Alzheimer's disease-related dysregulation of mRNA translation causes key pathological features with ageing
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE149540 | GEO | 2020/06/29
REPOSITORIES: GEO
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Project description:Alzheimer's disease (AD) is characterised by Aβ and tau pathology as well as synaptic degeneration, which correlates best with cognitive impairment. Previous work suggested that this pathological complexity may result from changes in mRNA translation. Here, we studied whether mRNA translation and its underlying signalling are altered in an early model of AD, and whether modelling this deficiency in mice causes pathological features with ageing. Using an unbiased screen, we show that exposure of primary neurons to nanomolar amounts of Aβ increases FMRP-regulated protein synthesis. This selective regulation of mRNA translation is dependent on a signalling cascade involving MAPK-interacting kinase 1 (Mnk1) and the eukaryotic initiation factor 4E (eIF4E), and ultimately results in reduction of CYFIP2, an FMRP-binding protein. Modelling this CYFIP2 reduction in mice, we find age-dependent Aβ accumulation in the thalamus, development of tau pathology in entorhinal cortex and hippocampus, as well as gliosis and synapse loss in the hippocampus, together with deficits in memory formation. Therefore, we conclude that early stages of AD involve increased translation of specific CYFIP2/FMRP-regulated transcripts. Since reducing endogenous CYFIP2 expression is sufficient to cause key features of AD with ageing in mice, we suggest that prolonged activation of this pathway is a primary step toward AD pathology, highlighting a novel direction for therapeutic targeting.
| S-EPMC7297996 | biostudies-literature
Project description:Alzheimer's disease-related dysregulation of mRNA translation causes key pathological features with ageing
| PRJNA642886 | ENA
Project description:Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid β-protein (Aβ42) forms and novel intraneuronal Aβ oligomers (AβOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aβ uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aβ42, S100 calcium-binding protein B+ macrogliosis, and atrophy correlated with severity of brain Aβ pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aβ42, far-peripheral AβOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.
| S-EPMC10020290 | biostudies-literature
Project description:Purpose: we performed comparative RNA-seq analyses to identify molecular network characteristics of kidney injury at different ischemia times Methods: Unilateral clamping of the left renal pedicle plus contralateral nephrectomy was performed. Briefly, mice were anesthetized, right kidney was excised. The left kidney was clamped for indicated minutes (0min for sham-24h group, 16min for uIRIx16min-24h group, 18minfor uIRIx18min-24h group, 20min for uIRIx20min-24h group, 22min for uIRIx22min-24h group, 24min for uIRIx24min-24h group, 26min for uIRIx26min-24h group, 28min for uIRIx28min-24h group, 30min for uIRIx30min-24h group). Mice were placed on 37°C heating platform while operation, ischemia and before awakening. At 24h after ischemia, mice were anesthetized and blood was taken to detect creatinine, kidney was harvest for PAS staining and mRNA seq. Results: After sequence, the clean reads rate of all samples were ≥98%.The quality of the assembled transcriptome is good enough for functional annotation and further analysis. Conclusions: We performed RNA-sequencing (RNA-Seq) analyses to identify molecular network characteristics of kidney injury at different ischemia time.
2022-01-04 | GSE192883 | GEO
Project description:Physiological and pathological ageing (as exemplified by Alzheimer's disease, AD) are characterized by a progressive decline that also includes cognition. How this decline can be slowed or even reversed is a critical question. Here, we discuss therapeutic ultrasound as a novel modality to achieve this goal. In our studies, we explored three fundamental strategies, (i) scanning ultrasound on its own (SUSonly), (ii) therapeutic ultrasound in concert with intravenously injected microbubbles (which transiently opens the blood-brain barrier, SUS+MB), and (iii) SUS+MB in combination with therapeutic antibodies (SUS+MB+mAb). These studies show SUS+MB effectively clears amyloid and restores memory in amyloid-depositing mice and partially clears Tau and ameliorates memory impairments in Tau transgenic mice, with additional improvements found in combination trials (SUS+MB+mAb). Interestingly, both SUSonly and SUS+MB restored the induction of long-term potentiation (LTP, electrophysiological correlate of memory) in senescent wild-type mice. Both lead to increased neurogenesis, and SUSonly, in particular, resulted in improved spatial memory. We discuss these findings side-by-side with our findings obtained in AD mouse models. We conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may present a treatment option not only for AD but also for enhancing cognition in physiological ageing.
| S-EPMC8309087 | biostudies-literature
Project description: Not available
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Project description:The aim of this experiment is to compare nucleases used in ribosome profiling using Drosophila melanogaster Kc167 cells and human U2OS osteosarcoma cells. Ribosome profiling was performed from nuclease digested samples using sucrose cushion centrifugation separated ribosomes.
2015-01-08 | E-MTAB-2421 | biostudies-arrayexpress
Project description:The hypothesis that amyloid-beta (Abeta) peptides are the primary cause of Alzheimer's disease (AD) remains the best supported theory of AD pathogenesis. Yet, many observations are inconsistent with the hypothesis. Abeta peptides are generated when amyloid precursor protein (APP) is cleaved by presenilins, a process that also produces APP intracellular domain (AICD). We previously generated AICD-overexpressing transgenic mice that showed abnormal activation of GSK-3beta, a pathological feature of AD. We now report that these mice exhibit additional AD-like characteristics, including hyperphosphorylation and aggregation of tau, neurodegeneration and working memory deficits that are prevented by treatment with lithium, a GSK-3beta inhibitor. Consistent with its potential role in AD pathogenesis, we find AICD levels to be elevated in brains from AD patients. The in vivo findings that AICD can contribute to AD pathology independently of Abeta have important therapeutic implications and may explain some observations that are discordant with the amyloid hypothesis.
| S-EPMC2762847 | biostudies-literature
Project description:The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Ab42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Ab uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Ab phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant.
2018-05-31 | GSE102956 | GEO
Project description:Amyloid precursor protein (APP) is cleaved by gamma-secretase to simultaneously generate amyloid beta (Aβ) and APP Intracellular Domain (AICD) peptides. Aβ plays a pivotal role in Alzheimer's disease (AD) pathogenesis but recent studies suggest that amyloid-independent mechanisms also contribute to the disease. We previously showed that AICD transgenic mice (AICD-Tg) exhibit AD-like features such as tau pathology, aberrant neuronal activity, memory deficits and neurodegeneration in an age-dependent manner. Since AD is a tauopathy and tau has been shown to mediate Aβ-induced toxicity, we examined the role of tau in AICD-induced pathological features. We report that ablating endogenous tau protects AICD-Tg mice from deficits in adult neurogenesis, seizure severity, short-term memory deficits and neurodegeneration. Deletion of tau restored abnormal phosphorylation of NMDA receptors, which is likely to underlie hyperexcitability and associated excitotoxicity in AICD-Tg mice. Conversely, overexpression of wild-type human tau aggravated receptor phosphorylation, impaired adult neurogenesis, memory deficits and neurodegeneration. Our findings show that tau is essential for mediating the deleterious effects of AICD. Since tau also mediates Aβ-induced toxic effects, our findings suggest that tau is a common downstream factor in both amyloid-dependent and-independent pathogenic mechanisms and therefore could be a more effective drug target for therapeutic intervention in AD.
| S-EPMC4961442 | biostudies-literature