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27 pages, 13104 KiB

Open AccessArticle

Mulberry Leaf Compounds and Gut Microbiota in Alzheimer’s Disease and Diabetes: A Study Using Network Pharmacology, Molecular Dynamics Simulation, and Cellular Assays

by Xue Bai, Xinyi Zhao, Kaifeng Liu, Xiaotang Yang, Qizheng He, Yilin Gao, Wannan Li and Weiwei Han

Int. J. Mol. Sci. 2024, 25(7), 4062; https://doi.org/10.3390/ijms25074062 - 5 Apr 2024

Viewed by 821

Abstract

Recently, studies have reported a correlation that individuals with diabetes show an increased risk of developing Alzheimer’s disease (AD). Mulberry leaves, serving as both a traditional medicinal herb and a food source, exhibit significant hypoglycemic and antioxidative properties. The flavonoid compounds in mulberry [...] Read more.

Recently, studies have reported a correlation that individuals with diabetes show an increased risk of developing Alzheimer’s disease (AD). Mulberry leaves, serving as both a traditional medicinal herb and a food source, exhibit significant hypoglycemic and antioxidative properties. The flavonoid compounds in mulberry leaf offer therapeutic effects for relieving diabetic symptoms and providing neuroprotection. However, the mechanisms of this effect have not been fully elucidated. This investigation aimed to investigate the combined effects of specific mulberry leaf flavonoids (kaempferol, quercetin, rhamnocitrin, tetramethoxyluteolin, and norartocarpetin) on both type 2 diabetes mellitus (T2DM) and AD. Additionally, the role of the gut microbiota in these two diseases’ treatment was studied. Using network pharmacology, we investigated the potential mechanisms of flavonoids in mulberry leaves, combined with gut microbiota, in combating AD and T2DM. In addition, we identified protein tyrosine phosphatase 1B (PTP1B) as a key target for kaempferol in these two diseases. Molecular docking and molecular dynamics simulations showed that kaempferol has the potential to inhibit PTP1B for indirect treatment of AD, which was proven by measuring the IC₅₀ of kaempferol (279.23 μM). The cell experiment also confirmed the dose-dependent effect of kaempferol on the phosphorylation of total cellular protein in HepG2 cells. This research supports the concept of food–medicine homology and broadens the range of medical treatments for diabetes and AD, highlighting the prospect of integrating traditional herbal remedies with modern medical research. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease 2.0)

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18 pages, 4230 KiB

Open AccessArticle

Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders

by Jaunetta Hill, Karim E. Shalaby, Syed W. Bihaqi, Bothaina H. Alansi, Benjamin Barlock, Keykavous Parang, Richard Thompson, Khalid Ouararhni and Nasser H. Zawia

Int. J. Mol. Sci. 2023, 24(20), 15216; https://doi.org/10.3390/ijms242015216 - 16 Oct 2023

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Abstract

The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they [...] Read more.

The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs that interfere with sequence-specific DNA binding at transcription start sites and predominantly modulate the expression of SP1 target genes. More importantly, the proteome of treated cells displayed ~75% of the downregulated products as SP1 targets. Specific levels of SP1-driven genes and AD biomarkers such as amyloid precursor protein (APP) and Tau proteins were also decreased as part of this targeted systemic response. These small molecules, therefore, offer a viable alternative to achieving desired therapeutic outcomes by interfering with both amyloid and Tau pathways with limited off-target systemic changes. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease 2.0)

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13 pages, 2941 KiB

Open AccessArticle

Evaluation of the Polygenic Risk Score for Alzheimer’s Disease in Russian Patients with Dementia Using a Low-Density Hydrogel Oligonucleotide Microarray

by Anna Ikonnikova, Anna Morozova, Olga Antonova, Alexandra Ochneva, Elena Fedoseeva, Olga Abramova, Marina Emelyanova, Marina Filippova, Irina Morozova, Yana Zorkina, Timur Syunyakov, Alisa Andryushchenko, Denis Andreuyk, Georgy Kostyuk and Dmitry Gryadunov

Int. J. Mol. Sci. 2023, 24(19), 14765; https://doi.org/10.3390/ijms241914765 - 29 Sep 2023

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Abstract

The polygenic risk score (PRS), together with the ɛ4 allele of the APOE gene (APOE-ɛ4), has shown high potential for Alzheimer’s disease (AD) risk prediction. The aim of this study was to validate the model of polygenic risk in Russian patients [...] Read more.

The polygenic risk score (PRS), together with the ɛ4 allele of the APOE gene (APOE-ɛ4), has shown high potential for Alzheimer’s disease (AD) risk prediction. The aim of this study was to validate the model of polygenic risk in Russian patients with dementia. A microarray-based assay was developed to identify 21 markers of polygenic risk and ɛ alleles of the APOE gene. This case–control study included 348 dementia patients and 519 cognitively normal volunteers. Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau protein levels were assessed in 57 dementia patients. PRS and APOE-ɛ4 were significant genetic risk factors for dementia. Adjusted for APOE-ɛ4, individuals with PRS corresponding to the fourth quartile had an increased risk of dementia compared to the first quartile (OR 1.85; p-value 0.002). The area under the curve (AUC) was 0.559 for the PRS model only, and the inclusion of APOE-ɛ4 improved the AUC to 0.604. PRS was positively correlated with tTau and pTau181 and inversely correlated with Aβ42/Aβ40 ratio. Carriers of APOE-ɛ4 had higher levels of tTau and pTau181 and lower levels of Aβ42 and Aβ42/Aβ40. The developed assay can be part of a strategy for assessing individuals for AD risk, with the purpose of assisting primary preventive interventions. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease 2.0)

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13 pages, 732 KiB

Open AccessCommunication

In Silico Analysis Reveals the Modulation of Ion Transmembrane Transporters in the Cerebellum of Alzheimer’s Disease Patients

by Simone D’Angiolini, Maria Sofia Basile, Emanuela Mazzon and Agnese Gugliandolo

Int. J. Mol. Sci. 2023, 24(18), 13924; https://doi.org/10.3390/ijms241813924 - 10 Sep 2023

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. AD hallmarks are extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain. It is interesting to notice that Aβ plaques appear in the cerebellum only in late stages of the disease, [...] Read more.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. AD hallmarks are extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain. It is interesting to notice that Aβ plaques appear in the cerebellum only in late stages of the disease, and then it was hypothesized that it can be resistant to specific neurodegenerative mechanisms. However, the role of cerebellum in AD pathogenesis is not clear yet. In this study, we performed an in silico analysis to evaluate the transcriptional profile of cerebellum in AD patients and non-AD subjects in order to deepen the knowledge on its role in AD. The analysis evidenced that only the molecular function (MF) “active ion transmembrane transporter activity” was overrepresented. Regarding the 21 differentially expressed genes included in this MF, some of them may be involved in the ion dyshomeostasis reported in AD, while others assumed, in the cerebellum, an opposite regulation compared to those reported in other brain regions in AD patients. They might be associated to a protective phenotype, that may explain the initial resistance of cerebellum to neurodegeneration in AD. Of note, this MF was not overrepresented in prefrontal cortex and visual cortex indicating that it is a peculiarity of the cerebellum. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease 2.0)

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18 pages, 4061 KiB

Open AccessArticle

A Novel Bioactive Peptide, T14, Selectively Activates mTORC1 Signalling: Therapeutic Implications for Neurodegeneration and Other Rapamycin-Sensitive Applications

by Sanskar Ranglani, Anna Ashton, Kashif Mahfooz, Joanna Komorowska, Alexandru Graur, Nadine Kabbani, Sara Garcia-Rates and Susan Greenfield

Int. J. Mol. Sci. 2023, 24(12), 9961; https://doi.org/10.3390/ijms24129961 - 9 Jun 2023

Cited by 2 | Viewed by 1704

Abstract

T14 modulates calcium influx via the α-7 nicotinic acetylcholine receptor to regulate cell growth. Inappropriate triggering of this process has been implicated in Alzheimer’s disease (AD) and cancer, whereas T14 blockade has proven therapeutic potential in in vitro, ex vivo and in vivo [...] Read more.

T14 modulates calcium influx via the α-7 nicotinic acetylcholine receptor to regulate cell growth. Inappropriate triggering of this process has been implicated in Alzheimer’s disease (AD) and cancer, whereas T14 blockade has proven therapeutic potential in in vitro, ex vivo and in vivo models of these pathologies. Mammalian target of rapamycin complex 1 (mTORC1) is critical for growth, however its hyperactivation is implicated in AD and cancer. T14 is a product of the longer 30mer-T30. Recent work shows that T30 drives neurite growth in the human SH-SY5Y cell line via the mTOR pathway. Here, we demonstrate that T30 induces an increase in mTORC1 in PC12 cells, and ex vivo rat brain slices containing substantia nigra, but not mTORC2. The increase in mTORC1 by T30 in PC12 cells is attenuated by its blocker, NBP14. Moreover, in post-mortem human midbrain, T14 levels correlate significantly with mTORC1. Silencing mTORC1 reverses the effects of T30 on PC12 cells measured via AChE release in undifferentiated PC12 cells, whilst silencing mTORC2 does not. This suggests that T14 acts selectively via mTORC1. T14 blockade offers a preferable alternative to currently available blockers of mTOR as it would enable selective blockade of mTORC1, thereby reducing side effects associated with generalised mTOR blockade. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease 2.0)

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13 pages, 2782 KiB

Open AccessArticle

Heat Treatment Enhances the Neuroprotective Effects of Crude Ginseng Saponin by Increasing Minor Ginsenosides

by Yun-Jeong Ji, Hyung Don Kim, Eun Suk Lee, Gwi Yeong Jang and Hyun-A Seong

Int. J. Mol. Sci. 2023, 24(8), 7223; https://doi.org/10.3390/ijms24087223 - 13 Apr 2023

Cited by 3 | Viewed by 1603

Abstract

Ginsenoside is the primary active substance of ginseng and has many pharmacological effects, such as anti-cancer, immune, regulating sugar and lipid metabolism, and antioxidant effects. It also protects the nervous and cardiovascular systems. This study analyzes the effects of thermal processing on the [...] Read more.

Ginsenoside is the primary active substance of ginseng and has many pharmacological effects, such as anti-cancer, immune, regulating sugar and lipid metabolism, and antioxidant effects. It also protects the nervous and cardiovascular systems. This study analyzes the effects of thermal processing on the bioactivities of crude ginseng saponin. Heat treatment increased the contents of minor ginsenosides in crude saponins, such as Rg3, and heat-treated crude ginseng saponin (HGS) had better neuroprotective effects than non-treated crude saponin (NGS). HGS reduced glutamate-induced apoptosis and reactive oxygen species generation in pheochromocytoma 12 (PC12) cells, significantly more than NGS. HGS protected PC12 cells against glutamate-induced oxidative stress by upregulating Nrf2-mediated antioxidant signaling and downregulating MAPK-mediated apoptotic signaling. HGS has the potential for the prevention and treatment of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease 2.0)

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Review

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22 pages, 10476 KiB

Open AccessReview

Multi-Target-Directed Cinnamic Acid Hybrids Targeting Alzheimer’s Disease

by Aliki Drakontaeidi and Eleni Pontiki

Int. J. Mol. Sci. 2024, 25(1), 582; https://doi.org/10.3390/ijms25010582 - 1 Jan 2024

Cited by 3 | Viewed by 1295

Abstract

Progressive cognitive decline in Alzheimer’s disease (AD) is a growing challenge. Present therapies are based on acetylcholinesterase inhibition providing only temporary relief. Promising alternatives include butyrylcholinesterase (BuChE) inhibitors, multi-target ligands (MTDLs) that address the multi-factorial nature of AD, and compounds that target oxidative [...] Read more.

Progressive cognitive decline in Alzheimer’s disease (AD) is a growing challenge. Present therapies are based on acetylcholinesterase inhibition providing only temporary relief. Promising alternatives include butyrylcholinesterase (BuChE) inhibitors, multi-target ligands (MTDLs) that address the multi-factorial nature of AD, and compounds that target oxidative stress and inflammation. Cinnamate derivatives, known for their neuroprotective properties, show potential when combined with established AD agents, demonstrating improved efficacy. They are being positioned as potential AD therapeutic leads due to their ability to inhibit Aβ accumulation and provide neuroprotection. This article highlights the remarkable potential of cinnamic acid as a basic structure that is easily adaptable and combinable to different active groups in the struggle against Alzheimer’s disease. Compounds with a methoxy substitution at the para-position of cinnamic acid display increased efficacy, whereas electron-withdrawing groups are generally more effective. The effect of the molecular volume is worthy of further investigation. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease 2.0)

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12 pages, 1111 KiB

Open AccessReview

Neurofilament-Light, a Promising Biomarker: Analytical, Metrological and Clinical Challenges

by Salomé Coppens, Sylvain Lehmann, Christopher Hopley and Christophe Hirtz

Int. J. Mol. Sci. 2023, 24(14), 11624; https://doi.org/10.3390/ijms241411624 - 19 Jul 2023

Cited by 11 | Viewed by 2211

Abstract

Neurofilament-light chain (Nf-L) is a non-specific early-stage biomarker widely studied in the context of neurodegenerative diseases (NDD) and traumatic brain injuries (TBI), which can be measured in biofluids after axonal damage. Originally measured by enzyme-linked immunosorbent assay (ELISA) in cerebrospinal fluid (CSF), Nf-L [...] Read more.

Neurofilament-light chain (Nf-L) is a non-specific early-stage biomarker widely studied in the context of neurodegenerative diseases (NDD) and traumatic brain injuries (TBI), which can be measured in biofluids after axonal damage. Originally measured by enzyme-linked immunosorbent assay (ELISA) in cerebrospinal fluid (CSF), Nf-L can now be quantified in blood with the emergence of ultrasensitive assays. However, to ensure successful clinical implementation, reliable clinical thresholds and reference measurement procedures (RMP) should be developed. This includes establishing and distributing certified reference materials (CRM). As a result of the complexity of Nf-L and the number of circulating forms, a clear definition of what is measured when immunoassays are used is also critical to achieving standardization to ensure the long-term success of those assays. The use of powerful tools such as mass spectrometry for developing RMP and defining the measurand is ongoing. Here, we summarize the current methods in use for quantification of Nf-L in biofluid showing potential for clinical implementation. The progress and challenges in developing RMP and defining the measurand for Nf-L standardization of diagnostic tests are addressed. Finally, we discuss the impact of pathophysiological factors on Nf-L levels and the establishment of a clinical cut-off. Full article

(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease 2.0)

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