Laboratoire Of Neuropathologie Escourolle

Paris, France

Laboratoire Of Neuropathologie Escourolle

Paris, France
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Panchal M.,Laboratoire Of Neuropathologie Escourolle | Panchal M.,French Institute of Health and Medical Research | Gaudin M.,University of Paris Descartes | Lazar A.N.,Laboratoire Of Neuropathologie Escourolle | And 14 more authors.
Neurobiology of Disease | Year: 2014

The senile plaque is a hallmark lesion of Alzheimer disease (AD). We compared, without a priori, the lipidome of the senile plaques and of the adjacent plaque-free neuropil. The analysis by liquid chromatography coupled with electrospray ionization mass spectrometry revealed that laser microdissected senile plaques were enriched in saturated ceramides Cer(d18:1/18:0) and Cer(d18:1/20:0) by 33 and 78% respectively with respect to the surrounding neuropil. This accumulation of ceramides was not explained by their affinity for Aβ deposits: no interaction between ceramide-liposomes and Aβ fibrils was observed in vitro by surface plasmon resonance and fluorescent ceramide-liposomes showed no affinity for the senile plaques in AD brain tissue. Accumulation of ceramides could be, at least partially, the result of a local production by acid and neutral sphingomyelinases that we found to be present in the corona of the senile plaques. © 2014 Elsevier Inc.

Lazar A.N.,Laboratoire Of Neuropathologie Escourolle | Lazar A.N.,French Institute of Health and Medical Research | Bich C.,CNRS Natural Product Chemistry Institute | Panchal M.,Laboratoire Of Neuropathologie Escourolle | And 10 more authors.
Acta Neuropathologica | Year: 2013

Although cholesterol has been involved in the pathophysiology of Alzheimer disease (AD), its distribution in the cerebral cortex over the course of AD is unknown. We describe an original method to quantify cholesterol distribution using time-of-flight secondary ion mass spectrometry imaging. Cholesterol was unevenly distributed along the cortical thickness, being more abundant close to the white matter, in both control and AD cases. However, the mean cholesterol signal was significantly higher in the lower half of the cortex in AD samples compared to controls. This increase, when converted into cortical layers, was statistically significant for layers III and IV and did not reach significance in layers V + VI, the variability being too high at the interface between grey and white matter. The density of neurofibrillary tangles and of senile plaques was not statistically linked to the abundance of cholesterol. Cholesterol overload thus appears a new and independent alteration of AD cerebral cortex. The structure in which cholesterol accumulates and the mechanism of this accumulation remain to be elucidated. © 2012 Springer-Verlag Berlin Heidelberg.

Lazar A.N.,Laboratoire Of Neuropathologie Escourolle | Lazar A.N.,French Institute of Health and Medical Research | Mourtas S.,University of Patras | Youssef I.,French Institute of Health and Medical Research | And 7 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2013

Accumulation of amyloid peptide (Aβ) in senile plaques is a hallmark lesion of Alzheimer disease (AD). The design of molecules able to target the amyloid pathology in tissue is receiving increasing attention, both for diagnostic and for therapeutic purposes. Curcumin is a fluorescent molecule with high affinity for the Aβ peptide but its low solubility limits its clinical use. Curcumin-conjugated nanoliposomes, with curcumin exposed at the surface, were designed. They appeared to be monodisperse and stable. They were non-toxic in vitro, down-regulated the secretion of amyloid peptide and partially prevented Aβ-induced toxicity. They strongly labeled Aβ deposits in post-mortem brain tissue of AD patients and APPxPS1 mice. Injection in the hippocampus and in the neocortex of these mice showed that curcumin-conjugated nanoliposomes were able to specifically stain the Aβ deposits in vivo. Curcumin-conjugated nanoliposomes could find application in the diagnosis and targeted drug delivery in AD. From the Clinical Editor: In this preclinical study, curcumin-conjugated nanoliposomes were investigated as possible diagnostics and targeted drug delivery system in Alzheimer's disease, demonstrating strong labeling of Aβ deposits both in human tissue and in mice, and in vitro downregulation of amyloid peptide secretion and prevention of Aβ-induced toxicity. © 2013 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).

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.

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.

Panchal M.,Laboratoire Of Neuropathologie Escourolle | Panchal M.,French Institute of Health and Medical Research | Panchal M.,University Pierre and Marie Curie | Loeper J.,University Pierre and Marie Curie | And 9 more authors.
Journal of Lipid Research | Year: 2010

Extensive knowledge of the protein components of the senile plaques, one of the hallmark lesions of Alzheimer's disease, has been acquired over the years, but their lipid composition remains poorly known. Evidence suggests that cholesterol contributes to the pathogenesis of Alzheimer's disease. However, its presence within senile plaques has never been ascertained with analytic methods. Senile plaques were microdissected from sections of the isocortex in three Braak VI Alzheimer's disease cases and compared with a similar number of samples from the adjoining neuropil, free of amyloid-β peptide (A β) deposit. Two cases were apo α 4/apo α 3, and one case was apo α 3/apo α 3. A known quantity of 13 C-labeled cholesterol was added to the samples as a standard. After hexane extraction, cholesterol content was analyzed by liquid chromatography coupled with electrospray ionization mass spectrometry. The mean concentration of free cholesterol was 4.25 ± 0.1 attomoles/ μ 3 in the senile plaques and 2.2 ± 0.49 attomoles/μm 3 in the neuropil (t = 4.41, P < 0.0009). The quantity of free cholesterol per senile plaque (67 ± 16 femtomol) is similar to the published quantity of A β peptide. The highly signifi-cant increase in the cholesterol concentration, associated with the increased risk of Alzheimer's disease linked to the apo α 4 allele, suggests new pathogenetic mechanisms. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.

Ando K.,Laboratoire Of Neuropathologie Escourolle | Ando K.,Group 47 | Brion J.-P.,Free University of Colombia | Stygelbout V.,Free University of Colombia | And 11 more authors.
Acta Neuropathologica | Year: 2013

PICALM, a clathrin adaptor protein, plays important roles in clathrin-mediated endocytosis in all cell types. Recently, genome-wide association studies identified single nucleotide polymorphisms in PICALM gene as genetic risk factors for late-onset Alzheimer disease (LOAD). We analysed by western blotting with several anti-PICALM antibodies the pattern of expression of PICALM in human brain extracts. We found that PICALM was abnormally cleaved in AD samples and that the level of the uncleaved 65-75 kDa full-length PICALM species was significantly decreased in AD brains. Cleavage of human PICALM after activation of endogenous calpain or caspase was demonstrated in vitro. Immunohistochemistry revealed that PICALM was associated in situ with neurofibrillary tangles, co-localising with conformationally abnormal and hyperphosphorylated tau in LOAD, familial AD and Down syndrome cases. PHF-tau proteins co-immunoprecipitated with PICALM. PICALM was highly expressed in microglia in LOAD. These observations suggest that PICALM is associated with the development of AD tau pathology. PICALM cleavage could contribute to endocytic dysfunction in AD. © 2013 Springer-Verlag Berlin Heidelberg.

Giustiniani J.,French Institute of Health and Medical Research | Sineus M.,French Institute of Health and Medical Research | Sardin E.,French Institute of Health and Medical Research | Dounane O.,French Institute of Health and Medical Research | And 5 more authors.
Journal of Alzheimer's Disease | Year: 2012

Human neurodegenerative diseases characterized by abnormal intraneuronal inclusions of the tau protein, or "tauopathies", include Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy, corticobasal degeneration as well as fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Several abnormalities of tau may contribute to the pathological processes, yet the mechanisms involved in tau cellular toxicity remain unclear. Previously, we demonstrated an interaction between various isoforms of tau and the immunophilin FKBP52 (FK506-Binding Protein), suggesting a direct involvement of FKBP52 in tau function. Here we analyze the expression of FKBP52 in human brains of patients with different tauopathies, including AD. Immunohistofluorescence studies carried out on cerebral cortex in different tauopathies reveal that FKBP52 is not sequestered by filamentous tau inclusions while FKBP52 is colocalized with tau in the control case brains. We found that FKBP52 expression level is abnormally low in frontal cortex of AD and FTDP-17 brains, as compared to controls, despite no alteration in the FKBP52 mRNA expression level. The possible involvement of FKBP52 in pathological tau expression/function is discussed. © 2012-IOS Press and the authors. All rights reserved.

PubMed | Laboratoire Of Neuropathologie Escourolle, French Institute of Health and Medical Research and Free University of Colombia
Type: | Journal: Neurobiology of disease | Year: 2016

Single nucleotide polymorphisms in PICALM, a key component of clathrin-mediated endocytosis machinery, have been identified as genetic susceptibility loci for late onset Alzheimers disease (LOAD). We previously reported that PICALM protein levels were decreased in AD brains and that PICALM was co-localised with neurofibrillary tangles in LOAD, familial AD with PSEN1 mutations and Down syndrome. In the present study, we analysed PICALM expression, cell localisation and association with pathological cellular inclusions in other tauopathies and in non-tau related neurodegenerative diseases. We observed that PICALM was associated with neuronal tau pathology in Pick disease and in progressive supranuclear palsy (PSP) and co-localised with both 3R and 4R tau positive inclusions unlike in corticobasal degeneration (CBD) or in frontotemporal lobar degeneration (FTLD)-MAPT P301L. PICALM immunoreactivities were not detected in tau-positive tufted astrocytes in PSP, astrocytic plaques in CBD, Lewy bodies in Lewy body disease, diffuse type (LBD) and in TDP-43-positive inclusions in FTLD. In the frontal cortex in tauopathies, the ratio of insoluble to soluble PICALM was increased while the level of soluble PICALM was decreased and was inversely correlated with the level of phosphotau. PICALM decrease was also significantly correlated with increased LC3-II and decreased Beclin-1 levels in tauopathies and in non-tau related neurodegenerative diseases. These results suggest that there is a close relationship between abnormal PICALM processing, tau pathology and impairment of autophagy in human neurodegenerative diseases.

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