bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023‒04‒09
thirteen papers selected by
Mikaila Chetty
Goa University

  1. J Clin Orthop Trauma. 2023 Apr;39 102149
      Gut microbiome (GM) forms an integral part of homeostasis of an individual. Due to the recent development of metagenomics, the plausibility of sequencing GM and its therapeutic ability for various diseases has been explored. Dysbiosis or disequilibrium or pertubations of GM leads to disruption of intercommunication signaling among gut-bone axis, gut-bone-brain axis, and gut-disc axis resulting in the progression of various chronic diseases. The therapeutic interventions to restore the GM like prebiotics and probiotics, bacteriophage therapy, fecal microbiota transplantation, and physical biomodulation have been identified. This review throw the lime light on the effect of gut dysbiosis in musculoskeletal diseases.
    Keywords:  Gut microbiome; Osteoarthritis; Osteoporosis; Rheumatoid arthritis
  2. Physiol Rev. 2023 Apr 06.
      Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
    Keywords:  Apoptosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Mitophagy
  3. Aging Dis. 2023 Apr 01. 14(2): 309-318
      The pathogenesis of Alzheimer's disease (AD) is associated with the formation of cerebral amyloid plaques, the main components of which are the modified Aβ molecules as well as the metal ions. Aβ isomerized at Asp7 residue (isoD7-Aβ) is the most abundant isoform in amyloid plaques. We hypothesized that the pathogenic effect of isoD7-Aβ is due to the formation of zinc-dependent oligomers, and that this interaction can be disrupted by the rationally designed tetrapeptide (HAEE). Here, we utilized surface plasmon resonance, nuclear magnetic resonance, and molecular dynamics simulation to demonstrate Zn2+-dependent oligomerization of isoD7-Aβ and the formation of a stable isoD7-Aβ:Zn2+:HAEE complex incapable of forming oligomers. To demonstrate the physiological importance of zinc-dependent isoD7-Aβ oligomerization and the ability of HAEE to interfere with this process at the organismal level, we employed transgenic nematodes overexpressing human Aβ. We show that the presence of isoD7-Aβ in the medium triggers extensive amyloidosis that occurs in a Zn2+-dependent manner, enhances paralysis, and shortens the animals' lifespan. Exogenous HAEE completely reverses these pathological effects of isoD7-Aβ. We conclude that the synergistic action of isoD7-Aβ and Zn2+ promotes Aβ aggregation and that the selected small molecules capable of interrupting this process, such as HAEE, can potentially serve as anti-amyloid therapeutics.
    Keywords:  Alzheimer disease; Aβ-Peptides;; Caenorhabditis elegans; Isoaspartatic acid; Zinc
  4. Front Cell Neurosci. 2023 ;17 895017
      Introduction: Increasing evidence indicates that neurodegenerative diseases, including Alzheimer's disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis. Methods: Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed. Results: Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits. Discussion: Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.
    Keywords:  Alzheimer’s disease; T cells; electrophysiology; flow cytometry; macrophage; microbiome; neuroinflammation; soluble TNF
  5. Neuromolecular Med. 2023 Apr 07.
      Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia for which no effective medicine exists. Currently, the goal of therapy is only to slow down the inevitable progression of the disease and reduce some symptoms. AD causes the accumulation of proteins with the pathological structure of Aβ and tau and the induction of inflammation of nerves in the brain, which lead to the death of neurons. The activated microglial cells produce pro-inflammatory cytokines that induce a chronic inflammatory response and mediate synapse damage and the neuronal death. Neuroinflammation has been an often ignored aspect of ongoing AD research. There are more and more scientific papers taking into account the aspect of neuroinflammation in the pathogenesis of AD, although there are no unambiguous results regarding the impact of comorbidities or gender differences. This publication concerns a critical look at the role of inflammation in the progression of AD, based on the results of our own in vitro studies using model cell cultures and other researchers.
    Keywords:  Amyloid-β; Aβ oligomers; NSAIDs; Neuroinflammation
  6. Front Mol Biosci. 2023 ;10 1153839
      Aberrant self-assembly of an intrinsically disordered protein is a pathological hallmark of protein misfolding diseases, such as Alzheimer's and Parkinson's diseases (AD and PD, respectively). In AD, the 40-42 amino acid-long extracellular peptide, β-amyloid (Aβ), self-assembles into oligomers, which eventually aggregate into fibrils. A similar self-association of the 140 amino acid-long intracellular protein, α-synuclein (αS), is responsible for the onset of PD pathology. While Aβ and αS are primarily extracellular and intracellular polypeptides, respectively, there is evidence of their colocalization and pathological overlaps of AD and PD. This evidence has raised the likelihood of synergistic, toxic protein-protein interactions between Aβ and αS. This mini review summarizes the findings of studies on Aβ-αS interactions related to enhanced oligomerization via co-assembly, aiming to provide a better understanding of the complex biology behind AD and PD and common pathological mechanisms among the major neurodegenerative diseases.
    Keywords:  aggregation; alpha-synuclein; beta-amyloid; oligomer; protein-protein interaction
  7. Free Radic Biol Med. 2023 Apr 04. pii: S0891-5849(23)00370-2. [Epub ahead of print]
      Mild inhibition of mitochondrial function leads to longevity. Genetic disruption of mitochondrial respiratory components either by mutation or RNAi greatly extends the lifespan in yeast, worms, and drosophila. This has given rise to the idea that pharmacologically inhibiting mitochondrial function would be a workable strategy for postponing aging. Toward this end, we used a transgenic worm strain that expresses the firefly luciferase enzyme widely to evaluate compounds by tracking real-time ATP levels. We identified chrysin and apigenin, which reduced ATP production and increased the lifespan of worms. Mechanistically, we discovered that chrysin and apigenin transiently inhibit mitochondrial respiration and induce an early ROS, and the lifespan-extending effect is dependent on transient ROS formation. We also show that AAK-2/AMPK, DAF-16/FOXO, and SKN-1/NRF-2 are required for chrysin or apigenin-mediated lifespan extension. Temporary increases in ROS levels trigger an adaptive response in a mitohormetic way, thereby increasing oxidative stress capacity and cellular metabolic adaptation, finally leading to longevity. Thus, chrysin and apigenin represent a class of compounds isolated from natural products that delay senescence and improve age-related diseases by inhibiting mitochondrial function and shed new light on the function of additional plant-derived polyphenols in enhancing health and delaying aging. Collectively, this work provides an avenue for pharmacological inhibition of mitochondrial function and the mechanism underlining their lifespan-extending properties.
    Keywords:  Aging; Apigenin; C. elegans; Chrysin; Mitohormesis; ROS
  8. Nitric Oxide. 2023 Apr 03. pii: S1089-8603(23)00032-0. [Epub ahead of print]
      Nitric oxide (NO), an enzymatic product of nitric oxide synthase (NOS), has been associated with a variety of neurological diseases such as Alzheimer's disease (AD). NO has long been thought to contribute to neurotoxic insults caused by neuroinflammation in AD. This perception shifts as more attention is paid to the early stages before cognitive problems manifest. However, it has revealed a compensatory neuroprotective role for NO that protects synapses by increasing neuronal excitability. NO can positively affect neurons by inducing neuroplasticity, neuroprotection, and myelination, as well as having cytolytic activity to reduce inflammation. NO can also induce long-term potentiation (LTP), a process by which synaptic connections among neurons become more potent. Not to mention that such functions give rise to AD protection. Notably, it is unquestionably necessary to conduct more research to clarify NO pathways in neurodegenerative dementias because doing so could help us better understand their pathophysiology and develop more effective treatment options. All these findings bring us to the prevailing notion that NO can be used either as a therapeutic agent in patients afflicted with AD and other memory impairment disorders or as a contributor to the neurotoxic and aggressive factor in AD. In this review, after presenting a general background on AD and NO, various factors that have a pivotal role in both protecting and exacerbating AD and their correlation with NO will be elucidated. Following this, both the neuroprotective and neurotoxic effects of NO on neurons and glial cells among AD cases will be discussed in detail.
    Keywords:  Alzheimer's Disease; Memory; Neuron; Nitric oxide
  9. Ecotoxicol Environ Saf. 2023 Apr 05. pii: S0147-6513(23)00376-7. [Epub ahead of print]256 114872
      Manganese (Mn), as one of the environmental risk factors for Parkinson's disease (PD), has been widely studied. Though autophagy dysfunction and neuroinflammation mainly are responsible for the causative issue of Mn neurotoxicity, the molecular mechanism of parkinsonism caused by Mn has not been explored clearly. The results of in vivo and in vitro experiments showed that overexposure to Mn caused neuroinflammation impairment and autophagy dysfunction, accompanied by the increase of IL-1β, IL-6, and TNF-α mRNA expression, and nerve cell apoptosis, microglia cell activation, NF-κB activation, poor neurobehavior performance. This is due to Mn-induced the downregulation of SIRT1. Upregulation of SIRT1 in vivo and in vitro could alleviate Mn-induced autophagy dysfunction and neuroinflammation, yet these beneficial effects were abolished following 3-MA administration. Furthermore, we found that Mn interfered with the acetylation of FOXO3 by SIRT1 in BV2 cells, leading to a decrease in the nuclear translocation of FOXO3, and its binding of LC3B promoter and transcription activity. This could be antagonized by the upregulation of SIRT1. Finally, it is proved that SIRT1/FOXO3-LC3B autophagy signaling involves in Mn-induced neuroinflammation impairment.
    Keywords:  Autophagy; Forkhead box O3; Manganese; Neuroinflammation; Silent information regulator 1
  10. Pharmacol Rep. 2023 Apr 01.
      It is well known that amyloid precursor protein (APP), the enzyme β-secretase 1 (BACE1), cyclooxygenase 2 (COX-2), nicastrin (NCT), and hyperphosphorylated tau protein (p-tau) are closely related to the development of Alzheimer's disease (AD). In addition, recent evidence shows that neuroinflammation also contributes to the pathogenesis of AD. Although the mechanism is not clearly known, such inflammation could alter the activity of the aforementioned molecules. Therefore, the use of anti-inflammatory agents could slow the progression of the disease. Nimesulide, resveratrol, and citalopram are three anti-inflammatory agents that could contribute to a decrease in neuroinflammation and consequently to a decrease in the overexpression of APP, BACE1, COX-2, NCT, and p-Tau, as they possess anti-inflammatory effects that could regulate the expression of APP, BACE1, COX-2, NCT, and p-Tau of potent pro-inflammatory markers indirectly involved in the expression of APP, BACE1, NCT, COX-2, and p-Tau; therefore, their use could be beneficial as preventive treatment as well as in the early stages of AD.
    Keywords:  APP; Alzheimer’s disease; BACE1; COX-2; Inflammation; NCT; p-Tau
  11. JACS Au. 2023 Mar 27. 3(3): 657-681
      Beyond the well-explored proposition of protein aggregation or amyloidosis as the central event in amyloidogenic diseases like Alzheimer's Disease (AD), and Type 2 Diabetes Mellitus (T2Dm); there are alternative hypotheses, now becoming increasingly evident, which suggest that the small biomolecules like redox noninnocent metals (Fe, Cu, Zn, etc.) and cofactors (Heme) have a definite influence in the onset and extent of such degenerative maladies. Dyshomeostasis of these components remains as one of the common features in both AD and T2Dm etiology. Recent advances in this course reveal that the metal/cofactor-peptide interactions and covalent binding can alarmingly enhance and modify the toxic reactivities, oxidize vital biomolecules, significantly contribute to the oxidative stress leading to cell apoptosis, and may precede the amyloid fibrils formation by altering their native folds. This perspective highlights this aspect of amyloidogenic pathology which revolves around the impact of the metals and cofactors in the pathogenic courses of AD and T2Dm including the active site environments, altered reactivities, and the probable mechanisms involving some highly reactive intermediates as well. It also discusses some in vitro metal chelation or heme sequestration strategies which might serve as a possible remedy. These findings might open up a new paradigm in our conventional understanding of amyloidogenic diseases. Moreover, the interaction of the active sites with small molecules elucidates potential biochemical reactivities that can inspire designing of drug candidates for such pathologies.
  12. EMBO J. 2023 Apr 06. e114141
      The mitochondrial F1 Fo -ATP synthase uses a rotary mechanism to synthesise ATP. This mechanism can, however, also operate in reverse, pumping protons at the expense of ATP, with significant potential implications for mitochondrial and age-related diseases. In a recent study, Acin-Perez et al (2023) use an elegant assay to screen compounds for the capacity to selectively inhibit ATP hydrolysis without affecting ATP synthesis. They show that (+)-epicatechin is one such compound and has significant benefits for cell and tissue function in disease models. These findings signpost a novel therapeutic approach for mitochondrial disease.
  13. ACS Chem Neurosci. 2023 Apr 04.
      The overproduction and deposition of the amyloid-β (Aβ) aggregates are accountable for the genesis and development of the neurologic disorder Alzheimer's disease (AD). Effective medications and detection agents for AD are still deficient. General challenges for the diagnosis of Aβ aggregates in the AD brain are (i) crossing the blood-brain barrier (BBB) and (ii) selectivity to Aβ species with (iii) emission maxima in the 500-750 nm region. Thioflavin-T (ThT) is the most used fluorescent probe for imaging Aβ fibril aggregates. However, because of the poor BBB crossing (log P = -0.14) and short emission wavelength (482 nm) after binding with Aβ fibrils, ThT can be limited to in vitro use only. Herein, we have developed Aβ deposit-recognizing fluorescent probes (ARs) with a D-π-A architecture and a longer emission wavelength after binding with Aβ species. Among the newly designed probes, AR-14 showed an admirable fluorescence emission (>600 nm) change after binding with soluble Aβ oligomers (2.3-fold) and insoluble Aβ fibril aggregates (4.5-fold) with high affinities Kd = 24.25 ± 4.10 nM; Ka = (4.123 ± 0.69) × 107 M-1 for fibrils; Kd = 32.58 ± 4.89 nM; and Ka = (3.069 ± 0.46) × 107 M-1 for oligomers with high quantum yield, molecular weight of <500 Da, reasonable log P = 1.77, stability in serum, and nontoxicity, and it can cross the BBB efficiently. The binding affinity of AR-14 toward Aβ species is proved by fluorescence binding studies and fluorescent staining of 18-month-old triple-transgenic (3xTg) mouse brain sections. In summary, the fluorescent probe AR-14 is efficient and has an admirable quality for the detection of soluble and insoluble Aβ deposits in vitro and in vivo.
    Keywords:  Alzheimer’s disease; amyloid inhibitor; amyloid-β deposits; fluorescent probe