The Role of Mitochondrial Dysfunction in the Progression of Alzheimer’s Disease

Desler, Claus; Lillenes, Meryl S.; Tønjum, Tone; Rasmussen, Lene Juel

doi:10.2174/0929867324666170616110111

Cited by 51 publications

(34 citation statements)

References 126 publications

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“…BOK can trigger mitochondrial outer membrane permeabilization in the absence of other BCL-2 members, after inhibition of the proteasome ( Zheng et al., 2018 ). Importantly, each of these factors may contribute to neuronal degeneration ( Desler et al., 2017 ; Fang et al., 2019 ; Kam et al., 2018 ). In addition, hippocampal pyramidal neurons in the CA1 and CA3 display differential vulnerability to neuronal injury ( Mattson et al., 1989 ), and Bok's preferential expression in CA3 may contribute to this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease

et al. 2020

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Summary Alzheimer disease (AD) is a devastating neurological disease associated with progressive loss of mental skills and cognitive and physical functions whose etiology is not completely understood. Here, our goal was to simultaneously uncover novel and known molecular targets in the structured layers of the hippocampus and olfactory bulbs that may contribute to early hippocampal synaptic deficits and olfactory dysfunction in AD mice. Spatially resolved transcriptomics was used to identify high-confidence genes that were differentially regulated in AD mice relative to controls. A diverse set of genes that modulate stress responses and transcription were predominant in both hippocampi and olfactory bulbs. Notably, we identify Bok, implicated in mitochondrial physiology and cell death, as a spatially downregulated gene in the hippocampus of mouse and human AD brains. In summary, we provide a rich resource of spatially differentially expressed genes, which may contribute to understanding AD pathology.

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Section: Discussionmentioning

confidence: 99%

Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease

et al. 2020

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“…AD is characterized by a plethora of pathological features, including neuronal loss, dendritic hypotrophy and synaptic alteration, microglial malfunction, cerebrovascular amyloid angiopathy, inflammation, and mitochondrial dysfunction [ 2 , 3 ]. However, the most distinctive features are the presence of extracellular senile plaques, formed by fibrillary β-amyloid (Aβ) and neurofibrillary tangles (NFTs), composed of hyperphosphorylated Tau [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Multiple Layers of CDK5R1 Regulation in Alzheimer’s Disease Implicate Long Non-Coding RNAs

Spreafico

Grillo

Rusconi

et al. 2018

IJMS

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Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) gene encodes for p35, the main activator of Cyclin-dependent kinase 5 (CDK5). The active p35/CDK5 complex is involved in numerous aspects of brain development and function, and its deregulation is closely associated to Alzheimer’s disease (AD) onset and progression. We recently showed that miR-15/107 family can negatively regulate CDK5R1 expression modifying mRNA stability. Interestingly, miRNAs belonging to miR-15/107 family are downregulated in AD brain while CDK5R1 is upregulated. Long non-coding RNAs (lncRNAs) are emerging as master regulators of gene expression, including miRNAs, and their dysregulation has been implicated in the pathogenesis of AD. Here, we evaluated the existence of an additional layer of CDK5R1 expression regulation provided by lncRNAs. In particular, we focused on three lncRNAs potentially regulating CDK5R1 expression levels, based on existing data: NEAT1, HOTAIR, and MALAT1. We demonstrated that NEAT1 and HOTAIR negatively regulate CDK5R1 mRNA levels, while MALAT1 has a positive effect. We also showed that all three lncRNAs positively control miR-15/107 family of miRNAs. Moreover, we evaluated the expression of NEAT1, HOTAIR, and MALAT1 in AD and control brain tissues. Interestingly, NEAT1 displayed increased expression levels in temporal cortex and hippocampus of AD patients. Interestingly, we observed a strong positive correlation between CDK5R1 and NEAT1 expression levels in brain tissues, suggesting a possible neuroprotective role of NEAT1 in AD to compensate for increased CDK5R1 levels. Overall, our work provides evidence of another level of CDK5R1 expression regulation mediated by lncRNAs and points to NEAT1 as a biomarker, as well as a potential pharmacological target for AD therapy.

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“…Reversal of NAD loss as we age is currently undergoing human trials following successful age reversal of mitochondrial function in the skeletal muscle cells of mice [ 106 ]. Mitochondrial dysfunction, which is linked to ageing, also leads to a reduction of pyrimidine synthesis [ 107 , 108 ].…”

Section: Resultsmentioning

confidence: 99%

The poly-omics of ageing through individual-based metabolic modelling

Yaneske

Angione

2018

BMC Bioinformatics

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BackgroundAgeing can be classified in two different ways, chronological ageing and biological ageing. While chronological age is a measure of the time that has passed since birth, biological (also known as transcriptomic) ageing is defined by how time and the environment affect an individual in comparison to other individuals of the same chronological age. Recent research studies have shown that transcriptomic age is associated with certain genes, and that each of those genes has an effect size. Using these effect sizes we can calculate the transcriptomic age of an individual from their age-associated gene expression levels. The limitation of this approach is that it does not consider how these changes in gene expression affect the metabolism of individuals and hence their observable cellular phenotype.ResultsWe propose a method based on poly-omic constraint-based models and machine learning in order to further the understanding of transcriptomic ageing. We use normalised CD4 T-cell gene expression data from peripheral blood mononuclear cells in 499 healthy individuals to create individual metabolic models. These models are then combined with a transcriptomic age predictor and chronological age to provide new insights into the differences between transcriptomic and chronological ageing. As a result, we propose a novel metabolic age predictor.ConclusionsWe show that our poly-omic predictors provide a more detailed analysis of transcriptomic ageing compared to gene-based approaches, and represent a basis for furthering our knowledge of the ageing mechanisms in human cells.Electronic supplementary materialThe online version of this article (10.1186/s12859-018-2383-z) contains supplementary material, which is available to authorized users.

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The Role of Mitochondrial Dysfunction in the Progression of Alzheimer’s Disease

Cited by 51 publications

References 126 publications

Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease

Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease

Multiple Layers of CDK5R1 Regulation in Alzheimer’s Disease Implicate Long Non-Coding RNAs

The poly-omics of ageing through individual-based metabolic modelling

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