bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023‒07‒30
eight papers selected by
Mikaila Chetty
Goa University

  1. Environ Res. 2023 Jul 23. pii: S0013-9351(23)01526-8. [Epub ahead of print]236(Pt 1): 116722
      The ageing population has been steadily increasing worldwide, leading to a higher risk of cognitive decline and dementia. Environmental toxicants, particularly metals, have been identified as modifiable risk factors for cognitive impairment. Continuous exposure to metals occurs mainly through dietary sources, with older adults being particularly vulnerable. However, imbalances in the gut microbiota, known as dysbiosis, have also been associated with dementia. A literature review was conducted to explore the potential role of metals in the development of cognitive decline and the most prevalent primary neurodegenerative dementias, as well as their interaction with the gut microbiota. High levels of iron (Fe) and copper (Cu) are associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD), while low selenium (Se) levels are linked to poor cognitive status. Parkinson's disease dementia (PDD) is associated with elevated levels of iron (Fe), manganese (Mn), and zinc (Zn), but the role of copper (Cu) remains unclear. The relationship between metals and Lewy body dementia (LBD) requires further investigation. High aluminium (Al) exposure is associated with frontotemporal dementia (FTD), and elevated selenium (Se) levels may be linked to its onset. Challenges in comparing studies arise from the heterogeneity of metal analysis matrices and analytical techniques, as well as the limitations of small study cohorts. More research is needed to understand the influence of metals on cognition through the gut microbiota (GMB) and its potential relevance in the development of these diseases.
    Keywords:  Ageing; Cognition; Dementia; Gut microbiota; Metals
  2. Ecotoxicol Environ Saf. 2023 Jul 22. pii: S0147-6513(23)00764-9. [Epub ahead of print]263 115260
      Exposure to lead (Pb) and manganese (Mn) during early life influences neurodevelopment and increases the risk of neurodegenerative disorders. However, the level of developmental neurotoxicity due to combined exposure to the two metals remains unclear. Although the microbiota plays an essential part in the development of the nervous system via the gut-brain axis, there is a paucity of information regarding the interactions between exposure to Pb and Mn, the destruction of the microbiome, and neurodevelopmental impacts. To fill in this knowledge gap, we investigated the developmental neurotoxicity and effects on the microbiota of Pb (0.05 mg·L-1) alone and in combination with Mn (0.3 mg·L-1) in zebrafish larvae. Our results revealed that combined exposure precipitated higher malformation rates and lower locomotor activity levels than exposure to either Pb or Mn alone. Additionally, when we separated the combined exposure group from the other groups by applying unsupervised principal coordinates analysis (PCoA) and linear discriminant analysis (LEfSe) of microflora sequencing results, we observed extensive alterations in microbial abundances under combined-exposure conditions. Functional prediction analysis showed that combined exposure contributed to altered amino acid and lipid metabolism, and also that combined exposure to Pb and Mn reflected the greatest number of differentially activated biological pathways compared to the other three groups. ATP-binding cassette G (ABCG) genes and genes related to serotonin signaling and metabolism were altered following combined Pb and Mn exposure and exhibited disparate trends vis-à-vis Pb or Mn exposure alone. According to the results, the combined exposure to Pb and Mn led to more severe effects on both zebrafish locomotor activity and gut microbial composition. We suggest that the microbiota contributes to the combined neurotoxicity by increasing ABCG5 and ABCG8 gene expression.
    Keywords:  Concurrent exposure; Lead; Locomotor; Manganese; Microbiota; Toxicity; Zebrafish
  3. Biomedicines. 2023 Jun 27. pii: 1846. [Epub ahead of print]11(7):
      In the last decade, the role of the microbiota-gut-brain axis has been gaining momentum in the context of many neurodegenerative and metabolic disorders, including Alzheimer's disease (AD) and diabetes, respectively. Notably, a balanced gut microbiota contributes to the epithelial intestinal barrier maintenance, modulates the host immune system, and releases neurotransmitters and/or neuroprotective short-chain fatty acids. However, dysbiosis may provoke immune dysregulation, impacting neuroinflammation through peripheral-central immune communication. Moreover, lipopolysaccharide or detrimental microbial end-products can cross the blood-brain barrier and induce or at least potentiate the neuropathological progression of AD. Thus, after repeated failure to find a cure for this dementia, a necessary paradigmatic shift towards considering AD as a systemic disorder has occurred. Here, we present an overview of the use of germ-free and/or transgenic animal models as valid tools to unravel the connection between dysbiosis, metabolic diseases, and AD, and to investigate novel therapeutical targets. Given the high impact of dietary habits, not only on the microbiota but also on other well-established AD risk factors such as diabetes or obesity, consistent changes of lifestyle along with microbiome-based therapies should be considered as complementary approaches.
    Keywords:  Alzheimer’s disease; amyloid; dysbiosis; fecal microbiota transplantation; metabolic diseases; microbiota; neuroinflammation; probiotics; tau; transgenic mouse models
  4. Molecules. 2023 Jul 17. pii: 5467. [Epub ahead of print]28(14):
      Metal ions are fundamental to guarantee the regular physiological activity of the human organism. Similarly, vitamins play a key role in many biological functions of the metabolism, among which are coenzymes, redox mediators, and antioxidants. Due to their importance in the human organism, both metals and vitamins have been extensively studied for their involvement in neurodegenerative diseases (NDs). However, the full potential of the interaction between vitamins and metal ions has not been fully explored by researchers yet, and further investigation on this topic is needed. The aim of this review is to provide an overview of the scientific literature on the implications of vitamins and selected metal ions in two of the most common neurodegenerative diseases, Alzheimer's and Parkinson's disease. Furthermore, vitamin-metal ion interactions are discussed in detail focusing on their bioinorganic chemistry, with the perspective of arousing more interest in this fascinating bioinorganic field.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; bioinorganic chemistry; copper; iron; metal dyshomeostasis; metal ions; neurodegeneration; vitamin-metal complexes; vitamins
  5. Biomedicines. 2023 Jul 03. pii: 1884. [Epub ahead of print]11(7):
      Alzheimer's disease (AD) is a chronic neurodegenerative disease, characterized by the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) formed from abnormally phosphorylated tau proteins (ptau). To date, there is no cure for AD. Earlier therapeutic efforts have focused on the clinical stages of AD. Despite paramount efforts and costs, pharmaceutical interventions including antibody therapies targeting Aβ have largely failed. This highlights the need to alternate treatment strategies and a shift of focus to early pre-clinical stages. Approximately 25-40% of AD cases can be attributed to environmental factors including chronic stress. Gut dysbiosis has been associated with stress and the pathogenesis of AD and can increase both Aβ and NFTs in animal models of the disease. Both stress and enrichment have been shown to alter AD progression and gut health. Targeting stress-induced gut dysbiosis through probiotic supplementation could provide a promising intervention to delay disease progression. In this review, we discuss the effects of stress, enrichment, and gut dysbiosis in AD models and the promising evidence from probiotic intervention studies.
    Keywords:  Alzheimer’s disease; chronic mild stress; enrichment; environmental factors; gut dysbiosis; gut microbiome; probiotics; stress
  6. Front Neurosci. 2023 ;17 1219299
      Propagation of tau fibrils correlate closely with neurodegeneration and memory deficits seen during the progression of Alzheimer's disease (AD). Although it is not well-established what drives or attenuates tau spreading, new studies on human brain using positron emission tomography (PET) have shed light on how tau phosphorylation, genetic factors, and the initial epicenter of tau accumulation influence tau accumulation and propagation throughout the brain. Here, we review the latest PET studies performed across the entire AD continuum looking at the impact of amyloid load on tau pathology. We also explore the effects of structural, functional, and proximity connectivity on tau spreading in a stereotypical manner in the brain of AD patients. Since tau propagation can be quite heterogenous between individuals, we then consider how the speed and pattern of propagation are influenced by the starting localization of tau accumulation in connected brain regions. We provide an overview of some genetic variants that were shown to accelerate or slow down tau spreading. Finally, we discuss how phosphorylation of certain tau epitopes affect the spreading of tau fibrils. Since tau pathology is an early event in AD pathogenesis and is one of the best predictors of neurodegeneration and memory impairments, understanding the process by which tau spread from one brain region to another could pave the way to novel therapeutic avenues that are efficient during the early stages of the disease, before neurodegeneration induces permanent brain damage and severe memory loss.
    Keywords:  Alzheimer’s disease; PET; amyloid; fMRI; neurodegeneration; propagation; tau
  7. Nutrients. 2023 Jul 19. pii: 3204. [Epub ahead of print]15(14):
      Alzheimer's disease (AD) is a growing concern for the aging population worldwide. With no current cure or reliable treatments available for AD, prevention is an important and growing area of research. A range of lifestyle and dietary patterns have been studied to identify the most effective preventive lifestyle changes against AD and related dementia (ADRD) pathology. Of these, the most studied dietary patterns are the Mediterranean, DASH, MIND, ketogenic, and modified Mediterranean-ketogenic diets. However, there are discrepancies in the reported benefits among studies examining these dietary patterns. We herein compile a narrative/literature review of existing clinical evidence on the association of these patterns with ADRD symptomology and contemplate their preventive/ameliorative effects on ADRD neuropathology in various clinical milieus. By and large, plant-based dietary patterns have been found to be relatively consistently and positively correlated with preventing and reducing the odds of ADRD. These impacts stem not only from the direct impact of specific dietary components within these patterns on the brain but also from indirect effects through decreasing the deleterious effects of ADRD risk factors, such as diabetes, obesity, and cardiovascular diseases. Importantly, other psychosocial factors influence dietary intake, such as the social connection, which may directly influence diet and lifestyle, thereby also impacting ADRD risk. To this end, prospective research on ADRD should include a holistic approach, including psychosocial considerations.
    Keywords:  Alzheimer’s disease; Mediterranean diet; aging; brain health; cognitive impairment; dementia; diet; neurodegenerative disorders; neuroscience
  8. BMC Microbiol. 2023 07 22. 23(1): 196
      BACKGROUND: Recently, an important relationship between Parkinson's disease and the gut microbiota, through the brain-gut axis interactions, has been established. Previous studies have declared that alterations in the gut microbiota have a great impact on the pathogenesis and clinical picture of Parkinson's disease (PD). The present study aimed to identify the gut microbiome that is likely related to Parkinson's disease as well as their possible relation to clinical phenotypes.METHODS: Thirty patients with Parkinson's disease, who presented to the Parkinson's disease Neurology Clinic of Alexandria University Hospital were enrolled in our study. A cross-matching control group of 35 healthy subjects of similar age and sex were included. Stool specimens were taken from each. Quantitative SYBR Green Real-Time PCR was done for the identification and quantitation of selected bacterial phyla, genera and/or species.
    RESULTS: There was a significant increase in Bacteroides and a significant decrease of Firmicutes and Firmicutes / Bacteroidetes ratio and Bifidobacteria in PD patients. Although Prevotella was decreased among PD patients relative to the healthy control, the difference was not statistically significant. Comparing the PD clinical phenotypes with the control group, the Mixed phenotype had significantly higher Bacteroides, Tremors predominant had lower Firmicutes and Firmicutes / Bacteroidetes ratio, and both tremors and postural instability and gait disability (PIGD) phenotypes had lower Bifidobacteria. However, there was no statistically significant difference between these phenotypes. Furthermore, when comparing tremors and non-tremors predominant phenotypes; Lactobacilli showed a significant decrease in non-tremors predominant phenotypes.
    CONCLUSIONS: The current study showed evidence of changes in the gut microbiome of Parkinson's disease patients compared to the healthy controls. These observations may highlight the importance of the identification of microbiome and specific bacterial changes that can be targeted for the treatment of Parkinson's disease.
    Keywords:  16S rRNA; Brain-gut axis; Clinical phenotypes; Dysbiosis; Gut microbiome; Parkinson’s disease; Real-time PCR