Abeta 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis

Wei, Wanli; Norton, Darrell D.; Wang, Xiantao; Kusiak, John W.

doi:10.1093/brain/awf205

Cited by 137 publications

(117 citation statements)

References 36 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…Consistent with our findings in human islet beta cells, a previous in vitro study showed that synthetic hIAPP induces caspase-8 activation in rodent beta cells [42]. 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].…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 91%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Early MD simulations of amyloidogenic peptides (5,25) consisting of U-shaped β-strandturn-β-strand peptides in the bilayer predicted ion-permeable channels formed by loosely attached mobile subunits with morphologies and dimensions similar to the AFM-images of amyloid channels (7,8). U-shaped motifs, first predicted by modeling of Aβ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (26), appear as a general feature of amyloid organization, suggesting that other U-shaped amyloid organizations may also form dynamic ion channels in the fluidic membrane (8). Because N9 and p3 have membrane-spanning segments, we modeled their 3D structures in the bilayer using the previous successful protocol (5,25).…”

Section: Resultsmentioning

confidence: 99%

“…Because of their nonamyloidogenic nature, these peptides are assumed to be nonpathogenic and these pathways are even being targeted for AD therapeutics. Significantly, p3 peptides are present in AD amyloid plaques (17)(18)(19)(20), are the main constituent of cerebellar preamyloid lesions in Down syndrome (21) and induce neuronal toxicity (22)(23)(24). However, their biophysical properties, mechanism of toxicity, and pathological significance in AD and Down syndrome remain unclear.…”

mentioning

confidence: 99%

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Jang

Arce

Ramachandran

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

215

344

View full text Add to dashboard Cite

Full-length amyloid beta peptides (Aβ 1-40/42 ) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. However, recent transgenic animal models cast doubt on their direct role in AD pathology. Nonamyloidogenic truncated amyloid-beta fragments and Aβ ) are also found in amyloid plaques of AD and in the preamyloid lesions of Down syndrome, a model system for early-onset AD study. Very little is known about the structure and activity of these smaller peptides, although they could be the primary AD and Down syndrome pathological agents. Using complementary techniques of molecular dynamics simulations, atomic force microscopy, channel conductance measurements, calcium imaging, neuritic degeneration, and cell death assays, we show that nonamyloidogenic Aβ 9-42 and Aβ 17-42 peptides form ion channels with loosely attached subunits and elicit single-channel conductances. The subunits appear mobile, suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in amyloid precursor protein-deficient cells. The channel mediated calcium uptake induces neurite degeneration in human cortical neurons. Channel conductance, calcium uptake, and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus, truncated Aβ fragments could account for undefined roles played by full length Aβs and provide a unique mechanism of AD and Down syndrome pathologies. The toxicity of nonamyloidogenic peptides via an ion channel mechanism necessitates a reevaluation of the current therapeutic approaches targeting the nonamyloidogenic pathway as avenue for AD treatment.atomic force microscopy | molecular dynamics | cell calcium imaging | neurite degeneration and cell death assays | single-channel conductance A myloid-beta peptides (Aβ 1-40/42 ) produced by β-and γ-secretase processing of amyloid precursor protein (APP) in the amyloidogenic pathway are involved in Alzheimer's disease (AD) pathology. Aβ 1-40/42 peptides form β-sheet-rich ordered aggregates and soluble oligomers. Small oligomers are emerging as the predominant toxic species (1-3); the toxicity is believed to be a result of the loss of ionic homeostasis, presumably via ion channels formed in cellular membranes (4, 5). EM images of Aβ oligomers show doughnut-like morphologies (6). Atomic force microscopic (AFM) images of Aβ peptides reconstituted in lipid bilayers show heteromeric (rectangular to hexagonal) ion channel-like structures with a ∼2.0-nm central pore and 8-to 12-nm outer diameters (7,8). Electrophysiological studies show heterodisperse cationselective single-channel conductances (7)(8)(9)(10)(11)(12)(13)(14) that are consistent with features of other amyloid ion channels (6-8).On the other hand, when APP is cleaved by γ-and α-secretases, it forms the nonamyloidogenic pathway generating ∼2.6-kDa fragments (Aβ 17-40/42 ) known as the p3 peptides (15). Cleavage by γ and BACE between Tyr10 and Glu11 generates another...

show abstract

“…They demonstrated that A␤ and A␤ [25][26][27][28][29][30][31][32][33][34][35] induce apoptosis through caspase-dependent pathways. [41][42][43][44][45][46][47] In vivo, 1 week after A␤ [25][26][27][28][29][30][31][32][33][34][35] , an increase in caspase-3 activity in the hippocampus of rats 9 and increases in levels of pro-caspases 9, 12, and 3 in the hippocampus of mice 11 were observed. In the present study, we observed increases in pro-and cleaved forms for caspase-9 (mitochondrial stress marker) and caspase-12 (endoplasmic reticulum stress marker) in all structures except the hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Zussy

Brureau

Delair

et al. 2011

The American Journal of Pathology

121

129

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid ␤ protein (A␤) formed by pathological processing of the A␤ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated A␤ fragment 25-35 (A␤ 25-35 ) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled A␤ 25-35 peptide was used as negative control. The aggregated forms of A␤ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of A␤ 25-35 decreased body weight, induced short-and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, A␤ 25-35 , the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. Alzheimer's disease (AD) is a chronic neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss in brain areas responsible for learning and memory impairments. 1 The major component of senile plaques is an amyloid ␤ protein (A␤) derived from amyloid precursor protein (APP). Genetic, cell biological, and postmortem studies on AD brain, together with A␤ neurotoxicity findings, gave rise to the amyloid cascade hypothesis to explain A␤-associated neurodegenerative processes. 2 In normal healthy individuals, A␤ peptides are present only in small quantities, as soluble monomers that circulate in cerebrospinal fluid and blood. In AD patients, A␤ peptides, which vary in length from 40 to 43 amino acids, accumulate as insoluble fibrillar deposits. 3 When cultured rat hippocampal neurons are exposed to aggregated A␤ peptides, their neurites adopt a dystrophic appearance and become comparable to those observed surrounding and infiltrating senile plaques. This observation suggested that A␤ is responsible for the neuritic abnormalities in AD pathology. 4 Structure-activity studies revealed that peptides containing the highly hydrophobic 25-35 region formed stable aggregates and mediated neuronal death by necrosis or apoptosis. 5,6,7 The truncated A␤ 25-35 fragment includes extracellular and intramembrane residues that have been reported to represent an active region of A␤. 8

show abstract

Abeta 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis

Cited by 137 publications

References 36 publications

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

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

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Contact Info

Product

Resources

About