The Central Role of AMP-Kinase and Energy Homeostasis Impairment in Alzheimer’s Disease: A Multifactor Network Analysis (original) (raw)
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Background: Our understanding of the molecular mechanisms underlying Alzheimer's disease (AD) remains incomplete. Previous studies have revealed that genetic factors provide a significant contribution to the pathogenesis and development of AD. In the past years, numerous genes implicated in this disease have been identified via genetic association studies on candidate genes or at the genome-wide level. However, in many cases, the roles of these genes and their interactions in AD are still unclear. A comprehensive and systematic analysis focusing on the biological function and interactions of these genes in the context of AD will therefore provide valuable insights to understand the molecular features of the disease.
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Cells, 2022
Alzheimer’s disease (AD) is one of the most complicated progressive neurodegenerative brain disorders, affecting millions of people around the world. Ageing remains one of the strongest risk factors associated with the disease and the increasing trend of the ageing population globally has significantly increased the pressure on healthcare systems worldwide. The pathogenesis of AD is being extensively investigated, yet several unknown key components remain. Therefore, we aimed to extract new knowledge from existing data. Ten gene expression datasets from different brain regions including the hippocampus, cerebellum, entorhinal, frontal and temporal cortices of 820 AD cases and 626 healthy controls were analyzed using the robust rank aggregation (RRA) method. Our results returned 1713 robust differentially expressed genes (DEGs) between five brain regions of AD cases and healthy controls. Subsequent analysis revealed pathways that were altered in each brain region, of which the GABAer...
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Cell Communication and Signaling, 2014
Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer's disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-β aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed "anti-ageing pathways", for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.
Editorial: Molecular mechanisms of Alzheimer’s disease: From top to bottom
Frontiers in Aging
Editorial on the Research Topic Molecular mechanisms of Alzheimer's disease: From top to bottom Alzheimer's disease (AD) is a neurodegenerative disease related to aging. It is a type of senile dementia of high prevalence worldwide. It causes a gradual increase in irreversible cognitive decline that includes memory deficits, behavioral alterations and mental confusion, triggering devasting effects on daily life. In AD, the damage and destruction of neurons gradually affect different parts of the brain. Neurodegeneration is preceded by the deposition of soluble oligomers and fibrils of the amyloid-β (Aβ) peptide in the extracellular space and by intracellular aggregation of the tau protein in neurofibrillary tangles (Pratico, 2008; Paula-Lima et al., 2013). According to the amyloid cascade, the accumulation of the extracellular Aβ peptide triggers the dysfunction in the release of neurotransmitters, extensive oxidative stress (Butterfield and Lauderback, 2002; Ill-Raga et al., 2010), synaptic failure and neuronal loss, leading to macroscopic atrophy (Lane et al., 2015). Genetic and environmental factors are related to the risk of AD. Although current pharmacological treatments offer some relief from AD symptoms, the improvement is modest and temporary, indicating that the heterogeneity of the disease requires a stratified approach for effective treatment (Conway, 2020). Some non-pharmacological interventions have been investigated and show promissory effects. Between them, we highlighted the different types of physical exercise, which act by multiple neuroprotective mechanisms (Daré et al., 2020; Soares et al., 2021). However, until now, there is no curative treatment for AD, and researchers are still struggling to find therapeutic targets that promote significant improvements in the clinical conditions of Alzheimer's patients (Knopman et al., 2021). In this context,
Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Main protein components of these hallmarks include Aβ40, Aβ42, tau, phospho-tau and APOE. With the exception of the APOE-ϵ4 variant, genetic risk factors associated with brain biochemical measures of these proteins have yet to be characterized. We performed a genome-wide association study in brains of 441 AD patients for levels of these proteins collected from three distinct fractions reflecting soluble, membrane-bound and insoluble biochemical states. We identified 123 genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Although all bioch...
Signaling pathway cross talk in Alzheimer's
2014
Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer's disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-β aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed "anti-ageing pathways", for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.
PLOS ONE, 2015
Alzheimer's disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcriptionfactor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression.
INTERACTING CYTOSKELETAL AND METABOLIC PROTEINS: ROLE IN THE DEVELOPMENT OF ALZHEIMER'S DISEASE
Alzheimer's disease (AD) is a complex neurodegenerative disorder of impaired proteostasis. An in-depth understanding of protein complexes, their components, interaction and post translational modification (PTM) is crucial for gaining insight of AD pathology. This study aims to identify novel disease associated protein interactions and their potential phosphorylation and glycosylation (O-GlcNAc) involved in the progression of AD, to help unravel the underlying disease mechanisms. Thirteen protein complexes were obtained on Blue native PAGE (BN-PAGE) from human brain prefrontal cortex of AD and age matched controls. Complex VII (305Kda) entailing pronounced alteration was further resolved into its components on SDS-PAGE and identified by mass spectrometric analysis. The differentially expressed proteins were mapped to existing biological networks and analyzed for potential phosphorylation and O-GlcNAc. Glyceraldehyde-3-PO 4 dehydrogenase (GAPDH), actin cytoplasmic (ACTB), microtubule associated protein 1B (MAP1B), myelin proteolipid protein (PLP1), acyl amino acid releasing enzyme (APEH) were found to be differentially expressed among AD and control brain. Further, network analysis reveals a strong interaction between metabolic proteins (GAPDH, APEH) and their cytoskeletal counterparts (MAP1B, ACTB, PLP1). The annotated network and pathways associated with altered proteins along with their PTM warrants further research to study their actual contribution in AD pathology.