Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons

Um, Ji Won; Nygaard, Haakon B.; Heiss, Jacqueline K.; Kostylev, Mikhail A.; Stagi, Massimiliano; Vortmeyer, Alexander O.; Wısnıewskı, Thomas; Gunther, Erik C.; Strittmatter, Stephen M.

doi:10.1038/nn.3178

Cited by 579 publications

(750 citation statements)

References 52 publications

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“…The concept for repositioning of this agent was based on scientific discoveries that demonstrated that phosphorylation of Fyn tyrosine kinase is related to Aβ-and tau-associated synaptic dysfunction, as well as memory impairments in mouse models of AD [138][139][140].…”

Section: Private-public Partnership For Drug Repositioningmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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Section: Private-public Partnership For Drug Repositioningmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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“…14 In contrast, some studies indicate that PrP C is not required for Aβ oligomer-induced cognitive impairment since the PrP C expressing and knockout mice have no difference in Aβ oligomer-induced synaptic depression, spine density loss, and deficiency of long-term potentiation. 15 Two intracerebroventricular injections of Aβ oligomers to wild-type or PrP C null mice have suggested no PrP C effect on Aβ oligomer-induced memory dysfunction, 10 and modulation of PrP C in AD transgenic mouse models shows no effect on the impairment of the hippocampal synaptic plasticity.…”

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confidence: 99%

“…13 Aβ oligomer binding to PrP C results in Fyn activation, which leads to phosphorylation of the NR2B subunit of NMDARs. 14 Four replicas were performed. The mock group was used for normalization.…”

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confidence: 99%

Alzheimer’s Amyloid-β Oligomers Rescue Cellular Prion Protein Induced Tau Reduction via the Fyn Pathway

Chen

Chang

Lin

et al. 2013

ACS Chem. Neurosci.

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Amyloid-β (Aβ) and tau are the pathogenic hallmarks in Alzheimer's disease (AD). Aβ oligomers are considered the actual toxic entities, and the toxicity relies on the presence of tau. Recently, Aβ oligomers have been shown to specifically interact with cellular prion protein (PrP C ) where the role of PrP C in AD is still not fully understood. To investigate the downstream mechanism of PrP C and Aβ oligomer interaction and their possible relationships to tau, we examined tau expression in human neuroblastoma BE(2)-C cells transfected with murine PrP C and studied the effect under Aβ oligomer treatment. By Western blotting, we found that PrP C overexpression down-regulated tau protein and Aβ oligomer binding alleviated the tau reduction induced by wild type but not M128V PrP C , the high AD risk polymorphic allele in human prion gene. PrP C lacking the Aβ oligomer binding site was incapable of rescuing the level of tau reduction. Quantitative RT-PCR showed the PrP C effect was attributed to tau reduction at the transcription level. Treatment with Fyn pathway inhibitors, Fyn kinase inhibitor PP2 and MEK inhibitor U0126, reversed the PrP C -induced tau reduction and Aβ oligomer treatment modulated Fyn kinase activity. The results suggested Fyn pathway regulated Aβ−PrP C −tau signaling. Overall, our results demonstrated that PrP C down-regulated tau via the Fyn pathway and the effect can be regulated by Aβ oligomers. Our study facilitated the understanding of molecular mechanisms among PrP C , tau, and Aβ oligomers.

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“…14 The toxicity of small soluble Ab species has been proposed to depend on the interaction with specific neuronal proteins, such as the NMDA receptor 15 or the prion protein (PrP C ), 16 which modulates NMDA receptors through Fyn kinase. 17 Alternatively, soluble Ab oligomers may damage neurons by binding to multiple membrane components, including lipids, thereby changing membrane permeability and causing calcium ion leakage into the cell. 5,18 Neuroinflammation arguably has a role in promoting neurotoxicity of Ab plaques.…”

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Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

et al. 2013

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Alzheimer's disease (AD) is characterized by extracellular amyloid-b (Ab) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Ab species, rather than insoluble fibrils, are the most toxic forms of Ab. Preventing soluble Ab formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Ab species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Ab forms trafficked to MVs after Ab internalization into microglia. MV neurotoxicity was neutralized by the Ab-interacting protein PrP and anti-Ab antibodies, which prevented binding to neurons of neurotoxic soluble Ab species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease. Cell Death and Differentiation (2014) 21, 582-593; doi:10.1038/cdd.2013.180; published online 13 December 2013Alzheimer's disease (AD) is the major cause of dementia in humans. Neuronal loss and cognitive decline occurring in AD patients are traditionally linked to the accumulation in the brain of extracellular plaques consisting of short amyloid-b (Ab) peptides of 39-42 amino acids, generated by amyloidogenic cleavage of the amyloid precursor protein. 1 Among Ab peptides, Ab 1-42 and pyroglutamate-modified Ab very rapidly aggregate and initiate the complex multistep process that leads to mature fibrils and plaque. 2,3 Although association of amyloid plaques with AD has long been assumed, Ab load does not correlate with neuronal loss 4,5 and high plaque burden does not necessarily lead to dementia in humans. 6,7 Accordingly, recent evidence clearly showed that the amyloid load reaches a plateau early after the onset of clinical symptoms in AD patients 8 and does not substantially increase in size during clinical progression. 9 These observations agree with the current view that small, soluble pre-fibrillar Ab species, rather than plaques formed by insoluble Ab fibrils, are the most toxic forms of Ab. 10 These cause synaptic dysfunction and spine loss, and correlate most closely with the severity of human AD. 5,8,11 Recent biochemical studies indicated that natural sphingolipids and gangliosides, whose metabolism has been shown to be altered in AD patients, 12 destabilize and rapidly resolubilize long Ab fibrils to neurotoxic species. 13 These studies also showed that phospholipids stabilize toxic oligomers...

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Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons

Cited by 579 publications

References 52 publications

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Alzheimer’s Amyloid-β Oligomers Rescue Cellular Prion Protein Induced Tau Reduction via the Fyn Pathway

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

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