bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023‒03‒05
eight papers selected by
Mikaila Chetty
Goa University

  1. Prog Brain Res. 2023 ;pii: S0079-6123(22)00189-3. [Epub ahead of print]275 165-215
      This chapter utilizes genomic concepts and evolutionary perspectives to further understand the possible links between typical brain aging and neurodegenerative diseases, focusing on the two most prevalent of these: Alzheimer's disease and Parkinson's disease. Aging is the major risk factor for these neurodegenerative diseases. Researching the evolutionary and molecular underpinnings of aging helps to reveal elements of the typical aging process that leave individuals more vulnerable to neurodegenerative pathologies. Very little is known about the prevalence and susceptibility of neurodegenerative diseases in nonhuman species, as only a few individuals have been observed with these neuropathologies. However, several studies have investigated the evolution of lifespan, which is closely connected with brain size in mammals, and insights can be drawn from these to enrich our understanding of neurodegeneration. This chapter explores the relationship between the typical aging process and the events in neurodegeneration. First, we examined how age-related processes can increase susceptibility to neurodegenerative diseases. Second, we assessed to what extent neurodegeneration is an accelerated form of aging. We found that while at the phenotypic level both neurodegenerative diseases and the typical aging process share some characteristics, at the molecular level they show some distinctions in their profiles, such as variation in genes and gene expression. Furthermore, neurodegeneration of the brain is associated with an earlier onset of cellular, molecular, and structural age-related changes. In conclusion, a more integrative view of the aging process, both from a molecular and an evolutionary perspective, may increase our understanding of neurodegenerative diseases.
    Keywords:  Aging; Alzheimer's disease; Brain mass; Dementia; Evolutionary biology; Genomics; Hominin fossils; Neurodegeneration; Neurodegenerative diseases; Parkinson's disease
  2. Gut Liver. 2023 Feb 27.
      A growing body of evidence has demonstrated an intricate association between inflammatory bowel disease (IBD) and neurodegenerative conditions, expanding beyond previous foci of comorbidities between IBD and mood disorders. These new discoveries stem from an improved understanding of the gut-microbiome-brain axis: specifically, the ability of the intestinal microbiota to modulate inflammation and regulate neuromodulatory compounds. Clinical retrospective studies incorporating large sample sizes and population-based cohorts have demonstrated and confirmed the relevance of IBD and chronic neurodegeneration in clinical medicine. In this review, we expound upon the current knowledge on the gut-microbiome-brain axis, highlighting several plausible mechanisms linking IBD with neurodegeneration. We also summarize the known associations between IBD with Parkinson disease, Alzheimer disease, vascular dementia and ischemic stroke, and multiple sclerosis in a clinical context. Finally, we discuss the implications of an improved understanding of the gut-microbiome-brain axis in preventing, diagnosing, and managing neurodegeneration among IBD and non-IBD patients.
    Keywords:  Dementia; Gut-brain axis; Inflammatory bowel diseases; Multiple sclerosis; Parkinson disease
  3. Front Neurosci. 2023 ;17 1106623
      The human brain is a dynamic multiplex of information, both neural (neurotransmitter-to-neuron, involving 1.5×1015 action potentials per minute) and immunological (cytokine-to-microglia, providing continuous immune surveillance via 1.5×1010 immunocompetent cells). This conceptualization highlights the opportunity of exploiting "information" not only in the mechanistic understanding of brain pathology, but also as a potential therapeutic modality. Arising from its parallel yet interconnected proteopathic-immunopathic pathogeneses, Alzheimer's disease (AD) enables an exploration of the mechanistic and therapeutic contributions of information as a physical process central to brain disease progression. This review first considers the definition of information and its relevance to neurobiology and thermodynamics. Then we focus on the roles of information in AD using its two classical hallmarks. We assess the pathological contributions of β-amyloid peptides to synaptic dysfunction and reconsider this as a source of noise that disrupts information transfer between presynaptic and postsynaptic neurons. Also, we treat the triggers that activate cytokine-microglial brain processes as information-rich three-dimensional patterns, including pathogen-associated molecular patterns and damage-associated molecular patterns. There are structural and functional similarities between neural and immunological information with both fundamentally contributing to brain anatomy and pathology in health and disease. Finally, the role of information as a therapeutic for AD is introduced, particularly cognitive reserve as a prophylactic protective factor and cognitive therapy as a therapeutic contributor to the comprehensive management of ongoing dementia.
    Keywords:  Alzheimer’s disease; amyloid-beta; cytokine; information theory; psychotherapy; synaptic transmission
  4. Hepatology. 2023 Mar 06.
      Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is hepatic encephalopathy, which is characterized by cognitive and ataxic symptoms, resulting from buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and pre-clinical studies for modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.
  5. Semin Cell Dev Biol. 2023 Feb 28. pii: S1084-9521(23)00038-1. [Epub ahead of print]
      Aging is accompanied by a progressive decline in mitochondrial function, which in turn contributes to a variety of age-related diseases. Counterintuitively, a growing number of studies have found that disruption of mitochondrial function often leads to increased lifespan. This seemingly contradictory observation has inspired extensive research into genetic pathways underlying the mitochondrial basis of aging, particularly within the model organism Caenorhabditis elegans. The complex and antagonistic roles of mitochondria in the aging process have altered the view of mitochondria, which not only serve as simple bioenergetic factories but also as signaling platforms for the maintenance of cellular homeostasis and organismal health. Here, we review the contributions of C. elegans to our understanding of mitochondrial function in the aging process over the past decades. In addition, we explore how these insights may promote future research of mitochondrial-targeted strategies in higher organisms to potentially slow aging and delay age-related disease progression.
    Keywords:  Aging; C. elegans; Longevity; Mitochondrial stress; Mitokine
  6. Front Aging Neurosci. 2022 ;14 1073905
      Dozens of single nucleotide polymorphisms (SNPs) related to Alzheimer's disease (AD) have been discovered by large scale genome-wide association studies (GWASs). However, only a small portion of the genetic component of AD can be explained by SNPs observed from GWAS. Structural variation (SV) can be a major contributor to the missing heritability of AD; while SV in AD remains largely unexplored as the accurate detection of SVs from the widely used array-based and short-read technology are still far from perfect. Here, we briefly summarized the strengths and weaknesses of available SV detection methods. We reviewed the current landscape of SV analysis in AD and SVs that have been found associated with AD. Particularly, the importance of currently less explored SVs, including insertions, inversions, short tandem repeats, and transposable elements in neurodegenerative diseases were highlighted.
    Keywords:  Alzheimer’s disease; copy number variations; next-generation sequencing; short-tandem repeats; structural variations; transposable elements
  7. Mol Pharmacol. 2023 Mar 03. pii: MOLPHARM-AR-2021-000468. [Epub ahead of print]
      Alzheimer's disease (AD) is a neurodegenerative disease that is accompanied by memory decline and cognitive dysfunction. Aggregated amyloid β formation and accumulation may be one of the underlying mechanisms of the pathophysiology of AD. Therefore, compounds that can inhibit amyloid β aggregation may be useful for treatment. Based on this hypothesis, we screened plant compounds used in Kampo medicine for chemical chaperone activity and identified that alkannin had this property. Further analysis indicated that alkannin could inhibit amyloid β aggregation. Importantly, we also found that alkannin inhibited amyloid β aggregation after aggregates had already formed. Through the analysis of circular dichroism spectra, alkannin was found to inhibit β-sheet structure formation, which is an aggregation-prone toxic structure. Furthermore, alkannin attenuated amyloid β-induced neuronal cell death in PC12 cells, ameliorated amyloid β aggregation in the AD model of Caenorhabditis elegans (C. elegans), and inhibited chemotaxis observed in AD C. elegans, suggesting that alkannin could potentially inhibit neurodegeneration in vivo Overall, these results suggest that alkannin may have novel pharmacological properties for inhibiting amyloid β aggregation and neuronal cell death in AD. Significance Statement Aggregated amyloid β formation and accumulation is one of the underlying mechanisms of the pathophysiology of Alzheimer's disease. We found that alkannin had chemical chaperone activity, which can inhibit β-sheet structure formation of amyloid β and its aggregation, neuronal cell death, and Alzheimer's disease phenotype in C. elegans. Overall, alkannin may have novel pharmacological properties for inhibiting amyloid β aggregation and neuronal cell death in Alzheimer's disease.
    Keywords:  Alzheimer's Disease; amyloid; chaperones
  8. Ecotoxicol Environ Saf. 2023 Feb 28. pii: S0147-6513(23)00209-9. [Epub ahead of print]253 114705
      Deoxynivalenol (DON), as a widespread Fusarium mycotoxin in cereals, food products, and animal feed, is detrimental to both human and animal health. The liver is not only the primary organ responsible for DON metabolism but also the principal organ affected by DON toxicity. Taurine is well known to display various physiological and pharmacological functions due to its antioxidant and anti-inflammatory properties. However, the information regarding taurine supplementation counteracting DON-induced liver injury in piglets is still unclear. In our work, twenty-four weaned piglets were subjected to four groups for a 24-day period, including the BD group (a basal diet), the DON group (3 mg/kg DON-contaminated diet), the DON+LT group (3 mg/kg DON-contaminated diet + 0.3% taurine), and the DON+HT group (3 mg/kg DON-contaminated diet + 0.6% taurine). Our findings indicated that taurine supplementation improved growth performance and alleviated DON-induced liver injury, as evidenced by the reduced pathological and serum biochemical changes (ALT, AST, ALP, and LDH), especially in the group with the 0.3% taurine. Taurine could counteract hepatic oxidative stress in piglets exposed to DON, as it reduced ROS, 8-OHdG, and MDA concentrations and improved the activity of antioxidant enzymes. Concurrently, taurine was observed to upregulate the expression of key factors involved in mitochondrial function and the Nrf2 signaling pathway. Furthermore, taurine treatment effectively attenuated DON-induced hepatocyte apoptosis, as verified through the decreased proportion of TUNEL-positive cells and regulation of the mitochondria-mediated apoptosis pathway. Finally, the administration of taurine was able to reduce liver inflammation due to DON, by inactivating the NF-κB signaling pathway and declining the production of pro-inflammatory cytokines. In summary, our results implied that taurine effectively improved DON-induced liver injury. The underlying mechanism should be that taurine restored mitochondrial normal function and antagonized oxidative stress, thereby reducing apoptosis and inflammatory responses in the liver of weaned piglets.
    Keywords:  Apoptosis; Deoxynivalenol; Inflammation; Liver injury; Oxidative stress; Taurine