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The adipocyte differentiation protein APMAP is an endogenous suppressor of A? production in the brain.

ABSTRACT: The deposition of amyloid-beta (A?) aggregates in the brain is a major pathological hallmark of Alzheimer's disease (AD). A? is generated from the cleavage of C-terminal fragments of the amyloid precursor protein (APP-CTFs) by ?-secretase, an intramembrane-cleaving protease with multiple substrates, including the Notch receptors. Endogenous modulation of ?-secretase is pointed to be implicated in the sporadic, age-dependent form of AD. Moreover, specifically modulating A? production has become a priority for the safe treatment of AD because the inhibition of ?-secretase results in adverse effects that are related to impaired Notch cleavage. Here, we report the identification of the adipocyte differentiation protein APMAP as a novel endogenous suppressor of A? generation. We found that APMAP interacts physically with ?-secretase and its substrate APP. In cells, the partial depletion of APMAP drastically increased the levels of APP-CTFs, as well as uniquely affecting their stability, with the consequence being increased secretion of A?. In wild-type and APP/ presenilin 1 transgenic mice, partial adeno-associated virus-mediated APMAP knockdown in the hippocampus increased A? production by ?20 and ?55%, respectively. Together, our data demonstrate that APMAP is a negative regulator of A? production through its interaction with APP and ?-secretase. All observed APMAP phenotypes can be explained by an impaired degradation of APP-CTFs, likely caused by an altered substrate transport capacity to the lysosomal/autophagic system.

SUBMITTER: Mosser S

PROVIDER: S-EPMC4275069 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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The adipocyte differentiation protein APMAP is an endogenous suppressor of Aβ production in the brain.

Mosser Sebastien S Alattia Jean-René JR Dimitrov Mitko M Matz Alexandre A Pascual Justine J Schneider Bernard L BL Fraering Patrick C PC

Human molecular genetics 20140901 2

The deposition of amyloid-beta (Aβ) aggregates in the brain is a major pathological hallmark of Alzheimer's disease (AD). Aβ is generated from the cleavage of C-terminal fragments of the amyloid precursor protein (APP-CTFs) by γ-secretase, an intramembrane-cleaving protease with multiple substrates, including the Notch receptors. Endogenous modulation of γ-secretase is pointed to be implicated in the sporadic, age-dependent form of AD. Moreover, specifically modulating Aβ production has become a ...[more]

PMID: 25180020

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Project description:The yak (Bos grunniens) is subjected to nutritional deficiency during the whole winter grazing season; deciphering the adipose metabolism and energy homeostasis under cold and nutrients stress conditions could be a novel way to understand the specific mechanism of energy metabolism. Circular RNAs (circRNAs) have elucidated that they play a key role in many biological events, but the regulatory function of adipose development remains mostly unknown. Therefore, the expression pattern of circRNAs were identified for the first time during yak adipocyte differentiation to gain insight into their potential functional involvement in bovine adipogenesis. We detected 7203 circRNA candidates, most of them contained at least two exons, and multiple circRNA isoforms could be generated from one parental gene. Analysis of differential expression circRNAs displayed that 136 circRNAs were differentially expressed at day 12 (Ad) after adipocyte differentiation, compared with the control at day 0 (Pread 0), while 7 circRNAs were detected on day 2. Sanger sequencing validated that six circRNAs had head-to-tail junction, and quantitative real-time PCR (qPCR) results revealed that the expression patterns of ten circRNAs were consistent with their expression levels from RNA-sequencing (RNA-seq) data. We further predicted the networks of circRNA-miRNA-gene based on miRNAs sponging by circRNAs, in which genes were participated in the adipocyte differentiation-related signaling pathways. After that, we constructed several adipocyte differentiation-related ceRNAs and revealed six circRNAs (novel_circ_0009127, novel_circ_0000628, novel_circ_0011513, novel_circ_0010775, novel_circ_0006981 and novel_circ_0001494) were related to adipogenesis. Furthermore, we analyzed the homology among yak, human and mouse circRNAs and found that 3536 yak circRNAs were homologous to human and mouse circRNAs. In conclusion, these findings provide a solid basis for the investigation of yak adipocyte differentiation-related circRNAs and serve as a great reference to study the energy metabolism of high-altitude animals.

Dataset Information

The adipocyte differentiation protein APMAP is an endogenous suppressor of A? production in the brain.

Publications

The adipocyte differentiation protein APMAP is an endogenous suppressor of Aβ production in the brain.

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