bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023‒05‒14
eight papers selected by
Mikaila Chetty
Goa University

  1. Am J Alzheimers Dis Other Demen. 2023 Jan-Dec;38:38 15333175231174193
      Alzheimer's disease (AD) is a progressive neurological disease. Gut microbial dysbiosis is associated with AD. This study involves the comparative assessment of spatial learning, β-amyloid peptide accumulation, and fecal microbiota alterations in 3×Tg-AD mice from 3 age groups: AD asymptomatic stage (3 m), presymptomatic stage (6 m), and the symptomatic stage of AD (9 m). We demonstrate that spatial memory deficits, brain Aβ accumulation, and weight gain in 3×Tg-AD mice gradually appear after 6 months of age. However, the total gut bacterial counts underwent changes from 3 to 6 months of age and were further altered at 9 months of age. Importantly, changes in gut bacteria abundance of Desulfobacterota and Actinobacteriota phyla in 6-month-old mice preceded apparent spatial memory deficits. In summary, Changes in the gut microbial community are one of the mechanisms of early AD pathology.
    Keywords:  Alzheimer’s disease; amyloid β accumulation; gut microbiota dysbiosis; metabolic dysfunction; triple-transgenic mice
  2. Protein Cell. 2023 May 11. pii: pwad026. [Epub ahead of print]
      The gut microbiota has been found to interact with the brain through the microbiota-gut-brain axis, regulating various physiological processes. In recent years, the impacts of the gut microbiota on neurodevelopment through this axis have been increasingly appreciated. The gut microbiota is commonly considered to regulate neurodevelopment through three pathways, the immune pathway, the neuronal pathway, and the endocrine/systemic pathway, with overlaps and crosstalks in between. Accumulating studies have identified the role of the microbiota-gut-brain axis in neurodevelopmental disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and Rett Syndrome. The major aims of this review are to, first of all, discuss the mechanisms of the microbial regulation of neurodevelopment alongside the aforementioned three pathways on both the molecular and systemic scales; and second of all, present evidence for the roles of the microbiota-gut-brain axis in various neurodevelopmental disorders, the underlying mechanisms, and the potential therapeutic methods. Finally, we discuss the current situation in the field and propose the paucity in the exploration of the specific mechanisms of the microbiota-gut-brain axis in neurodevelopmental disorders.
    Keywords:  gut microbiome; microbiota-gut-brain axis; neurodevelopmental disorders
  3. Semin Cell Dev Biol. 2023 May 04. pii: S1084-9521(23)00101-5. [Epub ahead of print]
      Mitochondria perform a myriad of essential functions that ensure organismal homeostasis, including maintaining bioenergetic capacity, sensing and signalling the presence of pathogenic threats, and determining cell fate. Their function is highly dependent on mitochondrial quality control and the appropriate regulation of mitochondrial size, shape, and distribution during an entire lifetime, as well as their inheritance across generations. The roundworm Caenorhabditis elegans has emerged as an ideal model organism through which to study mitochondria. The remarkable conservation of mitochondrial biology has allowed C. elegans researchers to investigate complex processes that are challenging to study in higher organisms. In this review, we explore the key recent contributions of C. elegans to mitochondrial biology through the lens of mitochondrial dynamics, organellar removal, and mitochondrial inheritance, as well as their involvement in immune responses, various types of stress, and transgenerational signalling.
    Keywords:  Aging; Biogenesis; Fission; Fusion; Mitochondrial disease; Mitophagy; MtDNA; Neurodegeneration; Proteotoxicity; UPRmt
  4. Neuropharmacology. 2023 May 05. pii: S0028-3908(23)00156-9. [Epub ahead of print] 109566
      The microbiota-gut-brain axis' role in Parkinson's disease (PD) pathophysiology, and how this differs from typical ageing, is poorly understood. Presently, gut-bacterial diversity, taxonomic abundance and metabolic bacterial pathways were compared across healthy young (n = 22, 18-35 years), healthy older (n = 33, 50-80 years), and PD groups (n = 18, 50-80 years) using shotgun sequencing and compositional data analysis. Associations between the gut-microbiome and PD symptoms, and between lifestyle factors (fibre intake, physical activity, and sleep) and the gut-microbiome were conducted. Alpha-diversity did not differ between PD participants and older adults, whilst beta-diversity differed between these groups. Lower abundance of Butyricimonas synergistica, a butyrate-producer, was associated with worse PD non-motor symptoms in the PD group. Regarding typical ageing, Bifidobacterium bifidum, was greater in the younger compared to older group, with no difference between the older and PD group. Abundance of metabolic pathways related to butyrate production did not differ among the groups, while 100 other metabolic pathways differed among the three groups. Sleep efficiency was positively associated with Roseburia inulinivorans in the older group. These results highlight the relevance of gut-microbiota to PD and that reduced butyrate-production may be involved with PD pathophysiology. Future studies should account for lifestyle factors when investigating gut-microbiomes across ageing and in PD.
    Keywords:  Aging; Gut-brain-axis; Microbiome; Microbiota; PD; Short chain fatty acids
  5. Res Sq. 2023 Apr 28. pii: [Epub ahead of print]
      Spouses of Alzheimer's disease (AD) patients are at higher risk of developing AD dementia, but the reasons and underlying mechanism are unknown. One potential factor is gut microbiota dysbiosis, which has been associated with AD. However, it remains unclear whether the gut microbiota dysbiosis can be transmitted to non-AD individuals and contribute to the development of AD pathogenesis and cognitive impairment. The present study found that co-housing wild-type mice with AD transgenic mice or giving them AD transgenic mice feces caused AD-associated gut microbiota dysbiosis, Tau phosphorylation, and cognitive impairment. Gavage with Lactobacillus and Bifidobacterium restored these changes. The oral and gut microbiota of AD patient partners resembled that of AD patients but differed from healthy controls, indicating the transmission of oral and gut microbiota and its impact on cognitive function. The underlying mechanism of these findings includes that the butyric acid-mediated acetylation of GSK3β at lysine 15 regulated its phosphorylation at serine 9, consequently impacting Tau phosphorylation. These results provide insight into a potential link between gut microbiota dysbiosis and AD and underscore the need for further research in this area.
  6. Aging Dis. 2023 04 22.
      Alzheimer's disease (AD) is the most common form of dementia that remains incurable and has become a major medical, social, and economic challenge worldwide. AD is characterized by pathological hallmarks of senile plaques (SP) and neurofibrillary tangles (NFTs) that damage the brain up to twenty years before a clinical diagnosis is made. Interestingly these pathological features have also been observed in retinal neurodegenerative diseases including age related macular degeneration (ARMD), glaucoma and diabetic retinopathy (DR). An association of AD with these diseases has been suggested in epidemiological studies and several common pathological events and risk factors have been identified between these diseases. The E4 allele of Apolipoprotein E (APOE) is a well-established genetic risk factor for late onset AD. The ApoE ε4 allele is also associated with retinal neurodegenerative diseases however in contrast to AD, it is considered protective in AMD, likewise ApoE E2 allele, which is a protective factor for AD, has been implicated as a risk factor for AMD and glaucoma. This review summarizes the evidence on the effects of ApoE in retinal neurodegenerative diseases and discusses the overlapping molecular pathways in AD. The involvement of ApoE in regulating amyloid beta (Aβ) and tau pathology, inflammation, vascular integrity, glucose metabolism and vascular endothelial growth factor (VEGF) signaling is also discussed.
  7. Sci Data. 2023 May 09. 10(1): 261
      Alzheimer's disease (AD) is the most common form of dementia, with cerebrospinal fluid (CSF) β-amyloid (Aβ), total Tau, and phosphorylated Tau (pTau) providing the most sensitive and specific biomarkers for diagnosis. However, these diagnostic biomarkers do not reflect the complex changes in AD brain beyond amyloid (A) and Tau (T) pathologies. Here, we report a selected reaction monitoring mass spectrometry (SRM-MS) method with isotopically labeled standards for relative protein quantification in CSF. Biomarker positive (AT+) and negative (AT-) CSF pools were used as quality controls (QCs) to assess assay precision. We detected 62 peptides (51 proteins) with an average coefficient of variation (CV) of ~13% across 30 QCs and 133 controls (cognitively normal, AT-), 127 asymptomatic (cognitively normal, AT+) and 130 symptomatic AD (cognitively impaired, AT+). Proteins that could distinguish AT+ from AT- individuals included SMOC1, GDA, 14-3-3 proteins, and those involved in glycolysis. Proteins that could distinguish cognitive impairment were mainly neuronal proteins (VGF, NPTX2, NPTXR, and SCG2). This demonstrates the utility of SRM-MS to quantify CSF protein biomarkers across stages of AD.
  8. Eur J Neurol. 2023 May 09.
      BACKGROUND: Parkinson's disease (PD)-associated alterations in the gut microbiome have been observed in clinical and animal studies. However, it remains unclear whether this association reflects a causal effect in humans.METHODS: We performed two-sample bi-directional Mendelian randomization using summary statistics from the international consortium MiBioGen (n = 18,340), the Framingham Heart Study (n = 2076), and the International Parkinson's Disease Genomics Consortium for PD (33,674 cases and 449,056 controls) and PD 'age of onset' (17,996 cases).
    RESULTS: Twelve microbiota features presented suggestive associations with PD risk or age of onset. Genetically increased Bifidobacterium levels correlated with decreased PD risk (odds ratio, 0.77; 95% CI, [0.60,0.99]; P = 0.040). Conversely, high levels of five short-chain fatty acids (SCFA)-producing bacteria (LachnospiraceaeUCG010, RuminococcaceaeUCG002, Clostridium sensustricto1, Eubacterium hallii group, and Bacillales) correlated with increased PD risk, and three SCFA-producing bacteria (Roseburia, RuminococcaceaeUCG002, and Erysipelatoclostridium) correlated with an earlier age of PD onset. Gut production of serotonin was associated with an earlier age of PD onset (beta, -0.64; 95% CI, [-1.15,-0.13]; P = 0.013). In the reverse direction, genetic predisposition to PD was related to altered gut microbiota composition.
    CONCLUSIONS: These results support a bidirectional relationship between gut microbiome dysbiosis and PD, and highlight the role of elevated endogenous SCFAs and serotonin in PD pathogenesis. Future clinical studies and experimental evidence are needed to explain the observed associations and to suggest new therapeutic approaches, such as dietary probiotic supplementation.
    Keywords:  GWAS; Gut Microbiota; Mendelian randomization; Parkinson's Disease