Intracellular APP Domain  Regulates Serine‐Palmitoyl‐CoA Transferase  Expression and Is Affected in Alzheimer′s Disease

Grimm, Marcus O. W.; Grösgen, Sven; Rothhaar, Tatjana L.; Burg, Verena K.; Hundsdörfer, Benjamin; Haupenthal, Viola J.; Friess, Petra; Müller, Ulrike; Faßbender, Klaus; Riemenschneider, Matthias; Grimm, Heike S.; Hartmann, Tobias

doi:10.4061/2011/695413

Cited by 50 publications

(61 citation statements)

References 76 publications

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“…To determine the effect of AICD (sequence in 1-letter code: KMQQNGYENPTYKFFEQMQN) (2µM) (Genscript Corporation, Piscatway, USA) synthetic peptides were incubated for 9 days in cell culture. Utilizing this method it has been previously shown that AICD is efficiently taken up and biologically active [30,31]. …”

Section: Methodsmentioning

confidence: 99%

“…After isolation of the lipid phase as described above, 3ml szintilation solution (Perkin Elmer, Rodgau-Jügesheim, Germany) was added, mixed and radioactivity was measured by a Tri-Carb 2800TR (Perkin Elmer, Rodgau-Jügesheim, Germany) [31,41,42,43]. The assay was validated using a specific GCS inhibitor, DL-PDMP (5µM).…”

Section: Methodsmentioning

confidence: 99%

“…A modified Bligh and Dyer [31,40] method was utilized to extract GlcCer to measure GCS activity. After stopping the GCS activity by freezing in liquid nitrogen, 3.75ml CHCl 3 : MeOH: HCl (1: 2: 0.06; v/v/v) was added and vortexed for 1h at RT.…”

Section: Methodsmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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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“…Among these alterations, abnormal sphingolipid metabolism has been reported in AD tissues (van Echten‐Deckert & Walter, 2012). Specifically, there is an upregulation of de novo ceramide synthesis (Grimm et al , 2011) and an increase in the activity of sphingomyelinase (SMase), which catabolizes sphingomyelin (SM) into ceramide (Filippov et al , 2012). These alterations act synergistically to increase ceramide content in AD brains (Filippov et al , 2012).…”

Section: Introductionmentioning

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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“…The α-secretase cleaves APP within the Aβ domain, thus precluding the formation of Aβ peptides. The γ-secretase cleavage of βCTF/C99 and αCTF/C83 liberates the APP intracellular domain (AICD), which translocates to the nucleus and regulates gene expression [306][307][308][309][310].…”

Section: Proteolytic Processing Of App Amyloidogenic App Processingmentioning

confidence: 99%

Recent Understanding of the Molecular Mechanisms of Alzheimer?s Disease

Grimm¹,

Hartmann²

2011

J Addict Res Ther

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Alzheimer's disease (AD) is the most common form of dementia in the elderly and is characterized in patients by an inexorably progression, causing problems with memory, thinking and behaviour. Currently 25 million people worldwide are estimated to be affected by AD with the highest number in North America, Latin America, Western Europe, China and the western pacific [1]. Epidemiological studies predict that the incidence of AD will increase due to increasing life expectancy to 42.3 million in 2020 and 81.1 million in 2040 [1,2], emphasizing AD as a major public health concern.The two main histopathological hallmarks of AD are extracellular amyloid plaques and intracellular neurofibrillary tangles in vulnerable brain regions like hippocampus and cortex [3]. The amyloid plaques, also called senile plaques, are mainly composed of amyloid-beta peptides (Aβ), most of which are 38 to 43 amino acids long [4]. Aβ peptides are generated by sequential processing of the amyloid precursor protein (APP), a large type-I transmembrane protein [5] that belongs to an evolutionary conserved protein family including beside APP, the APP-like protein 1 (APLP1) and 2 (APLP2) in mammals [6,7] with the Aβ domain to be unique to APP [8]. The second characteristic pathological hallmark of AD, the intracellular neurofibrillary tangles, consist of an abnormally phosphorylated form of the microtubule-associated protein tau [9]. In contrast to amyloid plaques, which accumulate extracellularly in the brains of AD affected individuals and have been long believed to cause neuronal damage and cell death, neurofibrillary tangles are found inside neurons and their branching points like axons and dendrites [10,11]. Proteolytic Processing of APP Amyloidogenic APP processingProteolytic processing of APP leading to Aβ peptides is a ubiquitous cellular process involving β-and γ-secretase activity (Figure 1). The first step in Aβ production is APP cleavage by β-secretase, generating the N-terminus of Aβ. BACE 1 (β-site APP cleaving enzyme, also called Asp2 or memapsin2) was identified as the major β-secretase, a membrane-bound protease that belongs to the pepsin family of aspartyl proteases [12][13][14]. Aβ generation is abolished in cultures of BACE1-deficient embryonic cortical neurons [15] and in BACE1 knock-out mice [16,17]. Whereas Luo and Roberds et al. [16,17] reported a normal phenotype of BACE1-deficient mice, more recent studies found severe phenotypic abnormalities in BACE1 knock-out mice [18], challenging BACE1 as safe drug target for AD. Furthermore, additional BACE1 substrates have been reported, suggesting a variety of BACE1 physiological functions. Identified substrates include proteins with important neuronal function, like the β2-subunit of the voltage-gated sodium channel (Navβ2) [19,20], important for normal action potential regulation and neuronal excitability, and neuregulin-1 [21,22], as ligand for members of the ErbB family of receptor-tyrosine kinases, involved in synapse formation, myelination of central and peripheral axon...

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Intracellular APP Domain Regulates Serine‐Palmitoyl‐CoA Transferase Expression and Is Affected in Alzheimer′s Disease

Cited by 50 publications

References 76 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

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

Recent Understanding of the Molecular Mechanisms of Alzheimer?s Disease

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