The amyloid precursor protein intracellular domain alters gene expression and induces neuron-specific apoptosis

Ohkawara, Takeshi; Nagase, Hisashi; Koh, Chang−Sung; Nakayama, Kohzo

doi:10.1016/j.gene.2010.11.014

Cited by 33 publications

(38 citation statements)

References 48 publications

(62 reference statements)

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“…In line with these findings, it has been recently reported that differentiated PC12 cells, treated with the γ-secretase inhibitor DAPT, show an increase in ganglioside level in neuritic terminals [62], further strengthening that PS proteolytic activity alters ganglioside homeostasis. Additionally, we and others recently found that cleavage products of APP are involved in the regulation of several proteins and that this regulation is disturbed in absence of PS, in mutated PS or in AD [11,30,31,32,63,64,65]. Main focus was attended to the APP intracellular domain (AICD), which is released to the cytosol and discussed to be involved in gene transcription.…”

Section: Discussionmentioning

confidence: 99%

PS Dependent APP Cleavage Regulates Glucosylceramide Synthase and is Affected in Alzheimer's Disease

Grimm

Hundsdörfer

Grösgen

et al. 2014

Cell Physiol Biochem

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Background: Gangliosides were found to be associated with Alzheimer's disease (AD). Here we addressed a potential function of γ-secretase (presenilin) dependent cleavage of the amyloid-precursor-protein (APP) in the regulation of ganglioside de novo synthesis. Methods: To identify a potential role of γ-secretase and APP in ganglioside de novo synthesis we used presenilin (PS) deficient and APP deficient cells and mouse brains, mutated PS as well as transgenic mice and AD post mortem brains. Changes in glucosylceramide synthase (GCS) activity were identified by incorporation of radiolabeled UDP-glucose in glucosylceramide, changes in gene expression via real-time PCR and Western blot analysis. Alterations in ganglioside levels were determined by thin layer chromatography and mass spectrometry. Results: We found that PS and APP deficiency, in vitro and in vivo, resulted in increased GCS gene expression, elevated enzyme activity and thus increased glucosylceramide and total ganglioside level. Using a specific γ-secretase inhibitor revealed that PS proteolytic activity alters ganglioside homeostasis. By the use of mutated PS causing early onset AD in cell culture and transgenic mice we found that GCS is increased in AD, further substantiated by the use of AD post mortem brains, suffering from sporadic AD. Conclusion: APP processing regulates ganglioside de novo synthesis and is affected in AD.

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Section: Discussionmentioning

confidence: 99%

PS Dependent APP Cleavage Regulates Glucosylceramide Synthase and is Affected in Alzheimer's Disease

Grimm

Hundsdörfer

Grösgen

et al. 2014

Cell Physiol Biochem

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“…Gene expression levels were deduced by hybridization signal intensity on the DNA microarrays, and the data from AICD-overexpressing cells were compared to data from control cells at the same 3 points during culture: 1) the undifferentiated state; 2) after 4 days of aggregation with RA (aggregated state); and 3) 2 days after replating (differentiated state). According to our expectations, AICD was shown to alter the expression of a great many genes; in the presence of AICD, the expression levels of 277 genes were upregulated by more than 10-fold, while those of 341 genes were downregulated to less than 10% of the original level [30].…”

Section: Aicd Changes the Gene Expression Profilementioning

confidence: 72%

“…Although neurons differentiated from these cell lines, AICD expression induced dynamic changes in gene expression profile and neuron-specific apoptosis [30]. These results suggest that APP also has a signaling mechanism, which may be closely related to AD.…”

Section: Introductionmentioning

confidence: 80%

“…To examine this possibility and identify the genes involved in this neuron-specific apoptosis, we performed DNA microarray analyses to evaluate the changes in the expression of more than 20,000 independent genes induced by AICD through the process of neuron-specific apoptosis [30]. Gene expression levels were deduced by hybridization signal intensity on the DNA microarrays, and the data from AICD-overexpressing cells were compared to data from control cells at the same 3 points during culture: 1) the undifferentiated state; 2) after 4 days of aggregation with RA (aggregated state); and 3) 2 days after replating (differentiated state).…”

Section: Aicd Changes the Gene Expression Profilementioning

confidence: 99%

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γ-Secretase — Regulated Signaling and Alzheimer's Disease

Nakayama¹,

Nagase²,

Koh³

et al. 2013

Understanding Alzheimer's Disease

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“…Of the APP fragments, AICD is by far the best characterized as a transcriptional regulator (31,(61)(62)(63). A large number of genes have been linked to AICD (64), with some consistently shown to be up-regulated, such as neprilysin (33,34), and a much smaller number to be down-regulated, such as the EGF receptor (65). However, the failure of a ␥-secretase inhibitor to affect AChE mRNA or activity levels demonstrates that AICD does not regulate AChE in the mammalian neuronal cell lines used, with the repression of AChE expression unchanged by ␥-secretase inhibition and, hence, ablation of AICD production.…”

Section: Discussionmentioning

confidence: 99%

The Amyloid Precursor Protein Represses Expression of Acetylcholinesterase in Neuronal Cell Lines

Hicks

Makova

Gough

et al. 2013

Journal of Biological Chemistry

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Background: Acetylcholinesterase (AChE) and amyloid precursor protein (APP) are implicated in Alzheimer's disease, but their specific biological roles remain unclear. Results: Overexpression or knockdown of neuronal APP modulates AChE mRNA, protein levels, and enzyme activity. Conclusion: APP can act as a transcriptional regulator through a novel mechanism independently of ␥-secretase. Significance: Understanding the physiological functions of APP will lead to a greater understanding of Alzheimer's disease etiology.

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The amyloid precursor protein intracellular domain alters gene expression and induces neuron-specific apoptosis

Cited by 33 publications

References 48 publications

PS Dependent APP Cleavage Regulates Glucosylceramide Synthase and is Affected in Alzheimer's Disease

PS Dependent APP Cleavage Regulates Glucosylceramide Synthase and is Affected in Alzheimer's Disease

γ-Secretase — Regulated Signaling and Alzheimer's Disease

The Amyloid Precursor Protein Represses Expression of Acetylcholinesterase in Neuronal Cell Lines

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