Plasmalogens Inhibit APP Processing by Directly Affecting<i>γ</i>-Secretase Activity in Alzheimer’s Disease

Rothhaar, Tatjana L.; Grösgen, Sven; Haupenthal, Viola J.; Burg, Verena K.; Hundsdörfer, Benjamin; Mett, Janine; Riemenschneider, Matthias; Grimm, Heike S.; Hartmann, Tobias; Grimm, Marcus O. W.

doi:10.1100/2012/141240

Cited by 61 publications

(65 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PML protein and PML mRNA level are upregulated in human AD brains [61]. Recent findings suggest that γ-secretase activity might be upregulated in human AD brains [62]. Presenilin (PS) is part of the γ-secretase complex that produces the Aß.…”

Section: Discussionmentioning

confidence: 99%

Structural Neuroimaging Genetics Interactions in Alzheimer’s Disease

Moon

Dinov

Kim

et al. 2015

JAD

View full text Add to dashboard Cite

This article investigates late-onset cognitive impairment using neuroimaging and genetics biomarkers for subjects participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Eight hundred and eight ADNI subjects were identified and divided into three groups: those with Alzheimer’s Disease (AD), those with mild cognitive impairment (MCI), and asymptomatic normal control (NC) group. Two hundred of the subjects qualified for AD diagnosis at the baseline; three hundred and eighty-three had MCI; and 225 were included in the NC group. The structural magnetic resonance imaging (MRI) data were parcellated using BrainParser, and the 80 most important neuroimaging biomarkers were extracted using the Global Shape Analysis (GSA) Pipeline workflow. We obtained 80 SNPs using Plink analysis via the Pipeline environment. In the AD cohort, rs2137962 was significantly associated with changes in left and right hippocampi and bilaterally in parahippocampal gyri, and rs1498853, rs288503, and rs288496 were significantly associated with hippocampi bilaterally, the right parahippocampal gyrus, and left inferior temporal gyrus. In the MCI cohort, rs17028008 and rs17027976 were significantly associated with right caudate and right fusiform gyrus, and rs2075650 (TOMM40) was significantly associated with right caudate, rs1334496 and rs4829605 were significantly associated with right inferior temporal gyrus. In the NC cohort, Chromosome 15 [rs734854 (STOML1), rs11072463 (PML), rs4886844 (PML) and rs1052242 (PML)] was significantly associated with the both hippocampi and both insular cortex and rs4899412 (RGS6) was significantly associated with caudate related biomarkers. We observed significant correlations between the SNPs and the neuroimaging phenotypes in the 808 subjects in terms of neuroimaging genetics. These results illustrate some of the neuroimaging-genetics associations between the AD, MCI and NC cohorts.

show abstract

Section: Discussionmentioning

confidence: 99%

Structural Neuroimaging Genetics Interactions in Alzheimer’s Disease

Moon

Dinov

Kim

et al. 2015

JAD

View full text Add to dashboard Cite

show abstract

“…Measurement of Secretase Activity-Detection of secretase activities in living cells was performed as described previously with slight modifications (29,30). Shortly, after incubation, cells were washed two times with prewarmed life cell imaging solution (HEPES buffer, pH 7,4).…”

Section: Methodsmentioning

confidence: 99%

Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein

Karaca

Tamboli

Glebov

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Sphingolipid metabolism is functionally linked to the proteolytic processing of APP. Results: Inhibition of S1P-lyase decreases APP degradation in lysosomes, and mobilization of Ca 2ϩ can partially rescue the accumulation of APP. Conclusion: S1P-lyase is critically involved in the regulation of lysosomal activity and degradation of APP. Significance: Alterations in S1P metabolism could play important roles in the pathogenesis of Alzheimer disease.

show abstract

“…Measurement was performed as described before [26]. Briefly, SH-SY5Y cells were homogenized in sucrose buffer with Minilys (Peqlab, Erlangen, Germany) for 30 s at maximum speed using ceramic beads.…”

Section: Methodsmentioning

confidence: 99%

Oxidized Docosahexaenoic Acid Species and Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing

Grimm¹,

Haupenthal²,

Mett³

et al. 2015

Neurodegener Dis

Self Cite

View full text Add to dashboard Cite

One of the main characteristics of Alzheimer's disease (AD) is the β-amyloid peptide (Aβ) generated by β- and γ-secretase processing of the amyloid precursor protein (APP). Previously it has been demonstrated that polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), are associated with a reduced risk of AD caused by decreased Aβ production. However, in epidemiological studies and nutritional approaches, the outcomes of DHA-dependent treatment were partially controversial. PUFAs are very susceptible to reactive oxygen species and lipid peroxidation, which are increased during disease pathology. In line with published results, lipid peroxidation was elevated in human postmortem AD brains; especially 4-hydroxy-nonenal (HNE) was increased. To investigate whether lipid peroxidation is only a consequence or might also influence the processes leading to AD, we analyzed 7 different oxidized lipid species including 5 oxidized DHA derivatives and the lipid peroxidation products of ω-3 and ω-6 PUFAs, HNE and 4-hydroxy-hexenal, in human neuroblastoma cells and mouse mixed cortical neurons. In the presence of oxidized lipids Aβ and soluble β-secreted APP levels were elevated, whereas soluble α-secreted APP was decreased, suggesting a shift from the nonamyloidogenic to the amyloidogenic pathway of APP processing. Furthermore, β- and γ-secretase activity was increased by oxidized lipids via increased gene expression and additionally by a direct effect on β-secretase activity. Importantly, only 1% oxidized DHA was sufficient to revert the protective effect of DHA and to significantly increase Aβ production. Therefore, our results emphasize the need to prevent DHA from oxidation in nutritional approaches and might help explain the divergent results of clinical DHA studies.

show abstract

Plasmalogens Inhibit APP Processing by Directly Affectingγ-Secretase Activity in Alzheimer’s Disease

Cited by 61 publications

References 75 publications

Structural Neuroimaging Genetics Interactions in Alzheimer’s Disease

Structural Neuroimaging Genetics Interactions in Alzheimer’s Disease

Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein

Oxidized Docosahexaenoic Acid Species and Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing

Contact Info

Product

Resources

About