bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023‒05‒07
nine papers selected by
Mikaila Chetty
Goa University

  1. Gut Microbes. 2023 Jan-Dec;15(1):15(1): 2206504
      The microbiota-gut-brain axis is an important pathway of communication and may dynamically contribute to Alzheimer's disease (AD) pathogenesis. Pathological commensal gut microbiota alterations, termed as dysbiosis, can influence intestinal permeability and break the blood-brain barrier which may trigger AD pathogenesis via redox signaling, neuronal, immune, and metabolic pathways. Dysbiosis increases the oxidative stress. Oxidants affect the innate immune system through recognizing microbial-derived pathogens by Toll-like receptors and initiating the inflammatory process. Most of the gut microbiome research work highlights the relationship between the gut microbiota and AD, but the contributory connection between precise bacteria and brain dysfunction in AD pathology cannot be fully demonstrated. Here, we summarize the current information of the fundamental connections between oxidative stress, inflammation, and gut dysbiosis in AD. This review emphasizes on the involvement of gut microbiota in the regulation of oxidative stress, inflammation, immune responses including central and peripheral cross-talk. It provides insights for novel preventative and therapeutic approaches in AD.
    Keywords:  Alzheimer’s disease; Microbiota-gut-brain axis; dysbiosis; gut microbiota; inflammation; oxidative stress
  2. Curr Alzheimer Res. 2023 May 04.
      Memory is empirically described as a brain function that connects the past to the present. This reductionist approach has focused on memory function within neurons and synapses, leading to an understanding that memory loss in dementia is caused by irreversible neuronal damage. However, recent palliative case reports and the Human Connectome Project have challenged the "irreversible" paradigm by indicating that some demented patients are able to retrieve supposed 'lost' memories and cognitive functions near death. The serotonin-centric hypothesis and the lifelong oligodendrocyte differentiation capacity may explain terminal awakening symptoms in these patients. Furthermore, an increased rate of serotonin-secreting and oligodendrocyte precursor cell-triggering gut bacteria near death temporally correlates with lucid improvements in demented patients. These findings may shift the context of terminal memory retrieval from a purely neuronal to a systemic idea that bridges terminal lucidity and gut microbiota. In this review, we take the systemic approach further and point out a temporal correlation between the gut microbiome and terminal lucid episodes in Alzheimer's patients.
    Keywords:  Alzheimer's disease; Gut microbiota; Memory; Serotonin; Terminal lucidity; terminal lucidity
  3. NPJ Aging. 2023 May 02. 9(1): 9
      Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia worldwide. Different pathologic changes have been introduced to be involved in its progression. Although amyloid-β (Aβ) deposition and tau hyperphosphorylation and aggregation are mainly considered the main characterizations of AD, several other processes are involved. In recent years, several other changes, including alterations in gut microbiota proportion and circadian rhythms, have been noticed due to their role in AD progression. However, the exact mechanism indicating the association between circadian rhythms and gut microbiota abundance has not been investigated yet. This paper aims to review the role of gut microbiota and circadian rhythm in AD pathophysiology and introduces a hypothesis to explain their association.
  4. Mol Neurobiol. 2023 May 01.
      With the acceleration of global population aging, neurodegenerative diseases (NDs) will become the second leading cause of death in the world, which seriously threatens human life and health. Alzheimer's disease and Parkinson's disease are the most common and typical NDs. The exact mechanisms of the NDs occurrence and development remain unclear, which may be related to immune, oxidative stress, and abnormal aggregation of pathogenic proteins. Studies have suggested that gut microbiota (GM) influences brain function and plays an important role in regulating emotional and cognitive function. Recently, bile acids (BAs) have become the "star molecule" in the microbiota-gut-brain (MGB) axis research. BAs have been reported to exert anti-inflammatory, antioxidant, and neuroprotective activities in NDs. However, the role of BAs in the connection between GM and the central nervous system (CNS) is still unclear. In this review, we will review the possible mechanisms of BAs between GM and NDs and explore the function of BAs to provide ideas for the prevention and treatment of NDs in the future.
    Keywords:  Alzheimer’s Diseases; Bile Acids; Gut Microbiota; Immunity; Neurological and Endocrine; Parkinson’s Diseases
  5. Biophys Rev. 2023 Apr;15(2): 239-255
      Mitochondria are the primary cellular energy generators, supplying the majority of adenosine triphosphate through oxidative phosphorylation, which is necessary for neuron function and survival. Mitophagy is the metabolic process of eliminating dysfunctional or redundant mitochondria. It is a type of autophagy and it is crucial for maintaining mitochondrial and neuronal health. Impaired mitophagy leads to an accumulation of damaged mitochondria and proteins leading to the dysregulation of mitochondrial quality control processes. Recent research shows the vital role of mitophagy in neurons and the pathogenesis of major neurodegenerative diseases. Mitophagy also plays a major role in the process of aging. This review describes the alterations that are being caused in the mitophagy process at the molecular level in aging and in neurodegenerative diseases, particularly Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis, also looks at how mitophagy can be exploited as a therapeutic target for these diseases.
    Keywords:  Aging; Alzheimer’s disease; Amyotrophic lateral sclerosis; Mitochondria; Mitophagy; Neurodegenerative diseases; Parkinson’s disease
  6. Front Sports Act Living. 2023 ;5 1168731
      The immune system is critical in defending against infection from pathogenic microorganisms. Individuals with weakened immune systems, such as the elderly, are more susceptible to infections and developing autoimmune and inflammatory diseases. The gut microbiome contains a plethora of bacteria and other microorganisms, which collectively plays a significant role in immune function and homeostasis. Gut microbiota are considered to be highly influential on host health and immune function. Therefore, dysbiosis of the microbiota could be a major contributor to the elevated incidence of multiple age-related pathologies. While there seems to be a general consensus that the composition of gut microbiota changes with age, very little is known about how diet and exercise might influence the aging microbiome. Here, we examine the current state of the literature regarding alterations to the gut microbiome as hosts age, drawing particular attention to the knowledge gaps in addressing how diet and exercise influence the aging microbiome. Further, we will demonstrate the need for more controlled studies to investigate the roles that diet and exercise play driving the composition, diversity, and function of the microbiome in an aging population.
    Keywords:  age; dysbiosis; gastrointestinal tract; inflammaging; inflammation; microbiota; physical activity
  7. Mech Ageing Dev. 2023 Apr 27. pii: S0047-6374(23)00045-3. [Epub ahead of print] 111819
      Methods allowing light energy to be modulated in a controllable fashion are potentially important for finding the correlation between light-related environmental factors and aging-related lifespan. Here, we report photo- and thermo-regulation based on photonic crystals (PCs) for extended longevity of C. elegans. We show that PCs can function as a regulator of visible spectrum to tune photonic energy received by C.elegans. We provide direct evidence that lifespan depends on photonic energy, and the use of PCs reflecting blue light (440-537nm) gives 8.3% increasement in lifespan. We demonstrate that the exposure to modulated light alleviates photo-oxidative stress and unfolded-protein response. We realize reflective passive cooling temperature using PCs, and favorable low temperature could be created for worms to extend lifespan. This work offers a new path based on PCs to resist negative effects light and temperature for longevity, provides an available platform for studying the role of light in aging.
    Keywords:  C. elegans; Light energy; Longevity; Photo effect; Photonic crystal; Thermal effect
  8. Microbiol Res. 2023 Apr 25. pii: S0944-5013(23)00094-0. [Epub ahead of print]272 127392
      Tryptophan (Trp) functions in host-disease interactions. Its metabolism is a multi-pathway process. Indole and its derivatives are Trp metabolites unique to the human gut microbiota. Changes in Trp metabolism have also been detected in colorectal cancer (CRC). Here, combined with the existing CRC biomarkers, we ascribed it to the altered bacteria having the indole-producing ability by making a genomic prediction. We also reviewed the anti-inflammatory and possible anti-cancer mechanisms of indoles, including their effects on tumor cells, the ability to repair the gut barrier, regulation of the host immune system, and provide resistance against oxidative stress. Indole and its derivatives, along with related bacteria, could be targeted as auxiliary strategies to restrain cancer development in the future.
    Keywords:  Colorectal cancer; Gut microbiota; Indole; Tryptophan
  9. Neurobiol Dis. 2023 Apr 28. pii: S0969-9961(23)00154-7. [Epub ahead of print]182 106140
      The rare A673T variant was the first variant found within the amyloid precursor protein (APP) gene conferring protection against Alzheimer's disease (AD). Thereafter, different studies have discovered that the carriers of the APP A673T variant show reduced levels of amyloid beta (Aβ) in the plasma and better cognitive performance at high age. Here, we analyzed cerebrospinal fluid (CSF) and plasma of APP A673T carriers and control individuals using a mass spectrometry-based proteomics approach to identify differentially regulated targets in an unbiased manner. Furthermore, the APP A673T variant was introduced into 2D and 3D neuronal cell culture models together with the pathogenic APP Swedish and London mutations. Consequently, we now report for the first time the protective effects of the APP A673T variant against AD-related alterations in the CSF, plasma, and brain biopsy samples from the frontal cortex. The CSF levels of soluble APPβ (sAPPβ) and Aβ42 were significantly decreased on average 9-26% among three APP A673T carriers as compared to three well-matched controls not carrying the protective variant. Consistent with these CSF findings, immunohistochemical assessment of cortical biopsy samples from the same APP A673T carriers did not reveal Aβ, phospho-tau, or p62 pathologies. We identified differentially regulated targets involved in protein phosphorylation, inflammation, and mitochondrial function in the CSF and plasma samples of APP A673T carriers. Some of the identified targets showed inverse levels in AD brain tissue with respect to increased AD-associated neurofibrillary pathology. In 2D and 3D neuronal cell culture models expressing APP with the Swedish and London mutations, the introduction of the APP A673T variant resulted in lower sAPPβ levels. Concomitantly, the levels of sAPPα were increased, while decreased levels of CTFβ and Aβ42 were detected in some of these models. Our findings emphasize the important role of APP-derived peptides in the pathogenesis of AD and demonstrate the effectiveness of the protective APP A673T variant to shift APP processing towards the non-amyloidogenic pathway in vitro even in the presence of two pathogenic mutations.
    Keywords:  2D/3D cell models; APP A673T variant; Alzheimer's disease; Cerebrospinal fluid; Protective mechanisms