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Table 1 Plasmalogen (Pls) deficiency and their therapeutic use in AD and related disorders, and emerging molecular evidence on their neuronal protection role

From: Plasmalogens and Alzheimer’s disease: a review

Author Design Objectives Outcomes
  Human studies
Fujino et al. 2017 Patients (aged 60–85 years) with mild AD and mild cognitive impairment (MCI) were randomized to a multi-center, double-blind, placebo-controlled trial to receive 24 weeks of treatment with either: 1 mg/d purified plasmalogens (Pls) extracted from scallops (n = 140), or placebo (n = 136) To test the efficacy of oral administration of Pls on cognitive function and blood Pls changes in patients with mild AD and MCI. Primary outcome: Mini Mental State Examination-Japanese (MMSE-J); secondary outcomes: Wechsler Memory Scale-Revised (WMS-R), Geriatric Depression Scale-Short Version-Japanese (GDS-S-J), and concentration of PlsEtns in circulation. Oral administration of Pls significantly improved memory among female mild AD patients and those aged below 77 years as shown in WMS-R test.
Mild AD patients showed a significantly greater decrease in plasma PlsEtns in the placebo group than in the treatment group.
Wood et al. 2016 Serum samples of clinical diagnosed Late-Onset AD (LOAD) patients (n = 90), patients with mild cognitive impairment (MCI, n = 77), and controls (n = 51) aged 76 = 78 were analyzed by lipidomics. To investigate the levels of PlsEtns and diacylglycerols utilizing high resolution mass spectrometry, and correlate the lipid levels with disease. Three patient cohorts within each clinical diagnosis (LOAD and MCI were observed: lower circulating PlsEtns; higher circulating diacylglycerols; and neither of these two lipid alterations. More patients showed low level of PlsEtns in advanced stage of disease.
Yamashita et al. 2016 Plasma and red blood samples of 28 AD patients (age: 72.5 ± 1.4) and 28 normal control subjects (age: 74.1 ± 1.3) were analyzed. Evaluation of plasma Aβ was correlated with phosphatidylcholine hydroperoxide (PCOOH), and PlsEtn in the blood of patients with AD. To investigate the interaction of Aβ, peroxidation of phosphatidylcholine and PlsEtn in AD patients. Plasma from patients with AD showed lower concentrations of PlsEtn species, especially DHA-containing PlsEtn. In addition, lower PlsEtn and higher PCOOH levels were observed in red blood cells (RBC) of AD patients. In both AD and control blood samples, PCOOH levels of RBC tended to correlate with plasma levels of Aβ40.
Wood et al. 2015 Lipidomics analysis of post-mortem cerebrospinal fluid (CSF), frontal cortex grey matter, and subjacent white matter To define potential biomarkers that distinguishes cognitively intact subjects from those with incipient or established dementia; and understands the role of brain lipids in pathophysiology of aging and age-related cognitive impairment. Monoacylglycerols (MAG), diacylglycerols (DAG), and fatty acid 26:0 were elevated in the grey matter of the mild cognitive impairment (MCI) and old dementia (OD) cohorts. PlsEtns were decreased in the grey matter of the young dementia (YD) and OD cohorts while and phosphatidylethanolamines were lower in the MCI, YD and OD cohorts.
Wood et al. 2010 The serum PlsEtns of 40 AD patients and 66 controls aged 67–89 years were analyzed and correlated with cognitive functions using AD assessment scale-cognitive (ADAS-Cog). Serum PlsEtns of AD patients were retested 1 year later. To evaluate the relation between the level of circulating PlsEtns and cognitive function using ADAS-Cog in AD patients in comparison with controls. Only subjects with serum DHA-PlsEtn ≤75% or less of normal levels exhibited cognitive decline over a 12 month period. There was no change in ADAS-Cog scores among participants with normal serum PlsEtn levels at baseline (>  75%).
Goodenowe et al. 2007 The serum samples of 324 dementia subjects (3 groups: low, moderate and severe cognitive impairments) were analyzed and compared with 68 cognitive normal subjects aged 50–90 years to investigate the relations between dementia severity and PlsEtns levels.
209 healthy subjects aged 50–95 years were divided into 3 age groups (50–59, 60–69, and 70–95 years) and their serum were analyzed to determine the effect of age on PlsEtns levels.
Postmortem serum samples of subjects with AD (n = 20) and those without AD pathology (n = 19) were analyzed to compare the serum PlsEtns levels.
Serum from 50 clinically diagnosed AD subjects (3 stages), who were later confirmed to have AD upon postmortem examination were analyzed to determine the DHA PlsEtns levels.
Serum samples of 80 Japanese AD subjects and 80 non-demented Japanese subjects living in Japan were analyzed to determine the effect of ethnic or environmental differences on serum DHA PlsEtns levels in AD
To determine PlsEtns depletion in the brain of subjects with AD; and whether decreased brain levels of PlsEtns in AD are a centrally mediated effect caused by Aβ accumulation or there are much broader changes occurred. The levels of PlsEtns species were significantly reduced in all three groups of AD subjects, and the decrease was correlated with the severity of AD. Peroxisome-derived PlsEtns was also significantly reduced in all stages of AD.
Subject % with very low PlsEtns in the 60–69 year cohort was more than double than other two groups.
↑ mortality rate in both AD subjects and peroxisomal disorders with ↓ PlsEtns.
Serum PlsEtns levels were significantly reduced in the postmortem (55%) AD subjects, and clinically diagnosed AD subject (47%). The decrease was related to the severity of disease.
Serum DHA-PlsEtns levels were significantly reduced in the AD subjects.
Han et al. 2001 Post-mortem human brain tissue and mouse brain tissues from two animal models of AD, APPV717F and APPsw were analyzed using Electrospray ionization mass spectrometry (ESI/MS) To examine systematically plasminogen content in cellular membranes of gray and white matter from different regions of human subjects with a spectrum of AD clinical dementia ratings A dramatic decrease in PlsEtns content (up to 40 mol% of total PlsEtns) in white matter at a very early stage of AD; a correlation of the deficiency in gray matter PlsEtns content (10 mol% - 30 mol% deficiency) with the severity of AD (very mild to severe); no alterations of PlsEtns content and molecular species in cerebellar gray matter despite dramatic alterations of PlsEtns content in cerebellar white matter. 10 mol% deficiencies was present in mice at age of 18 months in cerebral cortices but not in cerebella.
  Animal studies
Katafuchi et al. 2012 Male C57/6 J mice (10 months old) were randomly divided into 3 groups: Pls (20 mg/kg) + lipopolysaccharide (LPS), LPS, and control. Pls were extracted from chicken breast muscle. All treatments were for 7 days. To elucidate the effects of Pls on neuroinflammation and β-amyloid proteins accumulation in the hippocampus, and changes in hippocampal Pls content following peripheral administration of LPS in adult mice. Pls administration suppressed the activation of glial cells (microglia) induced by LPS, indicating attenuation of neuroinflammation in the hippocampus. Pls treatment also abolished β-amyloid proteins in the hippocampus; and suppressed the reduction of Pls contents in hippocampus induced by LPS.
Mawatari et al. 2012 20 male Zucker diabetic fatty (ZDF) rats aged 4 weeks were randomly divided into 2 groups (10 per group) and fed with either 0.1% PlsEtn or control diet for 4 weeks. In addition, 18 male Wistar rats aged 6 weeks were divided evenly into 2 groups and fed with PlsEtn or control diet for 9 weeks. To examine the health effects of dietary PlsEtn. Supplementation with 0.1% PlsEtn in both Zucker diabetic fatty rats and Wistar rats reduced the plasma cholesterol and phospholipids. Correspondingly, erythrocyte PlsEtn and phosphatidylethanolamine were increased.
  In vitro studies
Hossain et al. 2016 Mouse neuroblastoma derived cells, (Neuro 2A, or N2A), astrocyte cell lines (A1) and microglial cell lines (MG6) were treated with Pls extracted from chicken skin (96.5% PlsEtns). Primary hippocampal neurons were prepared from E-18 embryo of mice. To investigate how PlsEtns enhance AKT and ERK signaling and prevent neuronal cells. PlsEtns activated orphan GPCR (G-protein coupled receptor) proteins to induce ERK signaling in neuronal cells. Overexpression of GPCRs enhanced PlsEtns-mediated phosphorylation of ERK and Akt in cells. The GPCRs-mediated cellular signaling was reduced significantly when the endogenous PlsEtns were reduced.
Hossain et al. 2013 Neuroblastoma derived cells Neuro-2A and astrocyte-derived cells A1 were treated with Pls (96.5% PlsEtns). To investigate the molecular mechanism behind the neuronal protection of PlsEtns against apoptotic stimuli. PlsEtns prevent neuronal cell death by enhancing phosphorylation of AKT and ERK signaling in neuronal cells. They also inhibited primary mouse hippocampal neuronal cell death induced by nutrient deprivation which was associated with the inhibition of caspase-9 and caspase-3 cleavages.
Onodera et al. 2014 γ -secretase activity was measured in an in vitro assay using yeast microsomes and reconstituted liposomes. To investigate the effect of PlsEtns on γ--secretase activity in vitro. PlsEtns reduced γ--secretase activity. Bacterial PlsEtns preparation showed dose-dependent inhibition of γ -secretase activity.
Rothhaar et al. 2012 SH-SY5Y cells, and 58 postmortem brain samples from 37 AD patients and 21 controls aged 61–88 years were analyzed for γ-secretase activity.
For ex vivo analysis of γ-secretase activity postnuclear fractions, 6 additional human postmortem brains and brains of C57BI6/N wildtype mice were also analyzed.
To determine whether PlsEtns are able to modulate amyloid precursor protein (APP) processing or if the reduced PlsEtns level is a consequence of AD. PlsEtns levels were reduced in postmortem AD brains.
PlsEtns directly reduced γ-secretase activity in SH-SY5Y cells, postmortem AD brains and mouse brains.
Protein and RNA level of the secretases were unaffected.