Protein Kinase C Activation Increases Release of Secreted Amyloid Precursor Protein without Decreasing Aβ Production in Human Primary Neuron Cultures.

LeBlanc, Andréa C.; Koutroumanis, Maria; Goodyer, Cynthia G.

doi:10.1523/jneurosci.18-08-02907.1998

Cited by 68 publications

(55 citation statements)

References 47 publications

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“…These results once again show that the pathways of APP metabolism in human neurons are segregated so that the reduction of APP metabolism through one pathway does not necessarily increase metabolism through the other pathways (58).…”

Section: Involvement Of Caspases In App Metabolism: Caspase Inhibitormentioning

confidence: 64%

Caspase-6 Role in Apoptosis of Human Neurons, Amyloidogenesis, and Alzheimer's Disease

LeBlanc¹,

Liu²,

Goodyer³

et al. 1999

Journal of Biological Chemistry

272

232

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Neuronal cell death, neurofibrillary tangles, and amyloid ␤ peptide (A␤) deposition depict Alzheimer's disease (AD) pathology, but neuronal loss correlates best with dementia. We have shown that increased production of A␤ is a consequence of neuronal apoptosis, suggesting that apoptosis activates proteases involved in amyloid precursor protein (APP) processing. Here, we investigate key effectors of cell death, caspases, in human neuronal apoptosis and APP processing. We find that caspase-6 is activated and responsible for neuronal apoptosis by serum deprivation. Caspase-6 activity precedes the time of commitment to neuronal apoptosis by 10 h, indicating possible activity without subsequent apoptosis. Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of A␤. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an A␤-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons. A pulse-chase experiment reveals a precursor-product relationship between Capp6.5, intracellular A␤, and secreted A␤, indicating a potential alternate amyloidogenic pathway. Caspase-6 proenzyme is present in adult human brain tissue, and the p10 active caspase-6 fragment is detected in AD brain tissue. These results indicate a possible alternate pathway for APP amyloidogenic processing in human neurons and a potential implication for this pathway in the neuronal demise of AD. Neuronal loss distinguishes Alzheimer's disease (AD)1 from normal aging and correlates best with cognitive decline in AD individuals (Ref. 1, and reviewed in Ref. 2). In mild cases of AD, there is already a 50% loss of neurons in the entorhinal cortex, which forms the connections necessary for memory and learning between the hippocampus and the neocortex (3). Neuronal loss in AD is accompanied by the deposition of amyloid ␤ peptide (A␤) in senile plaques and cerebrovascular tissue and the presence of neurofibrillary tangles. Generally, A␤ deposition is considered important in AD. Increased production of an A␤ of 40 (A␤1-40) or 42 (A␤1-42) amino acids in length, which arises through proteolytic processing of the amyloid precursor protein (APP), is common to all familial forms of AD whether caused by mutations of APP, presenilin I, or presenilin II genes (reviewed in Ref. 4). The etiology of the most common sporadic form of the disease, which includes approximately 90% of AD cases, remains unknown. Whereas the pathology of sporadic cases of AD is identical to that of familial AD, the reason for increased A␤ in sporadic AD is unclear. We have previously shown that human primary neuron cultures committed to apoptosis produce 2-4-fold more A␤ than healthy neurons (5). Therefore, in sporadic AD, initiation of a neuronal cell death program may contribute significantly to the increased production of A␤. It is also possible that neuronal apoptosis contributes to increased A␤ in familial AD cases because overexpression of APP, and mutations of APP or presenilin, induce neuronal cell...

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Section: Involvement Of Caspases In App Metabolism: Caspase Inhibitormentioning

confidence: 64%

Caspase-6 Role in Apoptosis of Human Neurons, Amyloidogenesis, and Alzheimer's Disease

LeBlanc¹,

Liu²,

Goodyer³

et al. 1999

Journal of Biological Chemistry

272

232

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“…6,7 The extensive studies on regulation of APP processing by PKC suggest that the Ab forming amyloidogenic pathway and the non-amyloidogenic a-secretase pathway are balanced, the latter being activated by PKC. Although this simple view of APP metabolism may not fully reflect the complexity of the system, 22 PKC-defective pathways have been described in peripheral tissues of sporadic AD patients 10,23 and these defects have been associated with aberrant APP processing. 11 The central role of PKC in APP metabolism is therefore also connected to the fact that defective PKC is one of the most consistent findings in AD brain and peripheral tissues.…”

Section: Discussionmentioning

confidence: 99%

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

et al. 2003

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Protein kinase C (PKC) has a key role in the signal transduction machinery involved in the regulation of amyloid precursor protein (APP) metabolism. Direct and indirect receptor-mediated activation of PKC has been shown to increase the release of soluble APP (sAPPa) and reduce the secretion of b-amyloid peptides. Experimental evidence suggests that specific isoforms of PKC, such as PKCa and PKCe, are involved in the regulation of APP metabolism. In this study, we characterized the role of PKCa in the regulated secretion of APP using wild-type SH-SY5Y neuroblastoma cells and cells transfected with a plasmid expressing PKCa antisense cDNA. Cells expressing antisense PKCa secrete less sAPPa in response to phorbol esters. In contrast, carbachol increases the secretion of sAPPa to similar levels in wild-type cells and in cells transfected with antisense PKCa by acting on APP metabolism through an indirect pathway partially involving the activation of PKC. These results suggest that the direct PKC-dependent activation of the APP secretory pathway is compromised by reduced PKCa expression and a specific role of this isoform in these mechanisms. On the other hand, indirect pathways that are also partially dependent on the mitogen-activated protein kinase signal transduction mechanism remain unaffected and constitute a redundant, compensatory mechanism within the APP secretory pathway.

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“…39 The McGill Institutional Review Board approved the protocol. Briefly, 12-16-week-old fetal brains were dissociated with trypsin, treated with deoxyribonuclease I, filtered through 130 and 70 mm nylon mesh and plated on poly-lysine-coated coverslips or dishes at a density of 3 Â 10 6 cells/ml.…”

Section: Human Primary Neuronal Culturementioning

confidence: 99%

Caspase-1 activation of caspase-6 in human apoptotic neurons

et al. 2005

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Active caspase-6 (Csp-6) induces cell death in primary cultures of human neurons and is abundant in the neuropathological lesions of Alzheimer's disease. However, the mode of Csp-6 activation is not known. Here, we show that the Csp-1 inhibitor, Z-YVAD-fmk specifically prevents activation of Csp-6 and cell death in human neurons. A transient increase in Csp-1-like activity and an increase in the p23Csp-1 subunit occur early after serum deprivation. Recombinant active Csp-1 (R-Csp-1) cleaves recombinant and neuronal pro-Csp-6 in vitro resulting in Csp-6 activity. However, R-Csp-1 does not induce cell death when microinjected in human neurons despite the inhibition of serum-deprivation induced cell death with a Csp-1 dominant negative construct. These results show that Csp-1 is an upstream positive regulator of Csp-6-mediated cell death in primary human neurons. Furthermore, these results suggest that the activation of Csp-1 must be accompanied by an apoptotic insult to induce Csp-6-mediated cell death.

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Protein Kinase C Activation Increases Release of Secreted Amyloid Precursor Protein without Decreasing Aβ Production in Human Primary Neuron Cultures.

Cited by 68 publications

References 47 publications

Caspase-6 Role in Apoptosis of Human Neurons, Amyloidogenesis, and Alzheimer's Disease

Caspase-6 Role in Apoptosis of Human Neurons, Amyloidogenesis, and Alzheimer's Disease

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

Caspase-1 activation of caspase-6 in human apoptotic neurons

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