The link between metabolic syndrome and Alzheimer disease: A mutual relationship and long rigorous investigation

Al-kuraishy, Haydar M.; Jabir, Majid S.; Albuhadily, Ali K.; Al-Gareeb, Ali I.; Rafeeq, Mayyadah F.

doi:10.1016/j.arr.2023.102084

Cited by 15 publications

(11 citation statements)

References 158 publications

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“…Since glucose is the primary fuel for brain cells, this disruption can result in synaptic destruction and the progression of inflammation in Alzheimer’s disease. Insulin also plays a crucial role in neuronal processes such as learning and memory, and the emergence of central insulin resistance can contribute to impairing neuronal and synaptic function [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

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Deciphering molecular bridges: Unveiling the interplay between metabolic syndrome and Alzheimer’s disease through a systems biology approach and drug repurposing

Azizan,

Zali,

Mirmotalebisohi

et al. 2024

PLoS ONE

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The association between Alzheimer’s disease and metabolic disorders as significant risk factors is widely acknowledged. However, the intricate molecular mechanism intertwining these conditions remains elusive. To address this knowledge gap, we conducted a thorough investigation using a bioinformatics method to illuminate the molecular connections and pathways that provide novel perspectives on these disorders’ pathological and clinical features. Microarray datasets (GSE5281, GSE122063) from the Gene Expression Omnibus (GEO) database facilitated the way to identify genes with differential expression in Alzheimer’s disease (141 genes). Leveraging CoreMine, CTD, and Gene Card databases, we extracted genes associated with metabolic conditions, including hypertension, non-alcoholic fatty liver disease, and diabetes. Subsequent analysis uncovered overlapping genes implicated in metabolic conditions and Alzheimer’s disease, revealing shared molecular links. We utilized String and HIPPIE databases to visualize these shared genes’ protein-protein interactions (PPI) and constructed a PPI network using Cytoscape and MCODE plugin. SPP1, CD44, IGF1, and FLT1 were identified as crucial molecules in the main cluster of Alzheimer’s disease and metabolic syndrome. Enrichment analysis by the DAVID dataset was employed and highlighted the SPP1 as a novel target, with its receptor CD44 playing a significant role in the inflammatory cascade and disruption of insulin signaling, contributing to the neurodegenerative aspects of Alzheimer’s disease. ECM-receptor interactions, focal adhesion, and the PI3K/Akt pathways may all mediate these effects. Additionally, we investigated potential medications by repurposing the molecular links using the DGIdb database, revealing Tacrolimus and Calcitonin as promising candidates, particularly since they possess binding sites on the SPP1 molecule. In conclusion, our study unveils crucial molecular bridges between metabolic syndrome and AD, providing insights into their pathophysiology for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

“…Identifying the molecular links between AD and MetS may provide insight into the shared molecular pathways involved in the development and progression of both conditions [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Deciphering molecular bridges: Unveiling the interplay between metabolic syndrome and Alzheimer’s disease through a systems biology approach and drug repurposing

Azizan,

Zali,

Mirmotalebisohi

et al. 2024

PLoS ONE

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“…The KEGG pathway of differentially expressed RNAs has also provided many new insights into the mechanism of SPAM1 action. For example, the brain renin-angiotensin system has been implicated in Alzheimer's disease neuropathology [29], and it may serve as a novel potential therapeutic target for Alzheimer's disease [30]. It has been shown that the phospholipase D signaling pathway is a key signaling pathway in Alzheimer's disease [31]; additionally, PACAP activates PAC1, and PAC1 couples with the phospholipase D signaling pathway to trigger downstream effects [32].…”

Section: Discussionmentioning

confidence: 99%

“…It should be mentioned that the result of the Western blot analysis showed that the effect of 0.1 µmol/kg/day SPAM1 was more significant than that of 100 µmol/kg/day SPAM1. In fact, the positive allosteric modulation site of PAC1-R may be able to detect some type of stress metabolites, such as PACAP (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38), which is a natural metabolite of the stress hormone PACAP38. The working mechanism of SPAM1 involves the imitation (mimicry) of some type of stress metabolites, such as PACAP (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38), to trigger self-defensive responses in the nervous system, including anti-senescence, neuroprotection, and nerve regeneration.…”

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice

Liang,

Chen,

et al. 2024

IJMS

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Small-molecule positive allosteric modulator 1 (SPAM1), which targets pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R), has been found to have a neuroprotective effect, and the underlying mechanism was explored in this study. First, using a D-galactose (D-gal)-induced aging mouse model, we confirmed that SPAM1 improves the structure of the hippocampal dentate gyrus and restores the number of neurons. Compared with D-gal model mice, SPAM1-treated mice showed up-regulated expression of Sirtuin 6 (SIRT6) and Lamin B1 and down-regulated expression of YinYang 1 (YY1) and p16. A similar tendency was observed in senescent RGC-5 cells induced by long-term culture, indicating that SPAM1 exhibits significant in vitro and in vivo anti-senescence activity in neurons. Then, using whole-transcriptome sequencing and proteomic analysis, we further explored the mechanism behind SPAM1’s neuroprotective effects and found that SPAM is involved in the longevity-regulating pathway. Finally, the up-regulation of neurofilament light and medium polypeptides indicated by the proteomics results was further confirmed by Western blotting. These results help to lay a pharmacological network foundation for the use of SPAM1 as a potent anti-aging therapeutic drug to combat neurodegeneration with anti-senescence, neuroprotective, and nerve regeneration activity.

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“…Alzheimer's disease is the most prevalent neurodegenerative disease characterized by cognitive impairment and memory dysfunction. 46 , 47 , 48 AD neuropathology is characterized by extracellular accumulation of mutant amyloid beta (Aβ) peptide and intracellular accumulation of hyper‐phosphorylated tau protein which form neurofibrillary tangles (NFTs). 22 , 49 , 50 , 51 Of note, synaptic abnormalities are involved in AD neuropathology and linked with disease severity and progression of Aβ and NFTs.…”

Section: Bdnf and Neurodegenerative Diseasesmentioning

confidence: 99%

BDNF/TrkB activators in Parkinson's disease: A new therapeutic strategy

Ali,

Al‐Kuraishy,

Al‐Gareeb

et al. 2024

J Cellular Molecular Medi

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Parkinson's disease (PD) is a neurodegenerative disorder of the brain and is manifested by motor and non‐motor symptoms because of degenerative changes in dopaminergic neurons of the substantia nigra. PD neuropathology is associated with mitochondrial dysfunction, oxidative damage and apoptosis. Thus, the modulation of mitochondrial dysfunction, oxidative damage and apoptosis by growth factors could be a novel boulevard in the management of PD. Brain‐derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase type B (TrkB) are chiefly involved in PD neuropathology. BDNF promotes the survival of dopaminergic neurons in the substantia nigra and enhances the functional activity of striatal neurons. Deficiency of the TrkB receptor triggers degeneration of dopaminergic neurons and accumulation of α‐Syn in the substantia nigra. As well, BDNF/TrkB signalling is reduced in the early phase of PD neuropathology. Targeting of BDNF/TrkB signalling by specific activators may attenuate PD neuropathology. Thus, this review aimed to discuss the potential role of BDNF/TrkB activators against PD. In conclusion, BDNF/TrkB signalling is decreased in PD and linked with disease severity and long‐term complications. Activation of BDNF/TrkB by specific activators may attenuate PD neuropathology.

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The link between metabolic syndrome and Alzheimer disease: A mutual relationship and long rigorous investigation

Cited by 15 publications

References 158 publications

Deciphering molecular bridges: Unveiling the interplay between metabolic syndrome and Alzheimer’s disease through a systems biology approach and drug repurposing

Deciphering molecular bridges: Unveiling the interplay between metabolic syndrome and Alzheimer’s disease through a systems biology approach and drug repurposing

Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice

BDNF/TrkB activators in Parkinson's disease: A new therapeutic strategy

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