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Downregulated apoptosis and autophagy after anti-Aβ immunotherapy in Alzheimer’s disease

Published on Sep 1, 2018in Brain Pathology6.16
· DOI :10.1111/bpa.12567
Claire Paquet23
Estimated H-index: 23
(French Institute of Health and Medical Research),
James A. R. Nicoll57
Estimated H-index: 57
(University of Southampton)
+ 4 AuthorsDelphine Boche24
Estimated H-index: 24
(University of Southampton)
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Abstract
Aβ immunisation of Alzheimer's disease (AD) patients in the AN1792 (Elan Pharmaceuticals) trial caused Aβ removal and a decreased density of neurons in the cerebral cortex. As preservation of neurons may be a critical determinant of outcome after Aβ immunisation, we have assessed the impact of previous Aβ immunisation on the expression of a range of apoptotic proteins in post-mortem human brain tissue. Cortex from 13 AD patients immunised with AN1792 (iAD) and from 27 non-immunised AD (cAD) cases was immunolabelled for pro-apoptotic proteins implicated in AD pathophysiology: phosphorylated c-Jun N-terminal kinase (pJNK), activated caspase3 (a-casp3), phosphorylated GSK3β on tyrosine 216 (GSK3βtyr216), p53 and Cdk5/p35. Expression of these proteins was analysed in relation to immunisation status and other clinical data. The antigen load of all of these pro-apoptotic proteins was significantly lower in iAD than cAD (p < 0.0001). In cAD, significant correlations (p < 0.001) were observed between: Cdk5/p35 and GSK3βtyr216; a-casp3 and Aβ42; p53 and age at death. In iAD, significant correlations were found between GSK3βtyr216 and a-casp3; both spongiosis and neuritic curvature ratio and Aβ42; and Cdk5/p35 and Aβ-antibody level. Although neuronal loss was increased by immunisation with AN1792, our present findings suggest downregulation of apoptosis in residual neurons and other cells. This article is protected by copyright. All rights reserved.
  • References (45)
  • Citations (4)
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References45
Newest
Published on Jan 12, 2016in Frontiers in Pharmacology3.85
Ramon Yarza1
Estimated H-index: 1
(University of Navarra),
Silvia Vela1
Estimated H-index: 1
(University of Navarra)
+ 1 AuthorsMaría J. Ramírez38
Estimated H-index: 38
(University of Navarra)
c-Jun N-terminal kinases (JNKs) are a family of protein kinases that play a central role in stress signaling pathways implicated in gene expression, neuronal plasticity, regeneration, cell death and regulation of cellular senescence. It has been shown that there is a JNK pathway activation after exposure to different stressing factors, including cytokines, growth factors, oxidative stress, unfolded protein response signals or A peptides. Altogether, JNKs have become a focus of screening strateg...
Published on Apr 1, 2015in The Journal of Pathology5.94
Claire Paquet23
Estimated H-index: 23
(French Institute of Health and Medical Research),
Jay Amin4
Estimated H-index: 4
(University of Southampton)
+ 8 AuthorsJacques Hugon28
Estimated H-index: 28
(French Institute of Health and Medical Research)
Amyloid-beta peptide (Abeta) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal, but with little impact on cognitive decline. We have explored the consequences of Abeta immunotherapy on neurons in post mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases. Immunohistochemistry on sections of neocortex was performed for neuron-specific nuclear antigen (NeuN), neurofilament prote...
Published on Jan 2, 2015in Journal of Clinical Investigation12.28
Rebecca A. Frake1
Estimated H-index: 1
,
Thomas Ricketts5
Estimated H-index: 5
+ 1 AuthorsDavid C. Rubinsztein110
Estimated H-index: 110
Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons. Autophagy is a powerful process for removing such proteins. In this Review, we consider how certain neurodegenerative diseases may be associated with impaired autophagy and how this may affect pathology. We also discuss how autophagy induction may be a plausible therapeutic strategy for some conditions and review studies in various models that support th...
Published on Jan 1, 2015in Reviews in The Neurosciences2.16
Ameneh Zare-Shahabadi6
Estimated H-index: 6
,
Eliezer Masliah139
Estimated H-index: 139
+ 1 AuthorsNima Rezaei47
Estimated H-index: 47
Abstract Autophagy is a vesicle and lysosome-mediated degradative pathway that is essential for protein homeostasis and cell health. In particular, compared to nonneuronal cells, neurons are dependent on high basal autophagy for survival. There is emerging agreement that defects in autophagy are likely to contribute to the neurodegenerative processes in numerous diseases, including Alzheimer's disease (AD). Autophagy-lysosome defects occur early in the pathogenesis of AD and have been proposed t...
Published on Dec 1, 2014in Neurochemical Research2.78
M. Obulesu1
Estimated H-index: 1
(University of Tsukuba),
M. Jhansi Lakshmi1
Estimated H-index: 1
(CSIR-CFTRI: Central Food Technological Research Institute)
Alzheimer’s disease (AD) is a devastative neurodegenerative disorder with complex etiology. Apoptosis, a biological process that plays an essential role in normal physiology to oust a few cells and contribute to the normal growth, when impaired or influenced by various factors such as Bcl2, Bax, caspases, amyloid beta, tumor necrosis factor-α, amyloid precursor protein intracellular C-terminal domain, reactive oxygen species, perturbation of enzymes leads to deleterious neurodegenerative disorde...
Published on Apr 1, 2014in Pharmacology & Therapeutics9.40
Frédéric Checler51
Estimated H-index: 51
(CNRS: Centre national de la recherche scientifique),
Cristine Alves da Costa24
Estimated H-index: 24
(CNRS: Centre national de la recherche scientifique)
More than thirty years elapsed since a protein, not yet called p53 at the time, was detected to bind SV40 during viral infection. Thousands of papers later, p53 evolved as the main tumor suppressor involved in growth arrest and apoptosis. A lot has been done but the protein has not yet revealed all its secrets. Particularly important is the observation that in totally distinct pathologies where apoptosis is either exacerbated or impaired, p53 appears to play a central role. This is exemplified f...
Published on Feb 1, 2014in Nature Reviews Molecular Cell Biology43.35
Guillermo Mariño33
Estimated H-index: 33
,
Mireia Niso-Santano23
Estimated H-index: 23
+ 1 AuthorsGuido Kroemer191
Estimated H-index: 191
Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively. It is now clear that these processes often occur sequentially, and that crosstalk between the signalling pathways regulating them generally enables autophagy to block the induction of apoptosis, whereas apoptosis-associated caspase activation shuts off autophagy.
Published on Oct 1, 2013in Molecular & Cellular Proteomics4.83
Yuanhui Ma2
Estimated H-index: 2
(PKU: Peking University),
Jintao Bao2
Estimated H-index: 2
(PKU: Peking University)
+ 8 AuthorsQingsong Wang14
Estimated H-index: 14
(PKU: Peking University)
Amyloid plaques are crucial for the pathogenesis of Alzheimer disease (AD). Phagocytosis of fibrillar β-amyloid (Aβ) by activated microglia is essential for Aβ clearance in Alzheimer disease. However, the mechanism underlying Aβ clearance in the microglia remains unclear. In this study, we performed stable isotope labeling of amino acids in cultured cells for quantitative proteomics analysis to determine the changes in protein expression in BV2 microglia treated with or without Aβ. Among 2742 pr...
Published on Sep 1, 2013in Brain11.81
Elina Zotova7
Estimated H-index: 7
(Southampton General Hospital),
Viraj Bharambe1
Estimated H-index: 1
(Southampton General Hospital)
+ 7 AuthorsDelphine Boche24
Estimated H-index: 24
(Southampton General Hospital)
Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-b immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-b42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcreceptors I (CD64) and II (CD32); and also immunoglobuli...
Published on Aug 22, 2013in PLOS Pathogens6.46
Pauline Sebby Ogolla1
Estimated H-index: 1
(Case Western Reserve University),
Jose Andres C Portillo8
Estimated H-index: 8
(Case Western Reserve University)
+ 4 AuthorsCarlos S. Subauste25
Estimated H-index: 25
(Case Western Reserve University)
PKR is well characterized for its function in antiviral immunity. Using Toxoplasma gondii, we examined if PKR promotes resistance to disease caused by a non-viral pathogen. PKR−/− mice infected with T. gondii exhibited higher parasite load and worsened histopathology in the eye and brain compared to wild-type controls. Susceptibility to toxoplasmosis was not due to defective expression of IFN-γ, TNF-α, NOS2 or IL-6 in the retina and brain, differences in IL-10 expression in these organs or to im...
Cited By4
Newest
Published on May 8, 2019in Acta neuropathologica communications
Gábor M. Mórotz5
Estimated H-index: 5
('KCL': King's College London),
Elizabeth B. Glennon2
Estimated H-index: 2
('KCL': King's College London)
+ 6 AuthorsChristopher Miller78
Estimated H-index: 78
('KCL': King's College London)
Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesin-1 light chains (KLC1/2). Binding to KLC1/2 involves a C-terminal tryptophan/aspartate (WD) motif in LMTK2 and the tetratricopeptide repeat (TPR) domains in KLC1/2, and this interaction facilitates a...
Published on 2019in Cells
Lih-Fen Lue42
Estimated H-index: 42
,
Thomas G. Beach75
Estimated H-index: 75
,
Douglas G. Walker62
Estimated H-index: 62
Experimental studies of neuroinflammation in Alzheimer’s disease (AD) have mostly investigated microglia, the brain-resident macrophages. This review focused on human microglia obtained at rapid autopsies. Studies employing methods to isolate and culture human brain microglia in high purity for experimental studies were discussed. These methods were employed to isolate human microglia for investigation of a number of features of neuroinflammation, including activation phenotypes, neurotoxicity, ...
Published on Apr 4, 2019in Brain11.81
Seth Love54
Estimated H-index: 54
(UoB: University of Bristol),
James A. R. Nicoll57
Estimated H-index: 57
+ 6 AuthorsClive Holmes55
Estimated H-index: 55
Published on Apr 1, 2019
Mengsi Wu (CAS: Chinese Academy of Sciences), Kechi Fang (CAS: Chinese Academy of Sciences)+ 3 AuthorsJing Wang46
Estimated H-index: 46
(CAS: Chinese Academy of Sciences)
In this study, combined analysis of expression profiling in the hippocampus of 76 patients with Alzheimer’s disease (AD) and 40 healthy controls was performed. The effects of covariates (including age, gender, postmortem interval, and batch effect) were controlled, and differentially expressed genes (DEGs) were identified using a linear mixed-effects model. To explore the biological processes, functional pathway enrichment and protein–protein interaction (PPI) network analyses were performed on ...
Published on Dec 1, 2018in Virchows Archiv2.87
Emmanuel Cognat2
Estimated H-index: 2
(French Institute of Health and Medical Research),
Marion Tible4
Estimated H-index: 4
(French Institute of Health and Medical Research)
+ 4 AuthorsClaire Paquet23
Estimated H-index: 23
(French Institute of Health and Medical Research)
Cerebral autosomal dominant arteriolopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common form of hereditary small vessel disease (SVD) of the brain. Neuronal apoptosis has been demonstrated in the cortex of patients. Whether it is associated with an activation of the pro-apoptotic protein PKR pathway is unknown. Similarly, activation of autophagy in CADASIL has never been explored. Immunostaining of four CADASIL brains previously analyzed for cortical neuronal ap...
Published on Dec 1, 2018
Alice Bittar2
Estimated H-index: 2
(UTMB: University of Texas Medical Branch),
Urmi Sengupta17
Estimated H-index: 17
(UTMB: University of Texas Medical Branch),
Rakez Kayed50
Estimated H-index: 50
(UTMB: University of Texas Medical Branch)
With increasing age, as the incidence of Alzheimer’s disease is increasing, finding a therapeutic intervention is becoming critically important to either prevent or slow down the progression of the disease. Passive immunotherapy has been demonstrated as a successful way of reducing large aggregates and improving cognition in animal models of both tauopathies and Alzheimer’s disease. However, with all the continuous attempts and significant success of immunotherapy in preclinical studies, finding...
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