bims-metalz 2023-04-02 papers

bims-metalz

Biomed News

on Metabolic causes of Alzheimer’s disease

Issue of 2023‒04‒02
nine papers selected by
Mikaila Chetty
Goa University

The Influence of the Gut Microbiota on Alzheimer's Disease: A Narrative Review.
Structural basis of bioenergetic protein complexes in Alzheimer's disease pathogenesis.
TNF-α-Mediated Endothelial Cell Apoptosis Is Rescued by Hydrogen Sulfide.
Dietary Protection against Cognitive Impairment, Neuroinflammation and Oxidative Stress in Alzheimer's Disease Animal Models of Lipopolysaccharide-Induced Inflammation.
AD-1 Small Molecule Improves Learning and Memory Function in Scopolamine-Induced Amnesic Mice Model through Regulation of CREB/BDNF and NF-κB/MAPK Signaling Pathway.
A Comprehensive NMR Analysis of Serum and Fecal Metabolites in Familial Dysautonomia Patients Reveals Significant Metabolic Perturbations.
Shared and disease-specific glial gene expression changes in neurodegenerative diseases.
JNK Activation in Alzheimer's Disease Is Driven by Amyloid β and Is Associated with Tau Pathology.
Alteration of the blood-brain barrier by COVID-19 and its implication in the permeation of drugs into the brain.

J Integr Neurosci. 2023 Feb 16. 22(2): 38

The Influence of the Gut Microbiota on Alzheimer's Disease: A Narrative Review.

Jun-Ting Yin, Xiao-Wei Xu, Chen-Yang Jin, Xiao-Ying Yuan, Xu-Gang Wang.

  Alzheimer's disease (AD) is a common neurodegenerative disease that tends to occur in the elderly. The main symptom is hypomnesia. More and more older people are suffering from this disease worldwide. By 2050, 152 million people worldwide are expected to have AD. It is thought that the aggregation of amyloid-beta peptides and hyper-phosphorylated tau tangles contribute to AD. The microbiota-gut-brain (MGB) axis appears as a new concept. The MGB axis is a collection of microbial molecules produced in the gastrointestinal tract that influence the physiological function of the brain. In this review, we discuss how the gut microbiota (GM) and its metabolites affect AD in different ways. Dysregulation of the GM has been shown to be involved in various mechanisms involved in memory and learning functions. We review the current literature on the role of the entero-brain axis in the pathogenesis of AD and its potential role as a future therapeutic target in the treatment and/or prevention of AD.

Keywords:  Alzheimer's disease; human gut microbiota; neurodegenerative disease; neuroinflammation; neurotransmitters

DOI:  https://doi.org/10.31083/j.jin2202038
Curr Opin Struct Biol. 2023 Mar 24. pii: S0959-440X(23)00047-7. [Epub ahead of print]80 102573

Structural basis of bioenergetic protein complexes in Alzheimer's disease pathogenesis.

Lindsay McGregor, Montserrat Soler-López.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure where the underlying causes remain elusive. Mitochondrial dysfunction has become a prime suspect in AD pathogenesis since bioenergetic deficits precede the pathology. With advancing structural biology techniques at synchrotrons and cryo-electron microscopes, it is becoming possible to determine the structures of key proteins suspected to contribute to the initiation and propagation of AD, and investigate their interactions. In this review, we provide an overview of the recent developments concerning the structural aspects of mitochondrial protein complexes and their assembly factors involved the production of energy, in pursuit of therapies to halt or even reverse this disease in the early stages when mitochondria are most sensitive to amyloid toxicity.

DOI: https://doi.org/10.1016/j.sbi.2023.102573
Antioxidants (Basel). 2023 Mar 16. pii: 734. [Epub ahead of print]12(3):

TNF-α-Mediated Endothelial Cell Apoptosis Is Rescued by Hydrogen Sulfide.

Lorena Diaz Sanchez, Lissette Sanchez-Aranguren, Keqing Wang, Corinne M Spickett, Helen R Griffiths, Irundika H K Dias.

  Endothelial dysfunction is implicated in the development and aggravation of cardiovascular complications. Among the endothelium-released vasoactive factors, hydrogen sulfide (H2S) has been investigated for its beneficial effects on the vasculature through anti-inflammatory and redox-modulating regulatory mechanisms. Reduced H2S bioavailability is reported in chronic diseases such as cardiovascular disease, diabetes, atherosclerosis and preeclampsia, suggesting the value of investigating mechanisms, by which H2S acts as a vasoprotective gasotransmitter. We explored whether the protective effects of H2S were linked to the mitochondrial health of endothelial cells and the mechanisms by which H2S rescues apoptosis. Here, we demonstrate that endothelial dysfunction induced by TNF-α increased endothelial oxidative stress and induced apoptosis via mitochondrial cytochrome c release and caspase activation over 24 h. TNF-α also affected mitochondrial morphology and altered the mitochondrial network. Post-treatment with the slow-releasing H2S donor, GYY4137, alleviated oxidising redox state, decreased pro-caspase 3 activity, and prevented endothelial apoptosis caused by TNF-α alone. In addition, exogenous GYY4137 enhanced S-sulfhydration of pro-caspase 3 and improved mitochondrial health in TNF-α exposed cells. These data provide new insights into molecular mechanisms for cytoprotective effects of H2S via the mitochondrial-driven pathway.

Keywords:  hydrogen sulfide; inflammation; mitochondrial function; oxidative stress; vascular dysfunction

DOI:  https://doi.org/10.3390/antiox12030734
Int J Mol Sci. 2023 Mar 21. pii: 5921. [Epub ahead of print]24(6):

Dietary Protection against Cognitive Impairment, Neuroinflammation and Oxidative Stress in Alzheimer's Disease Animal Models of Lipopolysaccharide-Induced Inflammation.

Davide Decandia, Francesca Gelfo, Eugenia Landolfo, Francesca Balsamo, Laura Petrosini, Debora Cutuli.

  Alzheimer's disease (AD) is a rapidly growing epidemic with a heavy social and economic burden. Evidence suggests that systemic inflammation, dysregulation of the immune response and the resulting neuroinflammation and neurodegeneration play a significant role in AD pathogenesis. Currently, given that there is no fully convincing cure for AD, the interest in lifestyle factors (such as diet), which potentially delay onset and reduce the severity of symptoms, is increasing. This review is aimed at summarizing the effects of dietary supplementation on cognitive decline, neuroinflammation and oxidative stress in AD-like animal models with a focus on neuroinflammation induced by lipopolysaccharide (LPS) injection, which mimics systemic inflammation in animals. The compounds reviewed include curcumin, krill oil, chicoric acid, plasmalogens, lycopene, tryptophan-related dipeptides, hesperetin and selenium peptides. Despite the heterogeneity of these compounds, there is a strong consensus on their counteracting action on LPS-induced cognitive deficits and neuroinflammatory responses in rodents by modulating cell-signaling processes, such as the NF-κB pathway. Overall, dietary interventions could represent an important resource to oppose AD due to their influence in neuroprotection and immune regulation.

Keywords:  Alzheimer’s disease; animal models; cognition; neurodegeneration; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.3390/ijms24065921
Antioxidants (Basel). 2023 Mar 05. pii: 648. [Epub ahead of print]12(3):

AD-1 Small Molecule Improves Learning and Memory Function in Scopolamine-Induced Amnesic Mice Model through Regulation of CREB/BDNF and NF-κB/MAPK Signaling Pathway.

Rengasamy Balakrishnan, Ju-Young Park, Duk-Yeon Cho, Jae-Yong Ahn, Dong-Sun Yoo, Sang-Ho Seol, Sung-Hwa Yoon, Dong-Kug Choi.

  Cognitive decline and memory impairment induced by oxidative brain damage are the critical pathological hallmarks of Alzheimer's disease (AD). Based on the potential neuroprotective effects of AD-1 small molecule, we here explored the possible underlying mechanisms of the protective effect of AD-1 small molecule against scopolamine-induced oxidative stress, neuroinflammation, and neuronal apoptosis. According to our findings, scopolamine administration resulted in increased AChE activity, MDA levels, and decreased antioxidant enzymes, as well as the downregulation of the antioxidant response proteins of Nrf2 and HO-1 expression; however, treatment with AD-1 small molecule mitigated the generation of oxidant factors while restoring the antioxidant enzymes status, in addition to improving antioxidant protein levels. Similarly, AD-1 small molecule significantly increased the protein expression of neuroprotective markers such as BDNF and CREB and promoted memory processes in scopolamine-induced mice. Western blot analysis showed that AD-1 small molecule reduced activated microglia and astrocytes via the attenuation of iba-1 and GFAP protein expression. We also found that scopolamine enhanced the phosphorylation of NF-κB/MAPK signaling and, conversely, that AD-1 small molecule significantly inhibited the phosphorylation of NF-κB/MAPK signaling in the brain regions of hippocampus and cortex. We further found that scopolamine promoted neuronal loss by inducing Bax and caspase-3 and reducing the levels of the antiapoptotic protein Bcl-2. In contrast, AD-1 small molecule significantly decreased the levels of apoptotic markers and increased neuronal survival. Furthermore, AD-1 small molecule ameliorated scopolamine-induced impairments in spatial learning behavior and memory formation. These findings revealed that AD-1 small molecule attenuated scopolamine-induced cognitive and memory dysfunction by ameliorating AChE activity, oxidative brain damage, neuroinflammation, and neuronal apoptosis.

Keywords:  AD−1 small molecule; apoptosis; memory impairment; neuroinflammation; oxidative stress; scopolamine

DOI:  https://doi.org/10.3390/antiox12030648
Metabolites. 2023 Mar 16. pii: 433. [Epub ahead of print]13(3):

A Comprehensive NMR Analysis of Serum and Fecal Metabolites in Familial Dysautonomia Patients Reveals Significant Metabolic Perturbations.

Stephanann M Costello, Alexandra M Cheney, Annie Waldum, Brian Tripet, Maria Cotrina-Vidal, Horacio Kaufmann, Lucy Norcliffe-Kaufmann, Frances Lefcort, Valérie Copié.

  Central metabolism has a profound impact on the clinical phenotypes and penetrance of neurological diseases such as Alzheimer's (AD) and Parkinson's (PD) diseases, Amyotrophic Lateral Sclerosis (ALS) and Autism Spectrum Disorder (ASD). In contrast to the multifactorial origin of these neurological diseases, neurodevelopmental impairment and neurodegeneration in Familial Dysautonomia (FD) results from a single point mutation in the ELP1 gene. FD patients represent a well-defined population who can help us better understand the cellular networks underlying neurodegeneration, and how disease traits are affected by metabolic dysfunction, which in turn may contribute to dysregulation of the gut-brain axis of FD. Here, 1H NMR spectroscopy was employed to characterize the serum and fecal metabolomes of FD patients, and to assess similarities and differences in the polar metabolite profiles between FD patients and healthy relative controls. Findings from this work revealed noteworthy metabolic alterations reflected in energy (ATP) production, mitochondrial function, amino acid and nucleotide catabolism, neurosignaling molecules, and gut-microbial metabolism. These results provide further evidence for a close interconnection between metabolism, neurodegeneration, and gut microbiome dysbiosis in FD, and create an opportunity to explore whether metabolic interventions targeting the gut-brain-metabolism axis of FD could be used to redress or slow down the progressive neurodegeneration observed in FD patients.

Keywords:  ELP1; NMR metabolomics; elongator protein subunit 1; familial dysautonomia; gut–brain–metabolism axis; human stool and serum polar metabolite profiles; metabolism; multivariate statistical analysis; neurodegenerative diseases; neurological disorders

DOI:  https://doi.org/10.3390/metabo13030433
Nat Aging. 2023 Mar;3(3): 246-247

Shared and disease-specific glial gene expression changes in neurodegenerative diseases.

Guoyan Zhao.

We found evolutionarily conserved astrocyte and microglia subpopulations shared across multiple brain regions. We reveal similarities and differences between Alzheimer's disease glia and Parkinson's disease glia, as well as regional variance linked to disease pathology and neurodegeneration.

DOI: https://doi.org/10.1038/s43587-023-00378-1
ACS Chem Neurosci. 2023 Mar 28.

JNK Activation in Alzheimer's Disease Is Driven by Amyloid β and Is Associated with Tau Pathology.

Maite Solas, Silvia Vela, Cristian Smerdou, Eva Martisova, Iván Martínez-Valbuena, María-Rosario Luquin, María J Ramírez.

  c-Jun N-terminal kinase 3 (JNK3) is suggested to play a key role in neurodegenerative disorders, especially in Alzheimer's disease (AD). However, it remains unclear whether JNK or amyloid β (Aβ) appears first in the disease onset. Postmortem brain tissues from four dementia subtypes of patients (frontotemporal dementia, Lewy body dementia, vascular dementia, and AD) were used to measure activated JNK (pJNK) and Aβ levels. pJNK expression is significantly increased in AD; however, similar pJNK expression was found in other dementias. Furthermore, there was a significant correlation, co-localization, and direct interaction between pJNK expression and Aβ levels in AD. Significant increased levels of pJNK were also found in Tg2576 mice, a model of AD. In this line, Aβ42 intracerebroventricular injection in wild-type mice was able to induce a significant elevation of pJNK levels. JNK3 overexpression, achieved by intrahippocampal injection of an adeno-associated viral vector expressing this protein, was enough to induce cognitive deficiencies and precipitate Tau aberrant misfolding in Tg2576 mice without accelerating amyloid pathology. JNK3 overexpression may therefore be triggered by increased Aβ. The latter, together with subsequent involvement of Tau pathology, may be underlying cognitive alterations in early stages of AD.

Keywords:  Tau; beta-amyloid; cognition; hippocampus; neuroinflammation

DOI:  https://doi.org/10.1021/acschemneuro.3c00093
Front Cell Neurosci. 2023 ;17 1125109

Alteration of the blood-brain barrier by COVID-19 and its implication in the permeation of drugs into the brain.

Héctor Hernández-Parra, Octavio Daniel Reyes-Hernández, Gabriela Figueroa-González, Manuel González-Del Carmen, Maykel González-Torres, Sheila I Peña-Corona, Benjamín Florán, Hernán Cortés, Gerardo Leyva-Gómez.

  Diverse neurological symptoms have been reported in patients with SARS-CoV-2 disease (COVID-19), including stroke, ataxia, meningitis, encephalitis, and cognitive impairment. These alterations can cause serious sequelae or death and are associated with the entry of SARS-CoV-2 into the Central Nervous System (CNS). This mini-review discusses the main proposed mechanisms by which SARS-CoV-2 interacts with the blood-brain barrier (BBB) and its involvement in the passage of drugs into the CNS. We performed a search in PubMed with the terms "COVID-19" or "SARS-CoV-2" and "blood-brain barrier injury" or "brain injury" from the year 2019 to 2022. We found proposed evidence that SARS-CoV-2 infects neurovascular cells and increases BBB permeability by increasing the expression of matrix metalloproteinase-9 that degrades type IV collagen in the basement membrane and through activating RhoA, which induces restructuring of the cytoskeleton and alters the integrity of the barrier. The breakdown of the BBB triggers a severe inflammatory response, causing the cytokine storm (release of IL-1β, IL-6, TNF-α, etc.) characteristic of the severe phase of COVID-19, which includes the recruitment of macrophages and lymphocytes and the activation of astrocytes and microglia. We conclude that the increased permeability of the BBB would allow the passage of drugs that would not reach the brain in a normal physiological state, thus enhancing certain drugs' beneficial or adverse effects. We hope this article will encourage research on the impact of drugs on patients with COVID-19 and recovered patients with sequelae, focusing mainly on possible dose adjustments and changes in pharmacokinetic parameters.

Keywords:  COVID-19; blood-brain barrier; central nervous system; drug permeation; immune response

DOI:  https://doi.org/10.3389/fncel.2023.1125109