bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023‒03‒19
eleven papers selected by
Mikaila Chetty
Goa University

  1. Int J Biol Sci. 2023 ;19(4): 1178-1191
      Gut microbiota was only considered as a commensal organism that aids in digestion, but recent studies revealed that the microbiome play a critical role in both physiological and pathological immune system. The gut microbiome composition is altered by environmental factors such as diet and hygiene, and the alteration affects immune cells, especially T cells. Advanced genomic techniques in microbiome research defined that specific microbes regulate T cell responses and the pathogenesis of immune-mediated disorders. Here, we review features of specific microbes-T cell crosstalk and relationship between the microbes and immunopathogenesis of diseases including in cancers, autoimmune disorders and allergic inflammations. We also discuss the limitations of current experimental animal models, cutting-edge developments and current challenges to overcome in the field, and the possibility of considering gut microbiome in the development of new drug.
    Keywords:  T cell; autoimmune disease; fecal microbiota transplant; immune system; microbiome
  2. Arch Microbiol. 2023 Mar 16. 205(4): 118
      Alzheimer's disease (AD), the most prevalent neurodegenerative disease, has a significant relationship with alteration of the gut microbiota (GM), and the GM-gut-brain axis has been explored to find novel therapeutic approaches for AD. The present study aimed to evaluate the effect of human Lactobacillaceae (HLL) on cognitive function in APP/PS1 mice. The results showed that HLL treatment significantly improved the cognitive function of mice via MWM and NOR tests. Furthermore, the expression of Aβ plaques, tau phosphorylation and neuroinflammation were markedly reduced in the hippocampus. Meanwhile, HLL treatment significantly increased the activity of GSH-PX and decreased the expression levels of IL-6 and MDA in the brain, and simultaneously increased the abundance of beneficial bacteria and restrained pathogenic bacteria in the intestine. Interestingly, significant correlations were observed between significant changes in abundance of GMs and AD-related markers. Collectively, these findings reveal that HLL is a promising therapeutic agent and potential probiotics, which might improve the cognitive function and AD pathologies.
    Keywords:  Alzheimer’s disease; Aβ deposits; Cognitive dysfunction; Gut microbiota; Lactobacillaceae; Neuroinflammation
  3. Neurosci Biobehav Rev. 2023 Mar 10. pii: S0149-7634(23)00091-X. [Epub ahead of print] 105122
      Anorexia nervosa (AN) is a severe illness with diverse aetiological and maintaining contributors including neurobiological, metabolic, psychological, and social determining factors. In addition to nutritional recovery, multiple psychological and pharmacological therapies and brain-based stimulations have been explored; however, existing treatments have limited efficacy. This paper outlines a neurobiological model of glutamatergic and γ-aminobutyric acid (GABA)-ergic dysfunction, exacerbated by chronic gut microbiome dysbiosis and zinc depletion at a brain and gut level. The gut microbiome is established early in development, and early exposure to stress and adversity contribute to gut microbial disturbance in AN, early dysregulation to glutamatergic and GABAergic networks, interoceptive impairment, and inhibited caloric harvest from food (e.g., zinc malabsorption, competition for zinc ions between gut bacteria and host). Zinc is a key part of glutamatergic and GABAergic networks, and also affects leptin and gut microbial function; systems dysregulated in AN. Low doses of ketamine in conjunction with zinc, could provide an efficacious combination to act on NMDA receptors and normalise glutamatergic, GABAergic and gut function in AN.
    Keywords:  Anorexia Nervosa; Brain-Derived Neurotrophic Factor; Gamma-AminoButyric Acid; Glutamate; Gut Microbiome; Interoception; Ketamine; Neurobiological Model; Post-Traumatic Stress Disorder; Trauma Exposure; Zinc
  4. Inflamm Regen. 2023 Mar 15. 43(1): 20
      BACKGROUND: Alzheimer's disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-β (Aβ) aggregates and phosphorylated tau with aging. The aggregation of Aβ, which is the main component of senile plaques, is closely associated with disease progression. AppNL-G-F mice, a mouse model of AD, have three familial AD mutations in the amyloid-β precursor gene and exhibit age-dependent AD-like symptoms and pathology. Gut-brain interactions have attracted considerable attention and inflammatory bowel disease (IBD) has been associated with a higher risk of dementia, especially AD, in humans. However, the underlying mechanisms and the effects of intestinal inflammation on the brain in AD remain largely unknown. Therefore, we aimed to investigate the effects of intestinal inflammation on AD pathogenesis.METHODS: Wild-type and AppNL-G-F mice at three months of age were fed with water containing 2% dextran sulfate sodium (DSS) to induce colitis. Immune cells in the brain were analyzed using single-cell RNA sequencing (scRNA-seq) analysis, and the aggregation of Aβ protein in the brain was analyzed via immunohistochemistry.
    RESULTS: An increase in aggregated Aβ was observed in the brains of AppNL-G-F mice with acute intestinal inflammation. Detailed scRNA-seq analysis of immune cells in the brain showed that neutrophils in the brain increased after acute enteritis. Eliminating neutrophils by antibodies suppressed the accumulation of Aβ, which increased because of intestinal inflammation.
    CONCLUSION: These results suggest that neutrophils infiltrate the AD brain parenchyma when acute colitis occurs, and this infiltration is significantly related to disease progression. Therefore, we propose that neutrophil-targeted therapies could reduce Aβ accumulation observed in early AD and prevent the increased risk of AD due to colitis.
    Keywords:  Alzheimer’s disease; Inflammatory bowel disease; Neutrophils
  5. Rev Neurol (Paris). 2023 Mar 09. pii: S0035-3787(23)00870-6. [Epub ahead of print]
      Alzheimer's disease (AD) is a multi-etiology disease. The biological system of AD is associated with multidomain genetic, molecular, cellular, and network brain dysfunctions, interacting with central and peripheral immunity. These dysfunctions have been primarily conceptualized according to the assumption that amyloid deposition in the brain, whether from a stochastic or a genetic accident, is the upstream pathological change. However, the arborescence of AD pathological changes suggests that a single amyloid pathway might be too restrictive or inconsistent with a cascading effect. In this review, we discuss the recent human studies of late-onset AD pathophysiology in an attempt to establish a general updated view focusing on the early stages. Several factors highlight heterogenous multi-cellular pathological changes in AD, which seem to work in a self-amplifying manner with amyloid and tau pathologies. Neuroinflammation has an increasing importance as a major pathological driver, and perhaps as a convergent biological basis of aging, genetic, lifestyle and environmental risk factors.
    Keywords:  APOE; Alzheimer's disease; Biomarker; Neuroinflammation; Pathophysiology
  6. Cell Mol Life Sci. 2023 Mar 17. 80(4): 97
      The processing of the amyloid precursor protein (APP) is one of the key events contributing to Alzheimer's disease (AD) etiology. Canonical cleavages by β- and γ-secretases lead to Aβ production which accumulate in amyloid plaques. Recently, the matrix metalloprotease MT5-MMP, referred to as η-secretase, has been identified as a novel APP cleaving enzyme producing a transmembrane fragment, ηCTF that undergoes subsequent cleavages by α- and β-secretases yielding the Aηα and Aηβ peptides, respectively. The functions and contributions of ηCTF and its related fragments to AD pathology are poorly understood. In this study, we designed a novel immunological probe referred to as ηCTF-NTer antibody that specifically interacts with the N-terminal part of ηCTF targeting ηCTF, Aηα, Aηβ but not C99, C83 and Aβ. We examined the fate and localization of ηCTF fragment in various cell models and in mice. We found that overexpressed ηCTF undergoes degradation in the proteasomal and autophagic pathways and accumulates mainly in the Golgi and in endosomes. Moreover, we observed the presence of ηCTF in small extracellular vesicles purified from neuroblastoma cells or from mouse brains expressing ηCTF. Importantly, the expression of ηCTF in fibroblasts devoid on APP leads to Aβ production demonstrating its contribution to the amyloidogenic pathway. Finally, we observed an ηCTF-like immunoreactivity around amyloid plaques and an age-dependent accumulation of ηCTF in the triple-transgenic mouse AD model. Thus, our study suggests that the ηCTF fragment likely contributes to AD pathology by its exosomal spreading and involvement in Aβ production.
    Keywords:  Alzheimer’s disease; Autophagic degradation; Aβ-production; Endosomes; Extracellular vesicles; ηCTF
  7. J Cell Sci. 2023 Mar 15. pii: jcs260102. [Epub ahead of print]136(6):
      Neuroinflammation is causally associated with Alzheimer's disease (AD) pathology. Reactive glia cells secrete various neurotoxic factors that impair neuronal homeostasis eventually leading to neuronal loss. Although the glial activation mechanism in AD has been relatively well studied, how it perturbs intraneuronal signaling, which ultimately leads to neuronal cell death, remains poorly understood. Here, we report that compound stimulation with the neurotoxic factors TNF and glutamate aberrantly activates neuronal TAK1 (also known as MAP3K7), which promotes the pathogenesis of AD in mouse models. Glutamate-induced Ca2+ influx shifts TNF signaling to hyper-activate TAK1 enzymatic activity through Ca2+/calmodulin-dependent protein kinase II, which leads to necroptotic cellular damage. Genetic ablation and pharmacological inhibition of TAK1 ameliorated AD-associated neuronal loss and cognitive impairment in the AD model mice. Our findings provide a molecular mechanism linking cytokines, Ca2+ signaling and neuronal necroptosis in AD.
    Keywords:  Alzheimer's disease; Cell death; Inflammation; TAK1
  8. Curr Neuropharmacol. 2023 Mar 16.
      Mitochondria are critical for homeostasis and metabolism in all cellular eukaryotes. Brain mitochondria are the primary source of fuel that supports many brain functions, including intracellular energy supply, cellular calcium regulation, regulation of limited cellular oxidative capacity, and control of cell death. Much evidence suggests that mitochondria play a central role in neurodegenerative disorders (NDDs) such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Ongoing studies of NDDs have revealed that mitochondrial pathology is mainly found in inherited or irregular NDDs and is thought to be associated with the pathophysiological cycle of these disorders. Typical mitochondrial disturbances in NDDs include increased free radical production, decreased ATP synthesis, alterations in mitochondrial permeability, and mitochondrial DNA damage. The main objective of this review is to highlight the basic mitochondrial problems that occur in NDDs and discuss the use mitochondrial drugs, especially mitochondrial antioxidants, mitochondrial permeability transition blockade, and mitochondrial gene therapy, for the treatment and control of NDDs.
    Keywords:  Alzheimer’s disease; Mitochondria; Parkinson’s disease; antioxidants; gene therapy; neurodegenerative disorders
  9. Biochem Soc Trans. 2023 Mar 17. pii: BST20220830. [Epub ahead of print]
      A healthy brain is protected by the blood-brain barrier (BBB), which is formed by the endothelial cells that line brain capillaries. The BBB plays an extremely important role in supporting normal neuronal function by maintaining the homeostasis of the brain microenvironment and restricting pathogen and toxin entry to the brain. Dysfunction of this highly complex and regulated structure can be life threatening. BBB dysfunction is implicated in many neurological diseases such as stroke, Alzheimer's disease, multiple sclerosis, and brain infections. Among other mechanisms, inflammation and/or flow disturbances are major causes of BBB dysfunction in neurological infections and diseases. In particular, in ischaemic stroke, both inflammation and flow disturbances contribute to BBB disruption, leading to devastating consequences. While a transient or minor disruption to the barrier function could be tolerated, chronic or a total breach of the barrier can result in irreversible brain damage. It is worth noting that timing and extent of BBB disruption play an important role in the process of any repair of brain damage and treatment strategies. This review evaluates and summarises some of the latest research on the role of the BBB during neurological disease and infection with a focus on the effects of inflammation and flow disturbances on the BBB. The BBB's crucial role in protecting the brain is also the bottleneck in central nervous system drug development. Therefore, innovative strategies to carry therapeutics across the BBB and novel models to screen drugs, and to study the complex, overlapping mechanisms of BBB disruption are urgently needed.
    Keywords:  Blood–brain barrier; SARS-CoV-2; cerebral ischaemia; flow disturbances; inflammation; neurological disorders
  10. Neural Regen Res. 2023 Sep;18(9): 1890-1902
      Blood-brain barrier disruption occurs in the early stages of Alzheimer's disease. Recent studies indicate a link between blood-brain barrier dysfunction and cognitive decline and might accelerate Alzheimer's disease progression. Astrocytes are the most abundant glial cells in the central nervous system with important roles in the structural and functional maintenance of the blood-brain barrier. For example, astrocytic coverage around endothelial cells with perivascular endfeet and secretion of homeostatic soluble factors are two major underlying mechanisms of astrocytic physiological functions. Astrocyte activation is often observed in Alzheimer's disease patients, with astrocytes expressing a high level of glial fibrillary acid protein detected around amyloid-beta plaque with the elevated phagocytic ability for amyloid-beta. Structural alterations in Alzheimer's disease astrocytes including swollen endfeet, somata shrinkage and possess loss contribute to disruption in vascular integrity at capillary and arterioles levels. In addition, Alzheimer's disease astrocytes are skewed into proinflammatory and oxidative profiles with increased secretions of vasoactive mediators inducing endothelial junction disruption and immune cell infiltration. In this review, we summarize the findings of existing literature on the relevance of astrocyte alteration in response to amyloid pathology in the context of blood-brain barrier dysfunction. First, we briefly describe the physiological roles of astrocytes in blood-brain barrier maintenance. Then, we review the clinical evidence of astrocyte pathology in Alzheimer's disease patients and the preclinical evidence in animal and cellular models. We further discuss the structural changes of blood-brain barrier that correlates with Alzheimer's disease astrocyte. Finally, we evaluate the roles of soluble factors secreted by Alzheimer's disease astrocytes, providing potential molecular mechanisms underlying blood-brain barrier modulation. We conclude with a perspective on investigating the therapeutic potential of targeting astrocytes for blood-brain barrier protection in Alzheimer's disease.
    Keywords:  Alzheimer’s disease; amyloid-beta; astrocyte (astroglial)-endothelial interaction; astrocyte pathology; blood-brain barrier; blood-brain barrier disruption; brain endothelial cell; neuroinflammation; reactive astrocyte
  11. Front Neurosci. 2023 ;17 1047778
      As blood-brain barrier (BBB) disruption emerges as a common problem in the early stages of neurodegenerative diseases, the crucial roles of barrier-type brain endothelial cells (BECs), the primary part of the BBB, have been reported in the pathophysiology of neurodegenerative diseases. The mechanisms of how early vascular dysfunction contributes to the progress of neurodegeneration are still unclear, and understanding BEC functions is a promising start. Our understanding of the BBB has gone through different stages, from a passive diffusion barrier to a mediator of central-peripheral interactions. BECs serve two seemingly paradoxical roles: as a barrier to protect the delicate brain from toxins and as an interface to constantly receive and release signals, thus maintaining and regulating the homeostasis of the brain. Most previous studies about neurodegenerative diseases focus on the loss of barrier functions, and far too little attention has been paid to the active regulations of BECs. In this review, we present the current evidence of BEC dysfunction in neurodegenerative diseases and explore how BEC signals participate in the pathogenesis of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; blood–brain barrier; endothelial cells; neurodegenerative disease; neurovascular unit