Proteolytic processing of beta-amyloid precursor by calpain I

Siman, Robert; Card, J. Patrick; Davis, L. Gray

doi:10.1523/jneurosci.10-07-02400.1990

Cited by 104 publications

(47 citation statements)

References 42 publications

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“…In contrast, treatment with endosomal/lysosomal inhibitors stabilized the C-terminal fragments of ␤APP as described previously (40,53). In addition LLnL but not lactacystin lead to an augmentation of the ␤APP fragments, which is again in agreement with previous results (54). We therefore conclude from these data that the PS1 NTF and CTF 20 are not degraded by the proteasome or endosomal/lysosomal proteinases as well as other cysteine proteinases but are rather stable over long periods.…”

Section: Resultssupporting

confidence: 92%

Expression of Alzheimer’s Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation

Steiner¹,

Capell²,

Pesold³

et al. 1998

Journal of Biological Chemistry

185

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Numerous mutations causing early onset Alzheimer's disease have been identified in the presenilin (PS) genes, particularly the PS1 gene. Like the mutations identified within the ␤-amyloid precursor protein gene, PS mutations cause the increased generation of a highly neurotoxic variant of amyloid ␤-peptide. PS proteins are proteolytically processed to an N-terminal ϳ30-kDa (NTF) and a C-terminal ϳ20-kDa fragment (CTF 20 ) that form a heterodimeric complex. We demonstrate that this complex is resistant to proteolytic degradation, whereas the full-length precursor is rapidly degraded. Degradation of the PS1 holoprotein is sensitive to inhibitors of the proteasome. Formation of a heterodimeric complex is required for the stability of both PS1 fragments, since fragments that do not co-immunoprecipitate with the PS complex are rapidly degraded by the proteasome. Mutant PS fragments not incorporated into the heterodimeric complex lose their pathological activity in abnormal amyloid ␤-peptide generation even after inhibition of their proteolytic degradation. The PS1 heterodimeric complex can be attacked by proteinases of the caspase superfamily that generate an ϳ10-kDa proteolytic fragment (CTF 10 ) from CTF 20 . CTF 10 is rapidly degraded most likely by a calpain-like cysteine proteinase. From these data we conclude that PS1 metabolism is highly controlled by multiple proteolytic activities indicating that subtle changes in fragment generation/ degradation might be important for Alzheimer's diseaseassociated pathology.Alzheimer's disease (AD) 1 is the most common dementia worldwide. A pathological hallmark of AD is the invariant accumulation of numerous senile plaques in certain areas of the brain. Senile plaques are composed of the amyloid ␤-peptide (A␤), a proteolytic derivative of the ␤-amyloid precursor protein (␤APP; see Ref. 1). In the majority of cases, AD occurs as a sporadic disease with an increasing risk during aging (2). However, in about 10 -15% of the cases AD is caused by autosomal dominant mutations within three genes (2). A very limited set of families was identified carrying mutations in the ␤APP gene (2). These mutations occur at, or close to, the cleavage sites of the ␤APP-processing enzymes, the secretases (1). All ␤APP mutations analyzed so far cause an enhanced production of A␤, specifically the highly pathogenic 42-amino acid variant, A␤42 (2).By far the highest number of FAD-associated mutations were identified within the PS gene (see Ref. 3 and for review see Ref. 4). Two mutations were also observed in the highly homologous PS2 gene (5, 6). PS proteins are integral membrane proteins, which form 6 to 8 trans-membrane domains with the N-terminal domain, the large loop, and the C-terminal domain located within the cytoplasm (7,8). Both PS proteins are predominantly expressed within the endoplasmic reticulum, the nuclear envelope, and the early Golgi (7, 9 -12).Like ␤APP mutations, mutant PS proteins are involved in aberrant A␤ generation. All PS1 and PS2 mutations analyzed so far affect the ...

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Section: Resultssupporting

confidence: 92%

Expression of Alzheimer’s Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation

Steiner¹,

Capell²,

Pesold³

et al. 1998

Journal of Biological Chemistry

185

View full text Add to dashboard Cite

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“…These proteins are most likely C-terminal fragments resulting from proteolytic processing of APPs. Similar C-terminal fragments of APP have been detected in rat brain membranes [66], APP-transfected 293 cells [67] and PC12 cells [68]. The absence of these fragments in primary culture systems raises the possibility that post-translational processing of APP or turnover of APP C-terminal fragments changes in culture conditions.…”

Section: Discussionsupporting

confidence: 52%

Differential APP gene expression in rat cerebral cortex, meninges, and primary astroglial, microglial and neuronal cultures

et al. 1991

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Differential amyloid precursor protein (APP) gene expression wag investigated ~r. primary cultures of astrocytes, neurons and microglia from neonatal rat cerebral cortex as well as in meninges, and young and adult cerebral cortex tissues in order to define the possible contribution of individual CNS cell types in flAP deposition. Meninges and neurons contained higher levels of total APP mRNA than glial cells and APP6gs mRNA was abundant in neurons while glial ceils and meninges contained higher levels of KPI-containing mRNAs. These results demonstrate cell-specific transcriptional and post-transcriptional regulation of APP gene expression in CNS cell types. In addition, the steady-state level of APPs ha each cell type did not reflect mRNA levels indicating translational or post-translational regulation.

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“…24 Polypeptide sequences enriched in proline (P), glutamate (E), serine (S) and threonine (T), known as PEST sequences, have been shown to mark proteins for recognition and destruction. In particular, the PEST domain of three proteins: beta-amyloid, 32 ATP-binding cassette transporter A1 (ABCA1) 33 and i-kB 34 have been reported to be involved in degradation by calpain.…”

Section: Resultsmentioning

confidence: 99%

Ceramide triggers an NF-κB-dependent survival pathway through calpain

et al. 2005

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We have shown that C2 ceramide, a cell-permeable analog of this lipid second messenger, triggers an NF-jB dependent survival pathway that counteracts cell death. Activation of NF-jB and subsequent induction of prosurvival genes relies on calpain activity and is prevented on silencing of the calpain small subunit (Capn4) that is required for the function of ubiquitous calpains. We have demonstrated that p105 (NFjB1) and its proteolytic product p50 can be targets of microand milli-calpain in vitro and that a p50 deletion mutant, lacking both the N-and the C-terminal ends, is resistant to calpain-mediated degradation. Capn4 silencing results in stabilization of endogenous p105 and p50 in diverse human cell lines. Furthermore, p105 processing and activation of NFjB survival genes in response to C2 ceramide is impaired in Capn4À/À mouse embryonic fibroblasts defective in calpain activity. Altogether, these data argue for the existence of a ceramide-calpain-NF-jB axis with prosurvival functions.

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Proteolytic processing of beta-amyloid precursor by calpain I

Cited by 104 publications

References 42 publications

Expression of Alzheimer’s Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation

Expression of Alzheimer’s Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation

Differential APP gene expression in rat cerebral cortex, meninges, and primary astroglial, microglial and neuronal cultures

Ceramide triggers an NF-κB-dependent survival pathway through calpain

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