Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid- 1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model

Brouillette, Jonathan; Caillierez, Raphaëlle; Zommer, Nadège; Alves‐Pires, Claire; Benilova, Iryna; Blum, David; Strooper, Bart De; Buée, Luc

doi:10.1523/jneurosci.5901-11.2012

Cited by 162 publications

(160 citation statements)

References 57 publications

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“…Aβ oligomers lower neuronal activity, through various mechanisms (Bero et al ., 2011; Brouillette et al ., 2012; Pitt et al ., 2013; Tu et al ., 2014; Xu et al ., 2014; Lazzari et al ., 2015). Instead, Aβ monomers enhance various cellular functions (Giuffrida et al ., 2010).…”

Section: Discussionmentioning

confidence: 99%

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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SummaryThe mechanistic relationship between amyloid β1‐42 (Aβ1‐42) and the alteration of Tau protein are debated. We investigated the effect of Aβ1‐42 monomers and oligomers on Tau, using mice expressing wild‐type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aβ1‐42, mice were sacrificed after 3 h or 4 days. The short‐lasting treatment with Aβ monomers, but not oligomers, showed a conformational PHF‐like change of Tau, together with hyperphosphorylation. The same treatment induced increase in concentration of GSK3 and MAP kinases. The inhibition of the kinases rescued the Tau changes. Aβ monomers increased the levels of total Tau, through the inhibition of proteasomal degradation. Aβ oligomers reproduced all the aforementioned alterations only after 4 days of treatment. It is known that Aβ1‐42 monomers foster synaptic activity. Our results suggest that Aβ monomers physiologically favor Tau activity and dendritic sprouting, whereas their excess causes Tau pathology. Moreover, our study indicates that anti‐Aβ therapies should be targeted to Aβ1‐42 monomers too.

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Section: Discussionmentioning

confidence: 99%

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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“…Prepare the Aβo solution (0.2 µg/µl) as previously reported. 28,30 Allow Aβo to aggregate dynamically and spontaneously for 1 hr at room temperature before infusion. 2.…”

Section: Aβo Infusions In Awake and Freely Moving Ratsmentioning

confidence: 99%

“…We reported earlier that repeated hippocampal infusions of soluble Aβo induce gradual neuronal loss and tau hyperphosphorylation, two pathological hallmarks associated with memory decline in AD. 28 Here, we are showing a novel method to test AD therapies using cannula specially design for simultaneous infusions of Aβo and continuous infusion of Aβo antibody (6E10) with osmotic pumps.…”

Section: Introductionmentioning

confidence: 99%

Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps

Sajadi

Provost

Pham

et al. 2016

JoVE

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Decline in hippocampal-dependent explicit memory (memory for facts and events) is one of the earliest clinical symptom of Alzheimer's disease (AD). It is well established that synapse loss and ensuing neurodegeneration are the best predictors for memory impairments in AD. Latest studies have emphasized the neurotoxic role of soluble amyloid-beta oligomers (Aβo) that begin to accumulate in the human brain approximately 10 to 15 yr before the clinical symptoms become apparent. Many reports indicate that soluble Aβo correlate with memory deficits in AD models and humans. The Aβo-induced neurodegeneration observed in neuronal and brain slice cultures has been more challenging to reproduce in many animal models. The model of repeated Aβo infusions shown here overcome this issue and allow addressing two key domains for developing new disease modifying therapies: identify biological markers to diagnose early AD, and determine the molecular mechanisms underpinning Aβo-induced memory deficits at the onset of AD. Since soluble Aβo aggregate relatively fast into insoluble Aβ fibrils that correlate poorly with the clinical state of patients, soluble Aβo are prepared freshly and injected once per day during six days to produce marked cell death in the hippocampus. We used cannula specially design for simultaneous infusions of Aβo and continuous infusion of Aβo antibody (6E10) in the hippocampus using osmotic pumps. This innovative in vivo method can now be used in preclinical studies to validate the efficiency of new AD therapies that might prevent the deposition and neurotoxicity of Aβo in pre-dementia patients.

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“…Although the toxic species is still poorly defined, there is growing consensus that the process, rather than the end product, of amyloid formation is the main culprit in amyloid toxicity [31][32][33][34]. Small oligomers of Aβ secreted from cell lines that overproduce Aβ 42 inhibit long-term potentiation in hippocampal synaptic transmission [32] and induces neuronal toxicity in mice [35]. Oligomeric forms of αS and Aβ inhibit mitochondrial activity [31,36].…”

Section: Toxicity and Amyloid Formationmentioning

confidence: 99%

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

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Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

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Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid- 1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model

Cited by 162 publications

References 57 publications

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

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