Significant decreases in phosphatidylcholines and PEs with polyunsaturated fatty acids were also detected in the late symptomatic phase, indicating a perturbation of membrane properties.ConclusionOur results provide fundamental information on lipid dysregulation during various stages of human AD.

Highlights

Alzheimer’s disease (AD), the most common cause of dementia among neurodegenerative diseases, afflicts millions of elderly people worldwide
Analysis of brain tissues We first performed lipidomic analysis of Bligh & Dyer (BD) samples extracted from brain tissues of amyloid precursor protein (APP)/tau and wild-type mice at 4, 10, and 15 months of age using reverse-phase liquid chromatography (RPLC)-ESITOFMS
When creating a two-dimensional map of retention time (RT) versus m/z values of the individual precursor ion peaks in the positive ion mode, the intensities of a few spots that were apparently identified as cholesterol ester (ChE) were higher in APP/tau mice compared to wild-type mice at 4 months (Additional file 2: Figure S2)

Summary

Introduction

Alzheimer’s disease (AD), the most common cause of dementia among neurodegenerative diseases, afflicts millions of elderly people worldwide. In addition to amyloid-beta (Aβ) peptide and phosphorylated tau, lipid dysregulation is suggested to participate in AD pathogenesis. AD symptoms include impaired memory, aphasia, and visuospatial deficits while the histopathological changes of AD are characterized by senile plaques, neurofibrillary tangles, and lipid granule accumulation. The docosahexaenoic acid (DHA) content of phospholipids (PLs) was lower in brain tissue and plasma of AD patients compared to those without cognitive impairment [7]. An analysis of postmortem brain tissues obtained from patients with late-onset AD showed enrichment in lysobisphosphatidic acids, sphingomyelins (SMs), ganglioside GM3, and cholesterol esters (ChEs) as well as novel region-specific lipid anomalies that were potentially linked to AD pathogenesis [9]. Our current knowledge of the overall changes in lipids related to AD, especially for the time-course of their changes, remains low

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Conclusion