Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease

Chan, Robin B.; Oliveira, Tiago Gil; Cortés, Etty; Honig, Lawrence S.; Duff, Karen; Small, Scott A.; Wenk, Markus R.; Shui, Guanghou; Paolo, Gilbert Di

doi:10.1074/jbc.m111.274142

Cited by 480 publications

(557 citation statements)

References 57 publications

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“…Values are represented as mole fraction with respect to total lipid (% molarity). For this, lipid mass (in moles) of any specific lipid is normalized by the total mass (in moles) of all the lipids measured (Chan et al , 2012). In addition, all of our results were further normalized by protein content.…”

Section: Methodsmentioning

confidence: 99%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

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In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β‐secretase to generate a 99‐aa C‐terminal fragment (C99) that is then cleaved by γ‐secretase to generate the β‐amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ‐secretase activity is enriched in mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM) and that ER–mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ‐secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.

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Section: Methodsmentioning

confidence: 99%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

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“…However, levels of lysophosphatidylcholines, lysoetherphosphatidylcholines and phosphatidylethanolamines were lower in AD-patients, compared to the control group. As far as the entorhinal cortex is concerned, AD-brains had higher concentrations of the lysobisphosphatidic acid, ceramide-lactose-N-acetylneuraminic acid, sphingomyelins and cholesterol esters [118]. These differences in lipidomic profiles for each subregion suggest their different involvement in the pathogenesis of AD [118].…”

Section: Dementiamentioning

confidence: 97%

“…The low levels of sulphatides in pre-clinical AD patients indicates brain cell membrane changes from early stages of AD, hence, the authors suggest sulphatides as biomarkers in early AD diagnosis and monitoring treatment progress [117]. A lipidomic profile of the brain revealed that the lipid profile of the cerebellum of the AD-patients and the control group marked no alterations [118]. However, there were differences in the lipidomic profiles of the prefrontal and entorhinal cortices between AD-patients and the control group.…”

Section: Dementiamentioning

confidence: 99%

Application of fatty acid and lipid measurements in neuropsychiatry

Grela

Rachel

Cole

et al. 2016

Clinical Chemistry and Laboratory Medicine (CCLM)

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Abstract:The importance of lipids in the understanding of disease states is constantly increasing. Whilst the link between metabolic disorders and lipids seems to be clear, interpreting lipid regulation in the context of neuropsychiatric disorders is a new approach. Mental disorders account for almost 15% of the total global disease burden with Alzheimer's disease, depression or schizophrenia being amongst the most widespread mental disorders in the general population. For this reason rapid and early diagnosis is crucial and finding the right biomarkers is of great importance. Lipids appear to be essential in learning the aetiopathology of neuropsychiatric diseases as well as in biomarker research as they are most abundantly present in the brain. This study discusses recent findings in neuropsychiatry in the context of lipid analysis.

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“…Lipid extracts were prepared from 18-month-old cortical lysates using a modified Bligh/Dyer extraction procedure as described previously (Chan et al, 2012). Samples were analyzed using an Agilent Technologies 6490 Ion Funnel LC/MS Triple Quadrupole system with front-end 1260 Infinity HPLC.…”

Section: Lipid Analysis Using High-performance Liquid Chromatographymmentioning

confidence: 99%

“…Neutral lipids were separated on an Agilent Zorbax XDB-C18 column (i.d., 4.6 ϫ 100 mm) using an isocratic mobile phase chloroform/methanol/0.1 M ammonium acetate (100: 100:4) at a flow rate of 300 l/min. Multiple reaction monitoring transitions were set up for the quantitative analysis of different lipid species and their corresponding internal standards as described previously (Chan et al, 2012). Lipid levels for each sample were calculated relative to the spiked internal standards and then normalized to the total amount of all lipid species measured and presented as the relative mole percentage.…”

Section: Lipid Analysis Using High-performance Liquid Chromatographymmentioning

confidence: 99%

α-Synuclein-Independent Histopathological and Motor Deficits in Mice Lacking the Endolysosomal Parkinsonism Protein Atp13a2

Kett

Stiller

Bernath³

et al. 2015

J. Neurosci.

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Accumulating evidence from genetic and biochemical studies implicates dysfunction of the autophagic-lysosomal pathway as a key feature in the pathogenesis of Parkinson's disease (PD). Most studies have focused on accumulation of neurotoxic ␣-synuclein secondary to defects in autophagy as the cause of neurodegeneration, but abnormalities of the autophagic-lysosomal system likely mediate toxicity through multiple mechanisms. To further explore how endolysosomal dysfunction causes PD-related neurodegeneration, we generated a murine model of Kufor-Rakeb syndrome (KRS), characterized by early-onset Parkinsonism with additional neurological features. KRS is caused by recessive loss-of-function mutations in the ATP13A2 gene encoding the endolysosomal ATPase ATP13A2. We show that loss of ATP13A2 causes a specific protein trafficking defect, and that Atp13a2 null mice develop age-related motor dysfunction that is preceded by neuropathological changes, including gliosis, accumulation of ubiquitinated protein aggregates, lipofuscinosis, and endolysosomal abnormalities. Contrary to predictions from in vitro data, in vivo mouse genetic studies demonstrate that these phenotypes are ␣-synuclein independent. Our findings indicate that endolysosomal dysfunction and abnormalities of ␣-synuclein homeostasis are not synonymous, even in the context of an endolysosomal genetic defect linked to Parkinsonism, and highlight the presence of ␣-synucleinindependent neurotoxicity consequent to endolysosomal dysfunction.

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Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease

Cited by 480 publications

References 57 publications

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Application of fatty acid and lipid measurements in neuropsychiatry

α-Synuclein-Independent Histopathological and Motor Deficits in Mice Lacking the Endolysosomal Parkinsonism Protein Atp13a2

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