bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023‒06‒04
five papers selected by
Mikaila Chetty
Goa University

  1. Front Neurol. 2023 ;14 1149618
      Alzheimer's disease (AD), is a chronic age-related progressive neurodegenerative disorder, characterized by neuroinflammation and extracellular aggregation of Aβ peptide. Alzheimer's affects every 1 in 14 individuals aged 65 years and above. Recent studies suggest that the intestinal microbiota plays a crucial role in modulating neuro-inflammation which in turn influences Aβ deposition. The gut and the brain interact with each other through the nervous system and chemical means via the blood-brain barrier, which is termed the Microbiota Gut Brain Axis (MGBA). It is suggested that the gut microbiota can impact the host's health, and numerous factors, such as nutrition, pharmacological interventions, lifestyle, and geographic location, can alter the gut microbiota composition. Although, the exact relationship between gut dysbiosis and AD is still elusive, several mechanisms have been proposed as drivers of gut dysbiosis and their implications in AD pathology, which include, action of bacteria that produce bacterial amyloids and lipopolysaccharides causing macrophage dysfunction leading to increased gut permeability, hyperimmune activation of inflammatory cytokines (IL-1β, IL-6, IL-8, and NLRP3), impairment of gut- blood brain barrier causing deposition of Aβ in the brain, etc. The study of micro-organisms associated with dysbiosis in AD with the aid of appropriate model organisms has recognized the phyla Bacteroidetes and Firmicutes which contain organisms of the genus Escherichia, Lactobacillus, Clostridium, etc., to contribute significantly to AD pathology. Modulating the gut microbiota by various means, such as the use of prebiotics, probiotics, antibiotics or fecal matter transplantation, is thought to be a potential therapeutic intervention for the treatment of AD. This review aims to summarize our current knowledge on possible mechanisms of gut microbiota dysbiosis, the role of gut brain microbiota axis in neuroinflammation, and the application of novel targeted therapeutic approaches that modulate the gut microbiota in treatment of AD.
    Keywords:  Alzheimer's disease; blood brain barrier; gut brain microbiota axis; gut dysbiosis; gut microbiota; neuroinflammation; prebiotics
  2. Alzheimers Res Ther. 2023 May 31. 15(1): 101
      BACKGROUND: Increasing evidence links the gut microbiota (GM) to Alzheimer's disease (AD) but the mechanisms through which gut bacteria influence the brain are still unclear. This study tests the hypothesis that GM and mediators of the microbiota-gut-brain axis (MGBA) are associated with the amyloid cascade in sporadic AD.METHODS: We included 34 patients with cognitive impairment due to AD (CI-AD), 37 patients with cognitive impairment not due to AD (CI-NAD), and 13 cognitively unimpaired persons (CU). We studied the following systems: (1) fecal GM, with 16S rRNA sequencing; (2) a panel of putative MGBA mediators in the blood including immune and endothelial markers as bacterial products (i.e., lipopolysaccharide, LPS), cell adhesion molecules (CAMs) indicative of endothelial dysfunction (VCAM-1, PECAM-1), vascular changes (P-, E-Selectin), and upregulated after infections (NCAM, ICAM-1), as well as pro- (IL1β, IL6, TNFα, IL18) and anti- (IL10) inflammatory cytokines; (3) the amyloid cascade with amyloid PET, plasma phosphorylated tau (pTau-181, for tau pathology), neurofilament light chain (NfL, for neurodegeneration), and global cognition measured using MMSE and ADAScog. We performed 3-group comparisons of markers in the 3 systems and calculated correlation matrices for the pooled group of CI-AD and CU as well as CI-NAD and CU. Patterns of associations based on Spearman's rho were used to validate the study hypothesis.
    RESULTS: CI-AD were characterized by (1) higher abundance of Clostridia_UCG-014 and decreased abundance of Moryella and Blautia (p < .04); (2) elevated levels of LPS (p < .03), upregulation of CAMs, Il1β, IL6, and TNFα, and downregulation of IL10 (p < .05); (3) increased brain amyloid, plasma pTau-181, and NfL (p < 0.004) compared with the other groups. CI-NAD showed (1) higher abundance of [Eubacterium] coprostanoligenes group and Collinsella and decreased abundance of Lachnospiraceae_ND3007_group, [Ruminococcus]_gnavus_group and Oscillibacter (p < .03); (2) upregulation of PECAM-1 and TNFα (p < .03); (4) increased plasma levels of NfL (p < .02) compared with CU. Different GM genera were associated with immune and endothelial markers in both CI-NAD and CI-AD but these mediators were widely related to amyloid cascade markers only in CI-AD.
    CONCLUSIONS: Specific bacterial genera are associated with immune and endothelial MGBA mediators, and these are associated with amyloid cascade markers in sporadic AD. The physiological mechanisms linking the GM to the amyloid cascade should be further investigated to elucidate their potential therapeutic implications.
    Keywords:  Alzheimer’s disease; Cognitive impairment; Endothelial dysfunction; Gut microbiota; Lipopolysaccharide; Microbiota-gut-brain axis
  3. CNS Neurol Disord Drug Targets. 2023 May 26.
      Alzheimer's disease (AD) represents the most prevalent type of neurodegenerative dementia and the sixth leading cause of death worldwide. The so-called "non-calcemic actions" of vitamin D have been increasingly described, and its insufficiency has already been linked to the onset and progression of the main neurological diseases, including AD. Immune-mediated Aβ plaque's phagocytosis and clearance, immune response, oxidative stress, and mitochondrial function are all influenced by vitamin D, and these functions are considered relevant in AD pathogenesis. However, it has been shown that the genomic vitamin D signaling pathway is already impaired in the AD brain, making things more complicated. In this paper, we aim to summarise the role of vitamin D in AD and review the results of the supplementation trials in AD patients.
    Keywords:  Alzheimer's disease; amyloid beta; cholecalciferol; cognition; dementia; vitamin D
  4. Mech Ageing Dev. 2023 May 31. pii: S0047-6374(23)00053-2. [Epub ahead of print] 111827
      Since its introduction by Sydney Brenner, Caenorhabditis elegans has become a widely studied organism. Given its highly significant properties, including transparency, short lifespan, self-fertilization, high reproductive yield and ease in manipulation and genetic modifications, the nematode has contributed to the elucidation of several fundamental aspects of biology, such as development and ageing. Moreover, it has been extensively used as a platform for the modelling of ageing-associated human disorders, especially those related to neurodegeneration. The use of C. elegans for such purposes requires, and at the same time promotes the investigation of its normal ageing process. In this review we aim to summarize the major organismal alterations during normal worm ageing, in terms of morphology and functionality.
    Keywords:  Ageing; C. elegans; Frailty, Reproduction, Senescence, Somatic tissues
  5. Pharmaceuticals (Basel). 2023 Feb 16. pii: 312. [Epub ahead of print]16(2):
      The amyloid concept of Alzheimer's disease (AD) assumes the β-amyloid peptide (Aβ) as the main pathogenic factor, which injures neural and other brain cells, causing their malfunction and death. Although Aβ has been documented to exert its cytotoxic effect in a solitary manner, there is much evidence to claim that its toxicity can be modulated by other proteins. The list of such Aβ co-factors or interactors includes tau, APOE, transthyretin, and others. These molecules interact with the peptide and affect the ability of Aβ to form oligomers or aggregates, modulating its toxicity. Thus, the list of potential substances able to reduce the harmful effects of the peptide should include ones that can prevent the pathogenic interactions by specifically binding Aβ and/or its partners. In the present review, we discuss the data on Aβ-based complexes in AD pathogenesis and on the compounds directly targeting Aβ or the destructors of its complexes with other polypeptides.
    Keywords:  Alzheimer’s disease; GAPDH; amyloid fibrils; chaperones; cytotoxicity; protein–protein interaction; tau-protein; therapeutical agent; α-synuclein