Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology

Stygelbout, Virginie; Leroy, Karelle; Pouillon, Valérie; Ando, Kunie; D’Amico, Eva; Jia, Yonghui; Luo, Hongbo; Duyckaerts, Charles; Erneux, Christophé; Schurmans, Stéphane; Brion, Jean Pierre

doi:10.1093/brain/awt344

Cited by 61 publications

(48 citation statements)

References 44 publications

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“…It has been postulated that accumulation of damage from HSV infection and major neuroinflammatory effects can lead to the development of AD, and that apoE4 carriers suffer either greater viral damage or have poorer repair of such damage 54 . Previous studies have demonstrated that ITPKB expression is increased in human AD brains and exacerbates AD pathology in an animal model 64 . Our brain transcriptome findings for females with AD, including downregulation of autophagy and proteolysis pathways, upregulation of pathways related to the immune system and HSV infection, as well as ITPKB as a hub gene, particularly in female apoE4 carriers, highlight specific gene-encoded processes in the brain that may be more involved in AD for women than for men.…”

Section: Discussionmentioning

confidence: 98%

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Paranjpe

Belonwu

Wang

et al. 2020

Preprint

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In spite of evidence of females having a greater lifetime risk of developing Alzheimer's Disease (AD) and greater apolipoprotein E4-related (apoE4) AD risk compared to males, molecular signatures underlying these findings remain elusive. We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls. Gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features revealed an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males. These results help identify sex and apoE4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia 1,2 . It is pathologically characterized by the deposition of extracellular amyloid β (Aβ) and intracellular tau, otherwise referred to as plaques and neurofibrillary tangles, respectively 3-5 . AD is also marked by neuronal loss, impaired neurotransmitter signaling, neuroinflammation, and dysregulation of neuronal metabolism and immune response in the central nervous system 6-8 . AD prevalence increases dramatically with age, where the majority of cases are in individuals above the age of 65 1,9 . Although AD was identified more than a century ago 10 , its cause and pathophysiology are not fully understood, and there are no available treatments that aid in halting or reversing the disease 11 . Accordingly, it is of high priority to tackle AD, as it is projected to triple in incidence by 2050 as a consequence of population aging 6,8,12 and, to date, has no disease-modifying therapies.While the exact cause and pathophysiology remain unknown, a number of mutations and genetic risk factors have been identified as associated with AD. Apolipoprotein E (apoE) is the most common genetic risk factor for late onset AD 8,13-18 . ApoE is a lipid binding protein, that plays a central role in lipid transport and metabolism. It is highly expressed in the brain, and is important for maintaining neuronal membranes during inflammation and damage. In humans, apoE has three isoforms, apoE2, apoE3, and apoE4, which are encoded by the three alleles, ε2, ε3, and ε4, of the apoE gene, respectively. The ε2 isoform has been shown to be protective against AD, while the ε4 isoform (apoE4) is associated with increasing the risk and lowering the age of onset for developing late onset AD in a gene dose-dependent manner 19,20 . Specifically, one copy of the ε4 isoform confers a 3 to 4-fold increased risk and 7 year decrease in age of onset, while two copies confers a 12 to 15-fold increased r...

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Section: Discussionmentioning

confidence: 98%

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Paranjpe

Belonwu

Wang

et al. 2020

Preprint

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“…Clinical symptoms include the progressive cognitive function decline, memory loss, and behavior deficit. AD is considered as a major public health concern and a leading cause of disability (Castellani, Rolston, & Smith, ; Gjoneska et al., ; Stygelbout et al., ). According to the data from the European Prevention of Alzheimer’s Dementia (EPAD), currently more than 40 million people worldwide have suffered from AD and its prevalence is expected to double over the next 20 years (Ritchie et al., ).…”

Section: Introductionmentioning

confidence: 99%

Effects of mesenchymal stem cells transplantation on cognitive deficits in animal models of Alzheimer’s disease: A systematic review and meta‐analysis

Zhang

Qin

et al. 2018

Brain and Behavior

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BackgroundAlzheimer’s disease (AD) is a globally prevalent neurodegenerative disease, clinically characterized by progressive memory loss and gradual impairment of cognitive functions. Mesenchymal stem cells (MSCs) transplantation has been considered a possible therapeutic method for Alzheimer’s disease (AD). However, no quantitative data synthesis of MSC therapy for AD exists. We conducted a systematic review and meta‐analysis to study the effects of MSCs on cognitive deficits in animal models of AD.MethodsWe identified eligible studies published from January 1980 to January 2017 by searching four electronic databases (PubMed, MEDLINE, EMBASE, CNKI). The endpoint was the effects of MSCs on cognitive performance evaluated by the Morris water maze (MWM) test including escape latency, and/or number of platform crossing, and/or time in the target quadrant.ResultsNine preclinical studies incorporating 225 animals with AD were included for the meta‐analysis. The studies indicated that MSC‐based treatment significantly improved the learning function through measurements of the escape latency (SMD = −0.99, 95% CI = −1.33 to −0.64, p < .00001). Additionally, we observed that transplantation of MSCs significantly increased the number of platform crossing in six experiments (SMD = 0.78, 95% CI = 0.43 to 1.13, p < .0001). What’s more, the times in the target quadrant were increased in five studies indicated that transplantation of MSCs could ameliorate the cognitive impairments (SMD = 1.06, 95% CI = 0.46 to 1.67, p = .0005).ConclusionsThis study showed that MSC transplantation could reduce cognitive deficits in AD models. These findings support the further studies to translate MSCs in the treatment of AD in humans

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“…ERK1/2 activation in AD brain is well documented (35)(36)(37). Results from previous studies indicate that ERK1/2 is able to transform Tau into an AD-like state, but this is mainly documented by the detection of the epitope recognized by the AT8 antibody (19).…”

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confidence: 99%

Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-regulated Kinase

Prabakaran

Cantrelle

et al. 2016

Journal of Biological Chemistry

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Tau neuronal protein has a central role in neurodegeneration and is implicated in Alzheimer disease development. Abnormal phosphorylation of Tau impairs its interaction with other proteins and is associated with its dysregulation in pathological conditions. Molecular mechanisms leading to hyperphosphorylation of Tau in pathological conditions are unknown. Here, we characterize phosphorylation of Tau by extracellular-regulated kinase (ERK2), a mitogen-activated kinase (MAPK) that responds to extracellular signals. Analysis of in vitro phosphorylated Tau by activated recombinant ERK2 with nuclear magnetic resonance spectroscopy (NMR) reveals phosphorylation of 15 Ser/Thr sites. In vitro phosphorylation of Tau using rat brain extract and subsequent NMR analysis identifies the same sites. Phosphorylation with rat brain extract is known to transform Tau into an Alzheimer disease-like state. Our results indicate that phosphorylation of Tau by ERK2 alone is sufficient to produce the same characteristics. We further investigate the mechanism of ERK2 phosphorylation of Tau. Kinases are known to recognize their protein substrates not only by their specificity for a targeted Ser or Thr phosphorylation site but also by binding to linear-peptide motifs called docking sites. We identify two main ERK2 docking sites in Tau sequence using NMR. Our results suggest that ERK2 dysregulation in Alzheimer disease could lead to abnormal phosphorylation of Tau resulting in the pathology of the disease.Tau is an intrinsically disordered protein whose primary sequence is divided into several functional domains: an N-terminal region, a proline-rich domain (PRD), 2 a microtubule binding domain (MTBD) constituted of partially repeated sequences R1 to R4, and a C-terminal region (see Fig. 1A). Both PRD and MTBD are involved in microtubule stabilizing activity of Tau (1, 2).Phosphorylation of Tau is an essential process to regulate its physiological function(s); however, abnormal phosphorylation of Tau has been linked to neuronal dysfunction (3-5). In Alzheimer disease (AD) Tau is hyperphosphorylated and aggregated (6). The longest Tau protein isoform (441 residues) has 80 threonine (Thr) or serine (Ser) residues. These residues are exposed as Tau is an intrinsically disordered protein subject to modification by numerous kinases (7). Mass spectrometry (MS) analyses have identified ϳ45 phosphorylated sites on Tau aggregates extracted from AD patients with a typical paired helical filament (PHF) morphology (8, 9) ERK2 belongs to the mitogen-activated protein kinase (MAPKs) family and is activated by dual phosphorylation on a Thr-Xaa-Tyr sequence in its activation loop by MAP kinase kinases (MKK) (21-23). Human ERK2 is phosphorylated on Thr-183 and Tyr-185 by MEK kinase. MAP kinases have a classic kinase structure with an N-terminal lobe folded as a ␤ sheet associated to a larger C-terminal domain constituted of ␣-helices (24). The activation loop is located at the hinge between these domains and shows a large conformational change upon phosphor...

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Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology

Cited by 61 publications

References 44 publications

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Effects of mesenchymal stem cells transplantation on cognitive deficits in animal models of Alzheimer’s disease: A systematic review and meta‐analysis

Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-regulated Kinase

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