bims-metalz 2023-01-15 papers

bims-metalz

Biomed News

on Metabolic causes of Alzheimer’s disease

Issue of 2023–01–15
nine papers selected by
Mikaila Chetty, Goa University

Alzheimer's Disease is a Multi-Organ Disorder: It May Already Be Preventable.
The role of dietary antioxidants in type 2 diabetes and neurodegenerative disorders: An assessment of the benefit profile.
Molecular Investigations of Protein Aggregation in the Pathogenesis of Amyotrophic Lateral Sclerosis.
The interactions of amyloid β aggregates with phospholipid membranes and the implications for neurodegeneration.
Type 2 Diabetes Mellitus, Platelet Activation and Alzheimer's Disease: A Possible Connection.
Mitochondrial dysfunction in cognitive neurodevelopmental disorders: Cause or effect?
Distinct Effects of Beta-Amyloid, Its Isomerized and Phosphorylated Forms on the Redox Status and Mitochondrial Functioning of the Blood-Brain Barrier Endothelium.
Exposure of combination of environmental pollutant, lead (Pb) and β-amyloid peptides causes mitochondrial dysfunction and oxidative stress in human neuronal cells.
Methods for analyzing the coordination and aggregation of metal-amyloid-β.

J Alzheimers Dis. 2023 Jan 03.

Alzheimer's Disease is a Multi-Organ Disorder: It May Already Be Preventable.

Arnold R Eiser, Tamas Fulop.

  In this commentary, we offer an overview of the several environmental and metabolic factors that have been identified as contributing to the development of Alzheimer's disease (AD). Many of these factors involve extracranial organ systems including immune system dysfunction accompanied by neuroinflammation (inflammaging), gastrointestinal dysbiosis, insulin resistance, and hepatic dysfunction. A variety of microbial factors including mouth flora, viruses, and fungi appear to play a significant role. There is a role for the colonic microbiome becoming dysbiotic and producing toxic metabolites. Declining hepatic function contributes diminished neuronal precursors and reduces toxin elimination. Environmental toxins especially metals play an important role in impairing the blood-brain barrier and acting synergistically with biotoxins and other toxic chemicals. Prevention and treatment of AD appears to require measuring several of these biomarkers and implementing corrective actions regarding such toxicants and correcting metabolic dysfunction at early or preclinical stages of this disorder.

Keywords:  Alzheimer’s disease; biotoxins; dementia; dysbiosis; environmental exposure; metabolism; neuroinflammation

DOI:  https://doi.org/10.3233/JAD-221078
Heliyon. 2023 Jan;9(1): e12698

The role of dietary antioxidants in type 2 diabetes and neurodegenerative disorders: An assessment of the benefit profile.

Munazza Tamkeen Fatima, Ajaz Ahmed Bhat, Sabah Nisar, Khalid Adnan Fakhro, Ammira Sarah Al-Shabeeb Akil.

  Healthy diet is vital to cellular health. The human body succumbs to numerous diseases which afflict severe economic and psychological burdens on the patient and family. Oxidative stress is a possible crucial regulator of various pathologies, including type 2 diabetes and neurodegenerative diseases. It generates reactive oxygen species (ROS) that trigger the dysregulation of essential cellular functions, ultimately affecting cellular health and homeostasis. However, lower levels of ROS can be advantageous and are implicated in a variety of signaling pathways. Due to this dichotomy, the terms oxidative "eustress," which refers to a good oxidative event, and "distress," which can be hazardous, have developed. ROS affects multiple signaling pathways, leading to compromised insulin secretion, insulin resistance, and β-cell dysfunction in diabetes. ROS is also associated with increased mitochondrial dysfunction and neuroinflammation, aggravating neurodegenerative conditions in the body, particularly with age. Treatment includes drugs/therapies often associated with dependence, side effects including non-selectivity, and possible toxicity, particularly in the long run. It is imperative to explore alternative medicines as an adjunct therapy, utilizing natural remedies/resources to avoid all the possible harms. Antioxidants are vital components of our body that fight disease by reducing oxidative stress or nullifying the excess toxic free radicals produced under various pathological conditions. In this review, we focus on the antioxidant effects of components of dietary foods such as tea, coffee, wine, oils, and honey and the role and mechanism of action of these antioxidants in alleviating type 2 diabetes and neurodegenerative disorders. We aim to provide information about possible alternatives to drug treatments used alone or combined to reduce drug intake and encourage the consumption of natural ingredients at doses adequate to promote health and combat pathologies while reducing unwanted risks and side effects.

Keywords:  Antioxidants; Diet; Neurodegenerative diseases; Reactive oxygen species; Therapeutics; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.heliyon.2022.e12698
Int J Mol Sci. 2022 Dec 31. pii: 704. [Epub ahead of print]24(1):

Molecular Investigations of Protein Aggregation in the Pathogenesis of Amyotrophic Lateral Sclerosis.

Elisa Duranti, Chiara Villa.

  Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by selective loss of lower and upper motor neurons (MNs) in the brain and spinal cord, resulting in paralysis and eventually death due to respiratory insufficiency. Although the fundamental physiological mechanisms underlying ALS are not completely understood, the key neuropathological hallmarks of ALS pathology are the aggregation and accumulation of ubiquitinated protein inclusions within the cytoplasm of degenerating MNs. Herein, we discuss recent insights into the molecular mechanisms that lead to the accumulation of protein aggregates in ALS. This will contribute to a better understanding of the pathophysiology of the disease and may open novel avenues for the development of therapeutic strategies.

Keywords:  aggregation; amyotrophic lateral sclerosis; neurodegenerative diseases

DOI:  https://doi.org/10.3390/ijms24010704
Biochem Soc Trans. 2023 Jan 11. pii: BST20220434. [Epub ahead of print]

The interactions of amyloid β aggregates with phospholipid membranes and the implications for neurodegeneration.

Rima Budvytyte, Gintaras Valincius.

  Misfolding, aggregation and accumulation of Amyloid-β peptides (Aβ) in neuronal tissue and extracellular matrix are hallmark features of Alzheimer's disease (AD) pathology. Soluble Aβ oligomers are involved in neuronal toxicity by interacting with the lipid membrane, compromising its integrity, and affecting the function of receptors. These facts indicate that the interaction between Aβ oligomers and cell membranes may be one of the central molecular level factors responsible for the onset of neurodegeneration. The present review provides a structural understanding of Aβ neurotoxicity via membrane interactions and contributes to understanding early events in Alzheimer's disease.

Keywords:  Alzheimer's disease; amyloid β-membrane interaction; amyloid-β peptide; neurodegeneration; pore formation

DOI:  https://doi.org/10.1042/BST20220434
Clin Neuropsychiatry. 2022 Dec;19(6): 370-378

Type 2 Diabetes Mellitus, Platelet Activation and Alzheimer's Disease: A Possible Connection.

Manuel Glauco Carbone, Nunzio Pomara, Camilla Callegari, Donatella Marazziti, Bruno Pietro Imbimbo.

  Type 2 diabetes mellitus DM (T2DM) is associated with a 70% increased risk for dementia, including Alzheimer's disease (AD). Insulin resistance has been proposed to play a pivotal role in both T2DM and AD and the concept of "brain insulin resistance" has been suggested as an interpretation to the growing literature regarding cognitive impairment and T2DM. Subjects with T2DM present an abnormal platelet reactivity that together with insulin resistance, hyperglycaemia and dyslipidaemia effect the vascular wall by a series of events including endothelial dysfunction, oxidative stress and low-grade inflammation. Activated platelets directly contribute to cerebral amyloid angiopathy (CAA) by promoting the formation of β-amyloid (Aβ) aggregates and that Aβ, in turn, activates platelets, creating a feed-forward loop suggesting the involvement of platelets in the AD pathogenesis. Moreover, islet amyloid polypeptide deposition, co-localized with Aβ deposits, is a common finding in the brain of patients with T2DM. These observations raise the intriguing prospect that traditional or novel antiplatelet therapeutic strategies may alleviate fibril formation and could be used in the prevention or treatment of AD subjects with diabetes.

Keywords:  Alzheimer’s disease; neuroinflammation; perivascular inflammation; platelet activation; type 2 diabetes mellitus; β-amyloid

DOI:  https://doi.org/10.36131/cnfioritieditore20220604
Mitochondrion. 2023 Jan 05. pii: S1567-7249(23)00002-8. [Epub ahead of print]

Mitochondrial dysfunction in cognitive neurodevelopmental disorders: Cause or effect?

Ayyappan Anitha, Ismail Thanseem, Mary Iype, Sanjeev V Thomas.

  Mitochondria have a crucial role in brain development and neurogenesis, both in embryonic and adult brains. Since the brain is the highest energy consuming organ, it is highly vulnerable to mitochondrial dysfunction. This has been implicated in a range of brain disorders including, neurodevelopmental conditions, psychiatric illnesses, and neurodegenerative diseases. Genetic variations in mitochondrial DNA (mtDNA), and nuclear DNA encoding mitochondrial proteins, have been associated with several cognitive disorders. However, it is not yet clear whether mitochondrial dysfunction is a primary cause of these conditions or a secondary effect. Our review article deals with this topic, and brings out recent advances in mitochondria-oriented therapies. Mitochondrial dysfunction could be involved in the pathogenesis of a subset of disorders involving cognitive impairment. In these patients, mitochondrial dysfunction could be the cause of the condition, rather than the consequence. There are vast areas in this topic that remains to be explored and elucidated.

Keywords:  Antioxidant therapy; Brain energetics; Cause or effect; Cognitive disorders; Cybrid; Mitochondria

DOI:  https://doi.org/10.1016/j.mito.2023.01.002
Int J Mol Sci. 2022 Dec 22. pii: 183. [Epub ahead of print]24(1):

Distinct Effects of Beta-Amyloid, Its Isomerized and Phosphorylated Forms on the Redox Status and Mitochondrial Functioning of the Blood-Brain Barrier Endothelium.

Aleksandra V Petrovskaya, Artem M Tverskoi, Evgeny P Barykin, Kseniya B Varshavskaya, Alexandra A Dalina, Vladimir A Mitkevich, Alexander A Makarov, Irina Yu Petrushanko.

  The Alzheimer's disease (AD)-associated breakdown of the blood-brain barrier (BBB) promotes the accumulation of beta-amyloid peptide (Aβ) in the brain as the BBB cells provide Aβ transport from the brain parenchyma to the blood, and vice versa. The breakdown of the BBB during AD may be caused by the emergence of blood-borne Aβ pathogenic forms, such as structurally and chemically modified Aβ species; their effect on the BBB cells has not yet been studied. Here, we report that the effects of Aβ42, Aβ42, containing isomerized Asp7 residue (iso-Aβ42) or phosphorylated Ser8 residue (p-Aβ42) on the mitochondrial potential and respiration are closely related to the redox status changes in the mouse brain endothelial cells bEnd.3. Aβ42 and iso-Aβ42 cause a significant increase in nitric oxide, reactive oxygen species, glutathione, cytosolic calcium and the mitochondrial potential after 4 h of incubation. P-Aβ42 either does not affect or its effect develops after 24 h of incubation. Aβ42 and iso-Aβ42 activate mitochondrial respiration compared to p-Aβ42. The isomerized form promotes a greater cytotoxicity and mitochondrial dysfunction, causing maximum oxidative stress. Thus, Aβ42, p-Aβ42 and iso-Aβ42 isoforms differently affect the BBBs' cell redox parameters, significantly modulating the functioning of the mitochondria. The changes in the level of modified Aβ forms can contribute to the BBBs' breakdown during AD.

Keywords:  bEnd.3; beta-amyloid modifications; blood–brain barrier; mitochondrial function; redox parameters

DOI:  https://doi.org/10.3390/ijms24010183
J Bioenerg Biomembr. 2023 Jan 13.

Exposure of combination of environmental pollutant, lead (Pb) and β-amyloid peptides causes mitochondrial dysfunction and oxidative stress in human neuronal cells.

Lakshmi Jaya Madhuri Bandaru, Lokesh Murumulla, Bindu Lasya C, Krishna Prasad D, Suresh Challa.

  Exposure to the environmental pollutant lead (Pb) has been linked to Alzheimer's disease (AD), in which mitochondrial dysfunction is a pathological consequence of neuronal degeneration. The toxicity of Pb in combination with β-amyloid peptides (1-40) and (25-35) causes selective death in neuronal cells. However, the precise mechanism through which Pb induces Alzheimer's disease, particularly mitochondrial damage, is unknown. Changes in mitochondrial mass, membrane potential, mitochondrial complex activities, mitochondrial DNA and oxidative stress were examined in neuronal cells of human origin exposed to Pb and β-amyloid peptides (1-40) and (25-35) individually and in different combinations. The results showed depolarization of mitochondrial membrane potential, decrease in mitochondrial mass, ATP levels and mtDNA copy number in Pb and β-amyloid peptides (1-40) and (25-35) exposed cells. Also, significant reductions in the expression of mitochondrial electron transport chain (ETC) complex proteins (ATP5A, COXIV, UQCRC2, SDHB, NDUFS3), as well as down regulation of ETC complex gene expressions such as COXIV, ATP5F1 and NDUFS3 and antioxidant gene expressions like MnSOD and Gpx4 were observed in exposed cells. Furthermore, Pb and β-amyloid peptides exposure resulted in elevated mitochondrial malondialdehyde levels and a decrease in mitochondrial GSH levels. Our findings suggest that Pb toxicity could be one of the causative factors for the mitochondrial dysfunction and oxidative stress in Alzheimer's disease progression.

Keywords:  Electron transport chain (ETC); Lead toxicity; Mitochondrial dysfunction; Oxidative stress; β-Amyloid peptide

DOI:  https://doi.org/10.1007/s10863-023-09956-9
Metallomics. 2023 Jan 06. pii: mfac102. [Epub ahead of print]

Methods for analyzing the coordination and aggregation of metal-amyloid-β.

Seongmin Park, Chanju Na, Jiyeon Han, Mi Hee Lim.

  The misfolding and aggregation of amyloid-β (Aβ) peptides are a histopathological feature found in the brains of Alzheimer's disease (AD). To discover effective therapeutics for AD, numerous efforts have been made to control the aggregation of Aβ species and their interactions with other pathological factors, including metal ions. Metal ions, such as Cu(II) and Zn(II), can bind to Aβ peptides forming metal-bound Aβ (metal-Aβ) complexes and, subsequently, alter their aggregation pathways. In particular, redox-active metal ions bound to Aβ species can produce reactive oxygen species leading to oxidative stress. In this review, we briefly illustrate some experimental approaches for characterizing the coordination and aggregation properties of metal-Aβ complexes.

Keywords:  Aggregation; Alzheimer's disease; Amyloid-β; Binding affinity; Coordination mode; Metal ions

DOI:  https://doi.org/10.1093/mtomcs/mfac102