Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila

Sanokawa-Akakura, Reiko; Cao, Weihuan; Allan, Kirsten; Patel, K.; Ganesh, Anupama; Heiman, Gary A.; Burke, Richard; Kemp, Francis W.; Bogden, John D.; Camakaris, James; Birge, Raymond B.; Konsolaki, Mary

doi:10.1371/journal.pone.0008626

Cited by 55 publications

(64 citation statements)

References 42 publications

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“…This effect is dose-dependent: increasing the amount of Gal4 produced per cell by adding another motoneuron-specific driver OK371-Gal4 to D42-Gal4 to express the Aβ42 peptide further reduced the median life span to 10 days (p = 0.0028, Log-rank test) and the maximal survival to 14 days ( Figure 1B). Cumulatively, these findings suggest that the major effect of Aβ42 on the life span observed previously [15,16] by the pan-neuronal Aβ42 expression takes place in glutamatergic neurons.…”

Section: Resultssupporting

confidence: 52%

“…The genetic model organism Drosophila melanogaster has also been used to study the mechanisms of AD [14]. In this model, several possibilities to mimic AD are available; amongst others the neuronal expression of human Aβ42 peptide [15,16]. These flies recapitulate several aspects of AD observed in patients: they show learning deficits, reduced locomotion, shorter life span and neurodegeneration and amyloid deposition in the brain [15].…”

Section: Resultsmentioning

confidence: 99%

“…The following stock were used: elav-Gal4, D42-Gal4, GMR-Gal4 (all from Bloomington stock center), UASRNAi-Sgg (VCRC #7005), UAS-Aβ42 [16]. The lines OK371-Gal4, UAS-Fz2, and UAS-Gαo [Q205L] were used as described [17].…”

Section: Methodsmentioning

confidence: 99%

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Lack of evidence of the interaction of the Aß peptide with the Wnt signaling cascade in Drosophila models of Alzheimer¿s disease

Lüchtenborg

Katanaev

2014

Molecular Brain

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Background: Alzheimer's disease (AD) is the leading form of dementia worldwide. The Aβ-peptide is believed to be the major pathogenic compound of the disease. Since several years it is hypothesized that Aβ impacts the Wnt signaling cascade and therefore activation of this signaling pathway is proposed to rescue the neurotoxic effect of Aβ. Findings: Expression of the human Aβ42 in the Drosophila nervous system leads to a drastically shortened life span. We found that the action of Aβ42 specifically in the glutamatergic motoneurons is responsible for the reduced survival. However, we find that the morphology of the glutamatergic larval neuromuscular junctions, which are widely used as the model for mammalian central nervous system synapses, is not affected by Aβ42 expression. We furthermore demonstrate that genetic activation of the Wnt signal transduction pathway in the nervous system is not able to rescue the shortened life span or a rough eye phenotype in Drosophila.

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Section: Resultssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

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Lack of evidence of the interaction of the Aß peptide with the Wnt signaling cascade in Drosophila models of Alzheimer¿s disease

Lüchtenborg

Katanaev

2014

Molecular Brain

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“…Cu 2ϩ ions are found concentrated within senile plaques of AD patients directly bound to A␤ (3)(4)(5). Recent in vivo studies using a Drosophila model of AD have shown that impaired copper homeostasis enhances the toxic effects of A␤ (6). Furthermore, copper in a cholesterol high diet induces amyloid plaques and learning deficits in a rabbit model of AD (7).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

Sarell

Wilkinson

Viles

2010

Journal of Biological Chemistry

181

218

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A role for Cu 2؉ ions in Alzheimer disease is often disputed, as it is believed that Cu 2؉ ions only promote nontoxic amorphous aggregates of amyloid-␤ (A␤). In contrast with currently held opinion, we show that the presence of substoichiometric levels of Cu 2؉ ions in fact doubles the rate of production of amyloid fibers, accelerating both the nucleation and elongation of fiber formation. We suggest that binding of Cu 2؉ ions at a physiological pH causes A␤ to approach its isoelectric point, thus inducing self-association and fiber formation. We further show that Cu 2؉ ions bound to A␤ are consistently more toxic to neuronal cells than A␤ in the absence of Cu 2؉ ions, whereas Cu 2؉ ions in the absence of A␤ are not cytotoxic. The degree of Cu-A␤ cytotoxicity correlates with the levels of Cu 2؉ ions that accelerate fiber formation. We note the effect appears to be specific for Cu 2؉ ions as Zn 2؉ ions inhibit the formation of fibers. An active role for Cu 2؉ ions in accelerating fiber formation and promoting cell death suggests impaired copper homeostasis may be a risk factor in Alzheimer disease. Alzheimer disease (AD)2 is characterized by extracellular amyloid plaques, composed predominantly of fibrillar amyloid-␤ peptide (A␤), a 39 -43-residue peptide. Genetic alterations underlying familial AD are associated with mutations or increased production of A␤, indicating that A␤ plays a central role in the disease (1).A notable characteristic of AD is altered metal ion concentrations in the brain and disrupted metal ion homeostasis (2). Cu 2ϩ ions are found concentrated within senile plaques of AD patients directly bound to A␤ (3-5). Recent in vivo studies using a Drosophila model of AD have shown that impaired copper homeostasis enhances the toxic effects of A␤ (6). Furthermore, copper in a cholesterol high diet induces amyloid plaques and learning deficits in a rabbit model of AD (7). Other in vivo studies have shown that copper homeostasis can influence AD pathology. In contrast to the Drosophila model, transgenic mice have shown a reduced AD pathology with increased intracellular copper levels (8 -10).Although studies of A␤ neurotoxicity suggest that small diffusible oligomers, rather than mature amyloid fibers, are the more toxic form (11, 12), there remains strong evidence suggesting that amyloid plaques, or possibly intermediates of the fibrils, are critical in neuronal toxicity (13,14). A␤ oligomers may be precursors of fiber formation and may also arise from fiber fragmentation. Alternatively, oligomers may be in competition with fiber formation. Both possibilities require the self-association of monomeric A␤, and thus factors that affect fibrillization will also influence oligomer generation.The mechanism by which A␤ is toxic is hotly debated (11, 15). It has been proposed that A␤ can form ion channels or pores or can thin the membrane, all of which will cause membrane leakage and loss of cellular Ca 2ϩ ion homeostasis. One popular hypothesis is that the membrane integrity is compromised by lipid peroxida...

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“…Furthermore, FKBP52 is upregulated after injury in regenerating neurons and Alzheimer's patients have a lower expression of FKBP52 in the temporal lobe and hippocampus 131 . FKBP52 is involved in the regulation of intracellular copper and this may cause FKBP52 to have an effect on Aβ levels [144][145][146] . Furthermore, Conejero-Goldberg and colleagues demonstrated that FKBPL was one of the key genes differentially expressed in the brain tissue, where it appeared to act in a protective role, in young individuals at high risk of Alzheimers disease preselected by the APO4 signature 147 .…”

Section: The Role Of Ppiases In Neurodegenerationmentioning

confidence: 99%

The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases

McClements¹,

Annett²,

Yakkundi³

et al. 2015

CMP

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Peptidyl prolyl isomerases (PPIases) are proteins belonging to the immunophilin family and are characterised by their cis-trans isomerization activity at the X-Pro peptide bond, in addition to their tetratricopeptide repeat (TPR) domain, important for interaction with the molecular chaperone, Hsp90. Due to this unique structure these proteins are able to facilitate proteinprotein interactions which can impact significantly on a range of cellular processes such as cell signalling, differentiation, cell cycle progression, metabolic activity and apoptosis.Malfunction and/or dysregulation of most members of this class of proteins promotes cellular damage and tissue/organ failure, predisposing to ageing and age-related diseases. Many individual genes within the PPIase family are associated with several age-related diseases including cardiovascular diseases (CVDs), atherosclerosis, type II diabetes (T2D), chronic kidney disease (CDK), neurodegeneration, cancer and age-related macular degeneration (AMD), in addition to the ageing process itself. This review will focus on the different roles of PPIases, and their therapeutic/biomarker potential in these age-related vascular diseases.

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Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila

Cited by 55 publications

References 42 publications

Lack of evidence of the interaction of the Aß peptide with the Wnt signaling cascade in Drosophila models of Alzheimer¿s disease

Lack of evidence of the interaction of the Aß peptide with the Wnt signaling cascade in Drosophila models of Alzheimer¿s disease

Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases

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