Activation of Caspase-8 in the Alzheimer's Disease Brain

Rohn, Troy T.; Head, Elizabeth; Nesse, William H.; Cotman, Carl W.; Cribbs, David H.

doi:10.1006/nbdi.2001.0449

Cited by 157 publications

(98 citation statements)

References 30 publications

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“…In addition, significant roles of caspase-2 in Aß neurotoxicity have been reported (38). Activation of caspase-8 via Fas or tumor necrosis factor receptor (TNFR) by Aß peptide and in AD has also been demonstrated (39)(40)(41)(42). We reported an early activation of caspase-8 in neurons upon exposure to Aß peptide (28).…”

Section: Discussionmentioning

confidence: 66%

Characterization of the effects of anti-aging medicine Fructus lycii on β-amyloid peptide neurotoxicity

Lai²,

Ho³

et al. 2007

Int J Mol Med

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Abstract. Alzheimer's disease (AD) is an age-related neurodegenerative disease. There are increasing lines of evidence showing that the molecular signaling pathways in aged cells are altered so that cells are susceptible to injury. We and other laboratories have demonstrated the significant involvement of double-stranded RNA-dependent protein kinase (PKR) in ß-amyloid (Aß) peptide neurotoxicity and in AD. Fructus lycii (the fruit of Lycium barbarum) has long been used in oriental medicine as an anti-aging agent. Our previous studies demonstrated that the aqueous extract isolated from L. barbarum exhibited significant protection on cultured neurons against harmful chemical toxins such as Aß and dithiothreitol. We also showed that the polysaccharidecontaining extract (LBP) from L. barbarum exhibited neuroprotective effects in the retina against ocular hypertension in a laser-induced glaucoma animal model. In this study, we aimed to investigate whether LBP can elicit neuroprotection to neurons stressed by Aß peptides. Furthermore, we planned to isolate and identify the neuroprotective agent from LBP using chromatographic methods. Our results showed that pretreatment of LBP effectively protected neurons against Aß-induced apoptosis by reducing the activity of both caspase-3 and -2, but not caspase-8 and -9. A new arabinogalactan-protein (LBP-III) was isolated from LBP and attenuated Aß peptide-activated caspase-3-like activity.LBP-III markedly reduced the phosphorylation of PKR triggered by Aß peptide. Since the phosphorylation state of PKR increased with age, reduction of its phosphorylation triggered by Aß peptide may implicate that LBP-III from Fructus lycii is a potential neuroprotective agent in AD. As herbal medicine has received increasing attention for the treatment of AD, our study will open a window for the development of a neuroprotective agent for anti-aging from Chinese medicine.

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Section: Discussionmentioning

confidence: 66%

Characterization of the effects of anti-aging medicine Fructus lycii on β-amyloid peptide neurotoxicity

Lai²,

Ho³

et al. 2007

Int J Mol Med

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“…Interestingly, aggregates of amyloid beta peptide were also shown to induce caspase-8 activation and apoptosis in neural cells, probably via the Fas-mediated apoptotic pathway [43]. Moreover, active caspase-8 and Fas-positive cells have been reported in the brain in Alzheimer's disease [44,45]. Thus, it seems likely that hIAPP aggregates in type 2 diabetes and amyloid beta aggregates in Alzheimer's disease share the same apoptotic signalling pathway(s).…”

Section: Discussionmentioning

confidence: 99%

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

et al. 2014

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Aims/hypothesis Reduced beta cell mass due to increased beta cell apoptosis is a key defect in type 2 diabetes. Islet amyloid, formed by the aggregation of human islet amyloid polypeptide (hIAPP), contributes to beta cell death in type 2 diabetes and in islet grafts in patients with type 1 diabetes. In this study, we used human islets and hIAPP-expressing mouse islets with beta cell Casp8 deletion to (1) investigate the role of caspase-8 in amyloid-induced beta cell apoptosis and (2) test whether caspase-8 inhibition protects beta cells from amyloid toxicity. Methods Human islet cells were cultured with hIAPP alone, or with caspase-8, Fas or amyloid inhibitors. Human islets and wild-type or hIAPP-expressing mouse islets with or without caspase-8 expression (generated using a Cre/loxP system) were cultured to form amyloid. Caspase-8 and -3 activation, Fas and FLICE inhibitory protein (FLIP) expression, islet beta cell and amyloid area, IL-1β levels, and the beta:alpha cell ratio were assessed. Results hIAPP treatment induced activation of caspase-8 and -3 in islet beta cells (via Fas upregulation), resulting in apoptosis, which was markedly reduced by blocking caspase-8, Fas or amyloid. Amyloid formation in cultured human and hIAPP-expressing mouse islets induced caspase-8 activation, which was associated with Fas upregulation and elevated islet IL-1β levels. hIAPP-expressing mouse islets with Casp8 deletion had comparable amyloid, IL-1β and Fas levels with those expressing hIAPP and Casp8, but markedly lower beta cell apoptosis, higher beta:alpha cell ratio, greater beta cell area, and enhanced beta cell function. Conclusions/interpretation Beta cell Fas upregulation by endogenously produced and exogenously applied hIAPP aggregates promotes caspase-8 activation, resulting in beta cell apoptosis. The prevention of amyloid-induced caspase-8 activation enhances beta cell survival and function in islets.

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“…Light-level immunohistochemistry was performed using an avidin-biotin immunoperoxidase technique (ABC kit; Vector Laboratories Inc., Burlingame, California, USA) and was visualized with diaminobenzidine as previously described (22). Fluorescent immunolabeling followed either a standard two-way technique (primary antibody followed by fluorescent secondary antibody) or a three-way protocol (primary antibody, biotinylated secondary antibody, and then streptavidin-conjugated fluorophore).…”

Section: Methodsmentioning

confidence: 99%

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

et al. 2004

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Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid β (Aβ) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (ΔTau) by executioner caspases. Following caspase-cleavage, ΔTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. ΔTau can be phosphorylated by glycogen synthase kinase-3β and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, ΔTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, ΔTau colocalizes with Aβ 1-42 and is induced by Aβ 1-42 in vitro. Collectively, our data imply that Aβ accumulation triggers caspase activation, leading to caspase-cleavage of tau, and that this is an early event that may precede hyperphosphorylation in the evolution of AD tangle pathology. These results suggest that therapeutics aimed at inhibiting tau caspase-cleavage may prove beneficial not only in preventing NFT formation, but also in slowing cognitive decline.

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Activation of Caspase-8 in the Alzheimer's Disease Brain

Cited by 157 publications

References 30 publications

Characterization of the effects of anti-aging medicine Fructus lycii on β-amyloid peptide neurotoxicity

Characterization of the effects of anti-aging medicine Fructus lycii on β-amyloid peptide neurotoxicity

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

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