Alternative, Non-secretase Processing of Alzheimer's β-Amyloid Precursor Protein during Apoptosis by Caspase-6 and -8

Pellegrini, Luca; Passer, Brent J.; Tabaton, Massimo; Ganjei, J. Kelly; D’Adamio, Luciano

doi:10.1074/jbc.274.30.21011

Cited by 155 publications

(101 citation statements)

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“…However, it is also clear from our present work that caspase-cleaved APP per se is not a major contributor to A␤ generation, and therefore a scenario in which caspase-cleaved APP actively contributes to A␤ secretion remains unlikely. Thus, the possibility remains that cytotoxic effects derived from caspase cleavage of APP may result from the generation of new APP-derived C-terminal peptides (10,17,19) or C31, as we have proposed (12).…”

Section: Discussionmentioning

confidence: 99%

“…A number of laboratories have recently demonstrated that APP can be cleaved in the cytoplasmic domain by caspases after the aspartate residue at position 664, Val-Glu-Val-Asp 664 2Ala, (APP 695 numbering, or Asp 720 using APP 751 numbering) (7)(8)(9)(10)(11)(12). This cleavage would generate a C-terminal-truncated APP molecule that is ϳ3.5 kDa shorter (APP⌬C31) (7,12).…”

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The Amyloidogenic Pathway of Amyloid Precursor Protein (APP) Is Independent of Its Cleavage by Caspases

Soriano

Chandra

et al. 2001

Journal of Biological Chemistry

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Amyloid ␤-protein (A␤) is the main constituent of senile plaques in Alzheimer's disease and is derived by proteolysis from the amyloid precursor protein (APP). Generation and secretion of both A␤40 and A␤42 isoforms depend largely on internalization of APP and occurs mainly in the endocytic pathway. Evidence has also been presented (Gervais, F. G., Xu, D., Robertson, G. S., Vaillancourt, J. P., Zhu, Y., Huang, J., LeBlanc, A., Smith, D., Rigby, M., Shearman, M. S., Clarke, E. E., Zheng, H., Van der Ploeg, L. H. T., Ruffolo, S. C., Thornberry, N. A., Xanthoudakis, S., Zamboni, R. J., Roy, S., and Nicholson, D. W. (1999) Cell, 97, 395-406) that caspase cleavage of APP at its cytosolic tail affects its processing such that it is redirected to a more amyloidogenic pathway, resulting in enhanced A␤ generation. However, caspase cleavage of APP also results in loss of its endocytosis signal (YENP), an event that would predict a decline in internalization and a concomitant decrease, not an increase, in A␤ generation. In the present work, we examined whether caspase cleavage of APP is relevant to amyloidogenesis. We found that 1) caspase cleavage of APP results in reduced internalization and, accordingly, a decline in A␤ secretion; 2) masking of the caspase site in APP did not affect A␤ levels and, 3) caspase activation in cells by serum withdrawal did not increase A␤ secretion. Thus, caspase cleavage of APP is unlikely to play a direct role in amyloidogenesis.Alzheimer's disease is accompanied by deposition of the amyloid peptide A␤ in senile plaques and cerebral blood vessels. Two major species of amyloid ␤-protein (A␤), differing by two amino acids in length (A␤-(1-40) and A␤-(1-42)) at the C terminus, have been characterized. A␤-(1-42), the longer A␤ isoform, readily aggregates in vitro and appears to be the more amyloidogenic and hence pathogenic species (reviewed in Ref. 1). Although the precise mechanism by which A␤ is generated from its precursor, the amyloid precursor protein (APP), 1 is not well understood, internalization of APP from the cell surface with subsequent processing in the endocytic pathway is a major route for generation and secretion of both A␤ isoforms (2-4). Accordingly, deletion or site-directed mutagenesis of the endocytosis motif in APP abrogates secretion of A␤-(1-40) and A␤-(1-42) (3).Two reports have shown that neurons undergoing apoptotic cell death secrete approximately 2-to 3-fold more A␤ than healthy neurons (5, 6). Because A␤ is neurotoxic and contributes to apoptosis in a variety of cultured cells, it has been proposed that increased A␤ secretion, due to genetic predisposition or to other factors, causes increased cell death in susceptible neurons. This initiates a cycle in which dying neurons release more A␤, which in turn causes more cell death to account for death of neurons seen in Alzheimer's disease (6, 7).A number of laboratories have recently demonstrated that APP can be cleaved in the cytoplasmic domain by caspases after the aspartate residue at position 664, Val-Glu-Val-As...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The Amyloidogenic Pathway of Amyloid Precursor Protein (APP) Is Independent of Its Cleavage by Caspases

Soriano

Chandra

et al. 2001

Journal of Biological Chemistry

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“…14 Second, Casp6 activity in primary human neurons increases the production of Ab. 15,16 Although APP is a substrate of Casp6, [16][17][18] the caspasedependent increase of Ab is due to the cleavage of GGA3 (Golgi-associated, gamma adaptin ear containing, ARFbinding protein 3), an inhibitor of beta secretase. 19,20 Third, Casp6 cleaves valosin-containing protein resulting in the accumulation of cytosolic ubiquitinated misfolded proteins through an impairment of the ubiquitin-proteasomal system.…”

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Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

et al. 2014

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Active Caspase-6 is abundant in the neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer disease brains. However, its contribution to the pathophysiology of Alzheimer disease is unclear. Here, we show that higher levels of Caspase-6 activity in the CA1 region of aged human hippocampi correlate with lower cognitive performance. To determine whether Caspase-6 activity, in the absence of plaques and tangles, is sufficient to cause memory deficits, we generated a transgenic knock-in mouse that expresses a self-activated form of human Caspase-6 in the CA1. This Caspase-6 mouse develops agedependent spatial and episodic memory impairment. Caspase-6 induces neuronal degeneration and inflammation. We conclude that Caspase-6 activation in mouse CA1 neurons is sufficient to induce neuronal degeneration and age-dependent memory impairment. These results indicate that Caspase-6 activity in CA1 could be responsible for the lower cognitive performance of aged humans. Consequently, preventing or inhibiting Caspase-6 activity in the aged may provide an efficient novel therapeutic approach against Alzheimer disease. Cell Death and Differentiation (2014) 21, 696-706; doi:10.1038/cdd.2013; published online 10 January 2014The underlying molecular pathway for neuronal degeneration and dysfunction in Alzheimer's disease (AD) remains unknown. Yet, the identification of critical events initiating neuronal degeneration could provide a novel therapeutic approach to stem the progressive dementia of AD. We propose that Caspase-6 (Casp6), a cysteinyl protease of the caspase family, has a critical role in AD neuronal degeneration and cognitive impairment. Casp6 activity is intimately associated with the neuritic plaques (NP), neurofibrillary tangles (NFT), and neuropil threads (NPT) of AD. 1 Casp6 activity is abundant in familial AD 2 and at all stages of sporadic AD. 3 Although no Casp6 activity is present in younger brains, 1 several aged non-cognitively impaired (NCI) brains show significant amounts of Casp6 activity in the entorhinal cortex (ERC), 3 the first area showing NFT pathology in AD according to Braak staging. 4,5 Furthermore, higher levels of Casp6 activity in the ERC and cornu ammonis 1 (CA1) region of NCI brains correlate with lower episodic memory (EP) performance, one of the types of memory also affected early in AD. 6 Active Casp6 induces several parallel degenerative pathways associated with AD neuropathology. First, Casp6 activity disrupts the neuronal cytoskeleton. Casp6 cleaves neuronal microtubule protein alpha-tubulin, microtubuleassociated protein Tau, and actin-regulating post-synaptic density proteins, Spinophilin, Drebrin, and Actinins. 7 In mouse, caspase activity precedes and leads to the formation of NFT-like aggregation. 8 Casp6 activity is involved in axonal degeneration of mouse PNS neurons via amyloid precursor protein (APP) interaction with death receptor 6 9 and in nerve growth factor (NGF)-deprived dorsal root ganglion neurons. 10 Furthermore, Casp6-dependent axonal degeneration i...

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“…Each of the four caspases, 3, 6, 7, and 8, have been shown to cleave APP in in vitro assays, and a major caspase site has been identified at Asp-720 (VEVD), resulting in the release of a fragment containing the last 31 amino-acids of APP (C31) and the production of APP⌬C31 (lacking Ala 721 to Asn 751 ) (5)(6)(7)(8). Two other major caspase sites have been recently identified at the N-terminal domain of APP Asp 197 and Asp 219 , leading to the production of a ϳ90 kDa fragment (APP⌬N).…”

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confidence: 99%

Caspase Activation Increases β-Amyloid Generation Independently of Caspase Cleavage of the β-Amyloid Precursor Protein (APP)

Tesco

Koh

Tanzi

2003

Journal of Biological Chemistry

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The amyloid precursor protein (APP) undergoes "alternative" proteolysis mediated by caspases. Three major caspase recognition sites have been identified in the APP, i.e. one at the C terminus (Asp 720 ) and two at the N terminus (Asp 197 and Asp 219 ). Caspase cleavage at Asp 720 has been suggested as leading to increased production of A␤. Thus, we set out to determine which putative caspase sites in APP, if any, are cleaved in Chinese hamster ovary cell lines concurrently with the increased A␤ production that occurs during apoptosis. We found that cleavage at Asp 720 occurred concurrently with caspase 3 activation and the increased production of total secreted A␤ and A␤ 1-42 in association with staurosporineand etoposide-induced apoptosis. To investigate the contribution of caspase cleavage of APP to A␤ generation, we expressed an APP mutant truncated at Asp 720 that mimics APP caspase cleavage at the C-terminal site. This did not increase A␤ generation but, in contrast, dramatically decreased A␤ production in Chinese hamster ovary cells. Furthermore, the ablation of caspasedependent cleavage at Asp 720 , Asp 197 , and Asp 219 (by sitedirected mutagenesis) did not prevent enhanced A␤ production following etoposide-induced apoptosis. These findings indicate that the enhanced A␤ generation associated with apoptosis does not require cleavage of APP at its C-terminal (Asp 720 ) and/or N-terminal caspase sites.Alzheimer's disease (AD) 1 is a devastating neurodegenerative disorder that results in loss of memory and cognitive function, eventually leading to dementia. AD is characterized by ␤-amyloid deposition, intracellular neurofibrillary tangles, and extensive loss of neurons. Amyloid plaques are formed by aggregates of amyloid-␤-peptide, a 37-43 amino acid fragment (primarily A␤ 40 and A␤ 42 ) generated by proteolytic processing of the amyloid precursor protein (APP). APP is cleaved sequentially by ␤-secretase and ␥-secretase to release A␤ constitutively from neuronal and non-neuronal cells. APP proteolysis by ␤-and ␣-secretases results in the production of ␤-and ␣-APP secreted fragments (APPs) as well as the C99 and C83 APP-C-terminal fragments (APP-CTFs), respectively. The C99 and C83 APP-CTFs then serve as substrates for ␥-secretase, resulting in the production of A␤ or p3, respectively (1). In addition to the normal APP processing, "alternative" processing of APP by caspases has also been reported. Apoptosis is a form of cell death triggered by the activation of an intrinsic cellular program deliberately invoked by the cell in response to environmental and or developmentally associated signals (2). The death machinery can be activated by diverse stimuli and has as its central component a group of proteolytic enzymes called caspases. Caspases exhibit primary specificity for aspartic acid residues (3). To date, more then 280 proteins have been shown to be substrates of one or more caspases in mammalian cells. Among them are proteins involved in cell death, cell cycle regulation, cytoskeleton organization, DNA an...

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Alternative, Non-secretase Processing of Alzheimer's β-Amyloid Precursor Protein during Apoptosis by Caspase-6 and -8

Cited by 155 publications

References 44 publications

The Amyloidogenic Pathway of Amyloid Precursor Protein (APP) Is Independent of Its Cleavage by Caspases

The Amyloidogenic Pathway of Amyloid Precursor Protein (APP) Is Independent of Its Cleavage by Caspases

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

Caspase Activation Increases β-Amyloid Generation Independently of Caspase Cleavage of the β-Amyloid Precursor Protein (APP)

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