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Le Touquet – Paris-Plage, France

Epelbaum S.,French Institute of Health and Medical Research | Epelbaum S.,Institute Of La Memoire Et Of La Maladie Dalzheimer | Youssef I.,French Institute of Health and Medical Research | Lacor P.N.,Northwestern University | And 6 more authors.
Neurobiology of Aging | Year: 2015

Amyloid-β (Aβ) oligomers are the suspected culprit as initiators of Alzheimer's disease (AD). However, their diffusion in the brain remains unknown. Here, we studied Aβ oligomers' dissemination and evaluated their invivo toxicity. Wild-type mice were injected with 50 pmol of synthetic Aβ oligomers (of different size) in the hippocampus. Oligomers diffused largely in the brain as soon as 1 hour and up to 7 days after injection. A transient encephalopathy with memory impairment was induced by this unique injection. The immunoreactivity of the postsynaptic marker PSD95 was diffusely decreased. Similar results (both on memory and PSD95 immunoreactivity) were obtained with delipidated and high molecular weight oligomers (>50 kDa) but not with smaller assemblies. Tau hyperphosphorylation was observed in the oligomer-injected brains. Finally, fos immunostaining was increased in Aβ-derived diffusible ligands-injected mice, suggesting neuronal hyperactivity. Rapid and widespread diffusion of Aβ oligomers was demonstrated invivo and associated with decreased synaptic markers and memory deficits which gives new insight to the pathogenicity of Aβ. © 2015 Elsevier Inc.

Duyckaerts C.,Laboratoire Of Neuropathologie Escourolle | Duyckaerts C.,French Institute of Health and Medical Research | Braak H.,University of Ulm | Brion J.-P.,Free University of Colombia | And 9 more authors.
Acta Neuropathologica | Year: 2015

It has been proposed that tau aggregation confined to entorhinal cortex and hippocampus, with no or only minimal Aβ deposition, should be considered as a ‘primary age-related tauopathy’ (PART) that is not integral to the continuum of sporadic Alzheimer disease (AD). Here, we examine the evidence that PART has a pathogenic mechanism and a prognosis which differ from those of AD. We contend that no specific property of the entorhinal–hippocampal tau pathology makes it possible to predict either a limited progression or the development of AD, and that biochemical differences await an evidence base. On the other hand, entorhinal–hippocampal tau pathology is an invariant feature of AD and is always associated with its development. Rather than creating a separate disease entity, we recommend the continued use of an analytical approach based on NFT stages and Aβ phases with no inference about hypothetical disease processes. © 2015, The Author(s).

Seilhean D.,University Pierre and Marie Curie | Le Ber I.,University Pierre and Marie Curie | Sarazin M.,University Pierre and Marie Curie | Lacomblez L.,University Pierre and Marie Curie | And 11 more authors.
Journal of Neural Transmission | Year: 2011

Sixty cases of frontotemporal lobar degeneration (FTLD) were collected over 22 years. Brain weight was negatively correlated with disease duration. The neuronal and/or glial inclusions were labeled by anti-TDP, anti-FUS or anti-TAU antibodies, respectively, in 40, 3 and 12 cases. In the FTLD-TDP group, mutation of the progranulin gene was found in four cases (FTD-GRN), with nuclear, cat eye inclusions and severe neuronal loss in CA1 and subiculum. The motor neurons were involved in 27 cases (fronto-temporal dementia with amyotrophic lateral sclerosis = FTD-ALS). Familial FTD-ALS cases lived longer than sporadic ones. In nine cases, there was no ALS, no GRN mutation (FTD-NAP). The cases in the FTD-ALS and FTD-NAP subgroups were of Sampathu type 2 (TDP-positive inclusions located mostly in cell bodies and short neurites) with the exception of five cases which belonged to type 1 (long TDP-positive neurites in the superficial layers of the cortex). All of the FTLD-FUS of this series cases were affected by neuronal intermediate filament inclusion disease (NIFID). They were young. The survival was short. In the FTLD-tau group, mutations P301P (previously not recognized as pathogenic), P301L and S305N were identified. Pick disease (n = 5) appeared as a homogeneous sporadic disorder. The current nomenclature allows the neuropathological classification of nearly all the cases of FTD. The prevalence of the different types of FTD is tightly linked to the recruitment. This series was enriched in motor neuron disease (explaining the overall predominance of type 2 TDP inclusions). © 2011 Springer-Verlag.

Gaudin M.,University of Paris Descartes | Panchal M.,Laboratoire Of Neuropathologie Escourolle | Panchal M.,French Institute of Health and Medical Research | Auzeil N.,University of Paris Descartes | And 6 more authors.
Bioanalysis | Year: 2012

Background: Lipidomic studies related to Alzheimers disease have been reported on either biological fluids or large human brain samples. For a better understanding of the role of lipids, especially during the amyloid- peptide aggregation, it is crucial to determine the composition of the senile plaque versus the surrounding tissue, that is, the neuropil. Results: A laser microdissection step was added to the analysis by UPLC-MS/MS. Despite the very low amount of sample, two phosphatidylcholines that were significantly depleted in the senile plaque were identified. Conclusion: Changes in the phospholipid content have been shown between senile plaque versus neuropil. Nano HPLC, allowing a complete lipidomic profile, should further improve the results. © 2012 Future Science Ltd.

Mourtas S.,University of Patras | Lazar A.N.,Laboratoire Of Neuropathologie Escourolle | Lazar A.N.,French Institute of Health and Medical Research | Markoutsa E.,University of Patras | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2014

With the objective to formulate multifunctional nanosized liposomes to target amyloid deposits in Alzheimer Disease (AD) brains, a lipid-PEG-curcumin derivative was synthesized and characterized. Multifunctional liposomes incorporating the curcumin derivative and additionally decorated with a Blood Brain Barrier (BBB) transport mediator (anti-Transferin antibody) were prepared and characterized. The fluorescence intensity of curcumin derivative was found to increase notably when the curcumin moiety was in the form of a diisopropylethylamine (DIPEA) salt. Both curcumin-derivative liposomes and curcumin-derivative Anti-TrF liposomes showed a high affinity for the amyloid deposits, on post-mortem brains samples of AD patients. The ability of both liposomes to delay Aβ1-42 peptide aggregation was confirmed by Thioflavin assay. However, the decoration of the curcumin-derivative liposomes with the Anti-TrF improved significantly the intake by the BBB cellular model. Results verify that the attachment of an antibody on the curcumin-liposome surface does not block deposit staining or prevention of Aβ aggregation, while the presence of the curcumin-PEG-lipid conjugate does not reduce their brain-targeting capability substantially, proving the potential of such multifunctional NLs for application in Alzheimer disease treatment and diagnosis. © 2014 Elsevier Masson SAS. All rights reserved.

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