Trafficking and Proteolytic Processing of APP

Haass, Christian; Kaether, Christoph; Wang, Shuai; Sisodia, Sangram S.

doi:10.1101/cshperspect.a006270

Cited by 911 publications

(958 citation statements)

References 197 publications

(220 reference statements)

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“…Many reports have shown that C99 is localized mainly in endosomes (Haass et al , 2012; Das et al , 2016). Therefore, it is possible that the presence of C99 in MAM regions was the result of a cross‐contamination of MAM samples with endosomes during the process of subcellular fractionation.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with the data of others (Das et al , 2016), FL‐APP and BACE1 co‐migrated partially with a marker for endosomes (Rab7), but not with lysosomal, ER‐intermediate, or MAM markers (Fig 2C). Similarly, the APP‐CTFs C83 and C99 co‐migrated with endosomal and lysosomal markers (Rab5, Rab7, and LAMP‐2) (Haass et al , 2012; Das et al , 2016), whereas PS1 co‐migrated with MAM markers, such as FACL4 (Area‐Gomez et al , 2009; Newman et al , 2014; Schreiner et al , 2015). We reasoned that the difficulty in seeing APP‐CTFs and PS1 together was probably due to the rapid cleavage of the CTFs by γ‐secretase once both are in the same compartment.…”

Section: Resultsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

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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“…21 None of the other APP variants showed an altered Aβ spectrum. However, further studies are necessary to exclude that these variants could affect the structure and, accordingly, the aggregation potential of generated Aβ as has been demonstrated for some AD-linked variants (reviewed in Haass et al 22 ).…”

Section: Discussionmentioning

confidence: 99%

Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease

et al. 2015

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Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency o5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G4A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G4A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.

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“…The amyloid precursor protein is a single transmembrane receptor with an extracellular N-terminus and intracellular C-terminus (type I integral membrane protein), which can be processed to amyloid-β peptide (Aβ) by either the amyloidogenic or anti-amyloidogenic pathways [14] (Figure 2). Amyloid-β peptide (Aβ) accumulation is a major pathological hallmark of Alzheimer's disease [14].…”

Section: Amyloid Precursor Proteinmentioning

confidence: 99%

Roles of extracellular nucleotides and P2 receptors in ectodomain shedding

Pupovac

Sluyter

2016

Cell. Mol. Life Sci.

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Ectodomain shedding of integral membrane receptors results in the release of soluble molecules and modification of the transmembrane portions to mediate or modulate extracellular and intracellular signalling. Ectodomain shedding is stimulated by a variety of mechanisms, including the activation of P2 receptors by extracellular nucleotides. This review describes in detail the roles of extracellular nucleotides and P2 receptors in the shedding of various cell surface molecules, including amyloid precursor protein, CD23, CD62L, and members of the epidermal growth factor, immunoglobulin and tumour necrosis factor families. This review discusses the mechanisms involved in P2 receptor-mediated shedding, demonstrating central roles for the P2 receptors, P2X7 and P2Y2, and the sheddases, ADAM10 and ADAM17, in this process in a number of cell types.

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Trafficking and Proteolytic Processing of APP

Cited by 911 publications

References 197 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

Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease

Roles of extracellular nucleotides and P2 receptors in ectodomain shedding

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