Disease ⇒ Alzheimer’s disease {40000139} Record Keys Type:Disease Parent:[ ] Definition:Alzheimer’s disease Details Initialisation date:2020-09-06 Other Terms:AD, ASD LinksWickipediaMerck Manual Meta Information MedDra ID:10012271 MedDra Level:pt ICD:[ ] Category:Neurology Zone:[ ] Mechanism:[ ] Notes: - The reference 1 with the title "We might have Alzheimer’s all wrong - daily oral administration of B. breve A1 > suppress the hippocampal expressions of inflammation and immune-reactive genes that are induced by amyloid-β > reduced the cognitive dysfunction normally induced by amyloid beta > significantly higher levels of acetate, but not propionate or butyrate. - Butyrate activates the secretion of BDNF ( brain-derived neurotrophic factor) > ameloriate Coginitive dysfunction in AD. - Enterobacteria infection > exacerbate the progression of AD. - pro-inflammatory Clostridium Cluster I significantly correlated with anti-inflammatory Faecalibacterium prausnitzii. - Amyloid positive patients showed higher levels of pro-inflammatory cytokines.Shared Reference Notes [1.1] [#Bifidobacterium breve] [#Probiotic] [1.2] - Fungi in gut linked to higher Alzheimer’s risk can be reduced through ketogenic diet. [1.3] - Amyloid SUVR uptake is positively associated with - blood LPS - acetate and valerate - pro-inflammatory cytokines - biomarkers of endothelial dysfunction - Amyloid SUVR uptake is is negatively correlated with - butyrate - anti-inflammatory cytokine IL10 -Endothelial dysfunction is positively associated with - pro-inflammatory cytokines, acetate and valerate -Endothelial dysfunction is negatively associated with - butyrate and IL10 levels. [1.4] - The gut microbiome of AD participants has decreased microbial diversity. - Bacteroidetes are increased and Bifidobacterium and Firmicutes are decreased in the microbiome of AD participants. - Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, identified in the brain of Alzheimers disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimes patients, and levels correlated with tau and ubiquitin pathology. - Oral infections with Porphyromonas gingivalis, or introduction of its lipopolysaccharide (LPS), in various mouse models has demonstrated the development of key neuropathological hallmark lesions defining AD. [1.5] - Curli are cell surface amyloid proteins abundantly expressed by E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. [1.6] - Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer’s disease patients. - Toxic proteases from the bacterium called #Gingipains were also identified in the brain of Alzheimer’s patients, and levels correlated with tau and ubiquitin pathology. [1.7] - Resveratrol has been proposed as a beneficial compound to delay ageing and cellular senescence. [1.8] - The gut microbiota-derived metabolite TMAO is elevated in the CSF of individuals with MCI and AD dementia, and that levels of CSF TMAO are associated with CSF biomarkers of AD pathology and neuronal degeneration. [1.9] - #Bifidobacterium breve, improves cognition. - The improvement of cognitive function reveal an inverse correlation of HbA1c with total RBANS score amelioration after the study only in the probiotic group. - Increasing evidence points to several mitochondrial functions that are affected in AD. - Deficit in this mitochondrial may be at the heart of the progression of AD itself. [1.11] - Various gut microbes such as Actinobacteria, Bacteroidetes, E. coli, Firmicutes, Proteobacteria, Tenericutes, and Verrucomicrobia are known to play a crucial role in the pathogenesis of AD. - These microbes and their metabolites modulate various physiological processes that contribute to AD pathogenesis, such as neuroinflammation and other inflammatory processes, amyloid deposition, cytokine storm syndrome, altered BDNF and NMDA signaling, impairing neurodevelopmental processes. - Epigenetic markers associated with AD mainly include histone modifications and DNA methylation, which are under the direct control of a variety of enzymes, such as acetylases and methylases which activity is dependent upon the metabolites generated by the host’s gut microbiome. [1.12] [#Poor oraly Health] - At genera and species levels, higher subgingival periodontal dysbiosis was associated with reduced CSF amyloid beta (Aβ)42 but not with P‐tau. [1.13] - Colonization of the C. elegans gut with enteric bacterial pathogens disrupted proteostasis in the intestine, muscle, neurons, and the gonad. - The presence of bacteria that conditionally synthesize #Butyrate, a molecule previously shown to be beneficial in neurodegenerative disease models, suppressed aggregation and the associated proteotoxicity. [1.14] - The effects of gut microbiota in AD are mediated by microbial metabolites that either act on local neurons in the gut and surrounding tissues and send signals to the brain, and/or get absorbed from the gut and reach to brain through circulation. Such examples are monoamines, short-chain fatty acids (SCFAs), gamma-aminobutyric acid (GABA), beta-methylamino-L-alanine, brain-derived neurotrophic factor, serotonin, and dopamine [#Amyloid] - Specific bacteria, for example, Escherichia coli, Bacillus subtilis, Salmonella typhimurium, and Salmonella enterica can also produce amyloids. [#Keto diet] - MD-ketogenic diet improved the AD biomarkers viz. amyloid and tau proteins in the cerebrospinal fluids of MCI patients, wherein these changes linked with increased gut #Butyrate. - There is a significant reduction in Aβ levels and increase in behavioral responses after 12-weeks of sodium #Butyrate supplementation in mouse - #Lipopolysaccharide (LPS), an outer cell wall component of Gram-negative bacteria that can be highly pro-inflammatory, can enhance Aβ accumulation in brain and induce cognitive dysfunction. - AD patients show higher LPS levels in blood plasma, and neocortex and hippocampus. - LPS can also cause chronic neuroinflammation, nerve cell death in entorhinal cortex, and impairment of synaptic plasticity of neurons in hippocampus. [#Plant-based diet] - Oxidative stress can be modulated by diet, for example, high-fruit-and-vegetable diets improve cognition, which is linked with decreased oxidative stress in elderly; - Patients with MCI and AD also show higher levels of gut microbiota-derived trimethylamine N-oxide (#TMAO) in the cerebrospinal fluid. - #TMAO correlate with AD biomarkers including pTau, total Tau, and Aβ42. - #TMAO treatment reduces cognitive function and aging signs in mice, by ameliorating neuronal senescence and mitochondrial dysfunction. - #TMAO and its precursors have inflammatory biomarkers, possibly contributing to AD-related leaky gut. [#Western-style diet] - The Western diet consists of low-fiber, high-fat, and high-protein foods, where it is common to eat fatty red meats and eggs that are rich in TMA and choline, thus increase #TMAO production. [1.15] [1.16] - The #ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. - Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. [1.17] - AD elders had increased proportions of specific bacterial species that have associations with neurological disorders (including AD). These include Odoribacter splanchnicus, a bacterial species with genes that have been associated with the Alzheimers pathway (5) - Blautia were more abundant in AD patients. - Elevated GABA was potentially associated with a lower risk of AD. - Gut microbial neurotransmitter GABA, a downstream product of Blautia-dependent arginine metabolism, was related to a reduced risk of AD. - Lower levels of gut product of GABA were observed in patients with AD. - The biological mechanisms of GABA production include degradation of putrescine, decarboxylation of glutamate, or from arginine or ornithine. In - Blautia has a strong correlation with arginine metabolism, which may be involved in AD pathogenesis by regulating its downstream products such as GABA, supporting the potential pathway. - Elevated Enterobacteriales was also associated with a higher risk of ASD. - Gut microbiome may excrete large quantities of lipopolysaccharides and amyloids, resulting in the pathogenesis of AD during aging when the permeability of gastrointestinal tract epithelium or blood-brain barrier increases. [1.18] [#Vitamin K2] [1.19] [#Fecal Microbiota Transplantation] [#Parkinson’s Disease] [#Escherichia coli] - E. coli genes promote neurodegeneration. - Two of these genes, csgA and csgB, code for proteins that form #Curli, one type of bacterial amyloid fibers. - #Curli cross-seeds and colocalizes with α-syn both in C. elegans neurons and human neuroblastoma cells. - #Curli-induced α-syn aggregations down-regulate mitochondrial genes, causing energy failure in neurons. - #Curli may have general effects in promoting neuropathologies induced by different aggregation-prone proteins, such as A-β in Alzheimer’s disease, Huntingtin in #Huntington’s Disease, and SOD1 in #Amyotrophic lateral sclerosis. [1.21] - At the follow-up visit 2 months post-FMT, the patient’s wife reported improvements in the patient’s mental acuity and affect. The MMSE was re-administered by the gastroenterologist (and subsequently by the neurologist) and the patient scored 26, indicating normal cognition. Four months post-FMT, the patient reported continued improvement in memory, with no progression in symptoms. The patient now remembered his daughter’s birthday, which he had not been able to recall previously, and was able to correct the physician’s recollections of his symptoms. Six months post-FMT, the patient reported a marked improvement in mood, was more interactive, and showed more expressive affect. [1.22] [1.23] - Reduction of #Glutamine > causally associated with occurrence of AD. [1.24] [#Consuming Basil] [1.25] - #Treatment with Rifamixin > significant reduction in serum neurofilament-light levels >significant increase in fecal phylum Firmicutes microbiota. #Treatment with Rifamixin > reduces Serum pTau181 and GFAP levels and non-significant downward trend in serum cytokine IL-6 and IL-13 levels. Increases in stool #Erysipelatoclostridium > correlated significantly with reductions in serum pTau 181 and serum GFAP. [1.26] - The enrichment of #Actinomyces meyeri > inversely associated with the age of first #Cannabis smoking. - Oral exposure of #Actinomyces meyeri > decreased global activity, increased macrophage infiltration, and increased β-amyloid protein production in the mouse brains. [1.27] [#Carnitine] [1.28] - There is a significant inverse relationship between the onset of Alzheimer’s disease/#Parkinson’s Disease (AD/PD) and #Cancer. - An increase in PIN1 expression is related to a delay in the onset age of sporadic AD, whereas a decrease in PIN1 expression is associated with a reduced risk of various cancers. - prostate, ovarian, and lung cancers show the greatest negative correlation with AD. [#Colorectal cancer] - Serum #TMAO levels in AD/CRC patients are higher than those in healthy people, and its concentrations may be positively correlated with AD/cancer progression [#Parkinson’s Disease] - #Tryptophan metabolites can cross the blood-brain barrier > activate #AHR to regulate astrocytes and reduce central nervous system inflammation in AD and PD - Decrease in #Bacteroidetes and #Alloprevotella and increase in #Proteobacteria, #Verrucomicrobia, #Akkermansia, and #Desulfovibrio > improve short-term memory ability and cognitive level of AD mice - Increasing the relative abundance of #Bacteroides and #Faecalibacterium may improve cognitive levels - #Butyrate can reduce AD by affecting the #P-glycoprotein pathway [#Hydrogen sulfide] - H2S > important signaling molecule in organisms > improve the progression of AD by enhancing Nrf2 > reduce the production of Aβ by inhibiting β secretase 1 (BACE1) > and protect neurons by maintaining mitochondrial function [#Lipopolysaccharide] - LPS > Damage the blood-brain barrier so that it can enter the brain > hinder the outflow of Aβ from cells > neuroinflammation and the accumulation of neuronal Aβ in AD > induce hyperphosphorylation of tau protein. - #Mucispirillum and #Ruminiclostridium are enriched in AD model mice [1.29] - Absence of gut microbiota > prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology - absence of gut microbiota > altered inflammatory pathway and insulin/IGF-1 signalling in hippocampus. - #Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. - AD patients’ gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors’ microbiota transplants. [#Serotonin] [1.31] [#Fecal Microbiota Transplantation] [1.32] - Prevotella_9, Bacteroides, and members of the Ruminococcaceae family were among the top most significantly differentially abundant taxa [1.33] [#Sphingolipid] - High ceramide levels > associated with insulin resistance, hypercholesterolemia, liver steatosis, and the formation of lipid rafts. - Some classes of #Ceramides in the blood increase the risk for late-onset Alzheimer’s disease, as they are neurotoxic and induce apoptosis . - #Bacteroidetes phylum can synthesize sphingolipids > human epithelial cells > #Ceramides [1.34] [#Porphyromonas gingivalis] - tau to be a target of gingipain proteolysis and suggested that tau pathology in AD brains may be caused by transneural spread of P. gingivalis, tau damage by gingipain proteolysis, and activation of human proteases. They also hypothesized that #Gingipains might be a driver of a compensatory increase in tau production of AD patients. [1.35] [1.36] - #Verrucarin A, produced in #Myrothecium spp., showed 80% decrease in Aβ production. Furthermore, addition of #Mer-A2026A, produced in #Streptomyces pactum, showed increase in Aβ42/40 ratio at the low concentration, and decrease in Aβ production at the higher concentration. [1.37] [#Chlamydia pneumoniae] - Among different types of microbes, #Human immunodeficiency virus-1 (HIV-1), #Herpes simplex virus-1 (HSV-1), Chlamydia pneumonia, #Spirochetes and #Candida albicans are frequently detected in the brain of AD patients. - #Amyloid-beta protein has demonstrated to exhibit antimicrobial properties upon encountering these pathogens. [1.38] - Treatment with #Sodium oligomannate > as well as the recently approved aducanumab, provides hope that new therapeutics with novel mechanisms of action may provide disease-modifying effects and help slow disease progression in people with AD. [1.39] [#Short Chain Fatty Acid] - reduced levels of SCFAs were observed in patients with Alzheimer’s disease, and they also promoted #Depression-like behaviors and impairments of short-term memory in mice - #Indole-3-propionic acid has been shown to have neuroprotective and antioxidant effects, protecting primary neurons and neuroblastoma cells from oxidative damage and death caused by amyloid β protein (Aβ) [#Bacteroides fragilis] [#Amyloid-beta] - Presence of #Amyloid deposits was associated with greater abundance of proinflammatory taxa (#Escherichia/#Shigella), which were in turn correlated with proinflammatory cytokines, and with reduced abundance of #Eubacterium rectale and B. fragilis, 2 taxa with anti-inflammatory activity [#Helicobacter pylori] - Patients with the H. Pylori infection have been found to perform more poorly on the Mini–Mental State Examination, verbal memory tasks, and serial digit learning tasks; the infection causes inflammation and even tau hyperphosphorylation. [1.41] [#Fusobacterium nucleatum] [#Amyloid-beta, #Lipopolysaccharide] - antibodies to F. nucleatum can be detected in the serum of patients with AD or cognitive impairment. - F. nucleatum activates microglial cells causing morphological changes, accelerated proliferation and enhanced expression of TNF-α and IL-1β in microglial cells. - LPS promoted the proliferation of brain microglia - F. nucleatum-induced periodontitis resulted in the exacerbation of Alzheimer’s symptoms in 5XFAD mice including increased cognitive impairment, beta-amyloid accumulation and Tau protein phosphorylation in the mouse cerebrum. - The stimnuli like LPS, Aβ or IFN-γ would activate microglial M1 phenotype, leading to the expression of pro-inflammatory cytokines and irreversible neuron loss. - The main known virulence factors of F. nucleatum include FadA, Fap2, and LPS [1.42] - #Vitamin B12 deficiency at the brain level is associated with affective disorders, behavior changes, psychosis, cognitive impairment or decline, and #Dementia (including Alzheimer’s disease and vascular #Dementia protection) [1.43] - dementia-free older adults taking vitamin D3 supplements for over 146 days/year were 1.8 times more likely to develop dementia than those not taking the supplements. - supplementation of #Vitamin D led to increased Aβ deposition and exacerbated AD. [1.44] - beneficial bacteria such as Candidatus saccharimonas and Rikenellaceae decreased in APP/PS1 mice. Also, inflammatory or Aβ-associated bacteria such as Erysipelotrichaceae and Proteobacteria increased in APP/PS1 mice. [#Bacillus firmus] - B. firmus, Rikenella, #Clostridium sp. Culture-27, and #Deoxyuridine, may play important roles in AD pathology. - #Rikenella decreased in AD mice and was reversed in gut flora-targeted photobiomodulation therapy, indicating that #Rikenella may be a potential therapeutic target for AD. [1.45] [#Lipopolysaccharide] - #Bacteroides fragilis in the human gastrointestinal (GI) tract generates > neurotoxin #BF-LPS > #BF-LPS leaks out of the GI tract, crosses the blood brain barrier via the circulatory system, and accesses brain compartments > inreases inflammation in brain cells and inhibits neuron-specific neurofilament light (NF-L,) a protein that supports cell integrity > deficiency of NF-L > consequent atrophy of the neuronal cytoskeleton and the disruption of synaptic organization. [#Lipopolysaccharide] - LPS and other pro-inflammatory stressors strongly induce a defined set of NF-kB (p50/p65)-sensitive human microRNAs, including a brain-enriched Homo sapien microRNA-30b-5p (hsa-miRNA-30b-5p; miRNA-30b) > upregulated in AD brain and LPS-stressed human neuronal-glial (HNG) cells in primary culture targets the neurofilament light (NF-L) chain mRNA 3’-untranslated region (3’-UTR) > post-transcriptional downregulation of NF-L expression observed within both AD and LPS-treated HNG cells > A deficiency of NF-L is associated with consequent atrophy of the neuronal cytoskeleton and the disruption of synaptic organization. - Increased miRNA-30b expression induces neuronal injury, neuron loss, neuronal inflammation, impairment of synaptic transmission, and synaptic failure in neurodegenerative disease and transgenic murine models. [1.46] [#Sialic acid] - #Neisseria gonorrhoeae and Group B Streptococcus selectively bind huCD33 as part of immune evasive molecular mimicry of host SAMPs. - Human cells synthesize two forms of CD33: a full-length version and a mutated, inactive form that lacks the sugar-binding site. Those with a particular point mutation—different by a single changed nucleotide—produce a higher proportion of the mutant CD33, reducing the immune system’s ability to recognize sialic acids. [1.47] [#Multiple Sclerosis, #Parkinson’s Disease] [#Short Chain Fatty Acid] - SCFAs maintain the healthy mitochondrial function and stimulate the maturation of microglia, which consequently suppresses the progression of Neuro-Degenerative Diseases and cognitive decline by regulating inflammation and oxidative stress. - SCFAs functions as a cofactor for the host’s mitochondrial enzymes. - The properties of SCFAs depend on the G-protein coupled receptors (GPCR), histone deacetylases (HDAC) & peroxisome proliferator-activated receptor gamma (PPARγ) and regulatory T cells (Tregs) activation. [1.48] [#Porphyromonas gingivalis] [#Amyloid-beta, #Gingipains] - AβPP is an infection responsive protein cleaved via the amyloidogenic pathway on exposure to conditioned medium and in the presence of pro-inflammatory mediators. [1.49] [#Porphyromonas gingivalis] - nerve cells in the brain contain a type of protein called tau. When tau meets the #Gingipains enzyme, the tau released from the nerve cell. Once freed, tau physically changes, in the form of coils and non-coiling filaments. These filaments of tau then re-attach to the nerve cell and become incorporated into the lesion known as neurofibrillary tangles. - once a nerve cell dies and the free tau protein leaks into the brain, the tau may attach itself to healthy neighboring nerve cells, repeating the process and leading to further damage to the brain as the disease spreads - FMD (#Fasting-mimicking diet) cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain. [1.51] [#Amyloid-beta] - many people accumulate amyloid plaques in the brain as they age, but only some of these people go on to develop dementia. - dementia symptoms may result not from the formation of insoluble plaques but from a lack of soluble amyloid beta protein. [1.52] - Alzheimer’s disease brains tissue > presence of #HSV1, #Borrelia burgdorferi, and #Chlamydia pneumoniae in AD brains. [#Amyloid-beta] - #Fusobacterium nucleatum can increased TNF-α and IL-1β expression in microglial cells, and also in vivo it can increase cognitive impairment, beta-amyloid accumulation and Tau protein phosphorylation in the cerebrum of an AD animal model. - Local periodontal inflammation due to infection with #Helicobacter pylori, the agent of gastric ulcers, or with #Porphyromonas gingivalis, in fact, can stimulate brain tissue inflammation [1.53] [#Amyloid-beta] - #Chlamydia pneumoniae can infect the olfactory and trigeminal nerves, olfactory bulb and brain within 72 h in mice. - #Chlamydia pneumoniae infection also resulted in dysregulation of key pathways involved in Alzheimer’s disease pathogenesis at 7 and 28 days after inoculation. - Amyloid beta accumulations were also detected adjacent to the #Chlamydia pneumoniae inclusions in the olfactory system. - Injury to the nasal epithelium resulted in increased peripheral nerve and olfactory bulb infection, but did not alter general CNS infection. [1.54] - Brain-derived #Tau is a new blood-based biomarker that outperforms plasma total-#Tau and, unlike neurofilament light, shows specificity to Alzheimer’s disease-type neurodegeneration. [1.55] [#Saccharomyces boulardii] [#Amyloid-beta, #Lipopolysaccharide] [#Probiotic] - S. boulardii significantly reduced the elevated levels of serum interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, as well as hippocampal levels of NLRP3 and caspase-1 in the LPS model. - S. boulardii alleviated amyloid-β deposition in the rat hippocampus. - S. boulardii could inhibit memory impairment, neuroinflammation, and amyloid-β accumulation induced by LPS, possibly by modifying the gut microbiota. [1.56] - #Isoorientin treatment promoted the distribution of the class #Mollicutes, family #Prevotellaceae, and genus #Prevotellaceae UCG 001 in the fecal microbiota and the phylum Proteobacteria (Pasteurellales: #Prevotellaceae ) in the cecal microbiota of AD mice [1.57] [#Short Chain Fatty Acid] [#ApoE4 allele] - #Amyloid-beta is a necessary factor in AD pathogenesis, its accumulation in and of itself is insufficient for neurodegeneration and cognitive decline. - pathological #Tau accumulation is closely linked with neurodegeneration and cognitive decline in AD and primary tauopathies. - apolipoprotein E (ApoE) isoforms, which strongly influence AD risk and regulate #Tau-mediated neurodegeneration, differentially affect the gut microbiota. - microbially produced short-chain fatty acids (SCFAs) are mediators of the neuroinflammation-neurodegeneration axis. - Supplementation of SCFAs to GF TE4 mice resulted in more reactive glial morphologies and gene expression as well as increased p-#Tau pathology. [1.58] - The highest hazard ratio, was seen for the association between viral encephalitis and AD. [1.59] [#Amyloid-beta] - high-fat diets and #Obesity are associated with increased risk for developing AD and #Dementia. - the incidence of AD is higher in countries that typically consume high-fat diets as opposed to low-fat diets. - Increased Aβ plaques in the brain after consumption of a #High Fat Diet has been observed in mouse models of amyloidosis. - a high-fat diet can result in an increase in neuroinflammation and decreased performance on AD-related behavior tests. - AD > A positive correlation between the pro-inflammatory cytokines and Escherichia/Shigella (pro-inflammatory taxon) and a negative correlation with #Eubacterium rectale (anti-inflammatory taxon). - a decrease in #Firmicutes and #Bifidobacterium and increased levels of #Proteobacteria, #Actinobacteria - a disputed frequency of #Bacteroidetes in various studies.. [#Amyloid-beta] - All humans produce Aβ40 and Aβ42 throughout life and levels of these proteins are relatively high in both the CSF and serum throughout life. - Aβ plaques can be present in cognitively normal individuals. This suggests that perhaps Aβ is present for a reason and serves a beneficial physiologic purpose in the human body. - Several bacteria and viruses > enhance amyloidogenic processing and subsequent Aβ production. - Aβ plaques in humans contain viral and bacterial DNA. - Aβ have similar structure to other antimicrobial peptides. - Aβ protects against infection in mouse, cell culture, and C elegans models. - Perhaps Aβ is initially increasingly produced as a response to real or perceived brain infection, but too much Aβ production eventually becomes detrimental by inducing neuronal toxicity, excessive neuroinflammation, and pathological tau seeding. [#Amyloid-beta] - levels of Aβ are increased when mice and human are awake and decrease when they are asleep. - These diurnal oscillations in Aβ levels in brain ISF are dissipated and the #Sleep–wake cycle is disrupted after Aβ plaque formation in the APP/PS1 mouse model of amyloidosis. - amelioration of Aβ plaque pathology with Aβ immunotherapy restored a normal #Sleep wake cycle and diurnal oscillations in Aβ levels in the mice. - Lower neuronal activity during #Sleep likely leads to less Aβ production. [#Exercise training] - Exercise is protective in AD - Exercise alters Gut Microbiota composition. - The protective effect of exercise on AD progression maybe mediated by the Gut Microbiota. - AD Mouse > an increase in #Odoribacter and #Helicobacter genera and decreases in #Prevotella species. [#Keto diet] - The ketogenic diet can improve memory, reduce amyloid plaques, reduce neurodegeneration, and neuroinflammation. [#Lipopolysaccharide] - methylamine trimethylamine N-oxide (#TMAO), enhance BBB integrity by altering expression of annexin A1, a tight junction protein. - #TMAO limit LPS-mediated memory impairment by limiting microglial and astrocyte-mediated neuroinflammation. - BBB breakdown is well documented in AD. - #Probiotic combined with #Selenium supplementation in AD patients resulted in synergistic improvements in MMSE score, reductions in CRP, reductions in total antioxidant capacity, lower insulin levels, lower LDL levels, and lower serum triglycerides. [#Sleep Deprivation] - #Sleep deprivation exacerbates AD pathology, which clearly connects poor #Sleep quality with progression of AD. [#Amyloid-beta] - adding #Cinnamon or cinnamaldehyde to a cell medium can reduce #Tau aggregation, Amyloid β and increase cell viability. - #Cinnamon might be useful for preventing and reducing cognitive function impairment. [1.61] [1.62] - AD was causally associated with Reticulocalbin 2 and sphingomyelins, an association driven by the APOE isoform. [1.63] [#Olive] - A significantly decreased level of #Oleic acid has been observed in the brains of patients suffering from major depressive disorders and Alzheimer’s diseas [1.64] [#Hericerin] - N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity > resulting in significantly enhanced hippocampal memory. [1.65] [#Dementia with Lewy bodies (DLB), #Parkinson’s Disease] [#Short Chain Fatty Acid] - short-chain fatty acids-producing genera were decreased in DLB. - #Ruminococcus torques and #Collinsella were increased in DLB, which were not changed in PD. - high #Ruminococcus torques and high #Collinsella, which presumably increase intestinal permeability, as well as low #Bifidobacterium, which are also observed in Alzheimer’s disease, were predictive of DLB. [1.66] [#Multiple Sclerosis, #Parkinson’s Disease] [1.67] - The predominant bacterium of salivary microbiome and periodontal microbiome from AD patients was #Streptococcus oralis and #Porphyromonas gingivalis, respectively. - P. gingivalis was associated with AD only in GCF. - the dominant species were different between early-onset AD and late-onset AD patients. - the predominant species were changed as the clinical severity of AD. - The relative abundance of #Veillonella parvula significantly increased in oral microbiomes from AD patients. - The correlation analysis revealed that V. parvula was associated with AD in both saliva and GCF. [1.68] - The proinflammatory genus #Collinsella, identified as a risk factor for AD, was positively correlated with the APOE rs429358 risk allele in both samples. - 20 gut microbiota genera were initially identified as genetically associated with AD case/control status. Of these 20, three genera (#Eubacterium fissicatena as a protective factor, #Collinsella, and #Veillonella as a risk factor) were independently significant in the replication sample. [1.69] [#Gingipains] - #Porphyromonas gingivalis is a major pathogenic bacterium involved in the pathogenesis of periodontitis. Citrullination has been reported as the underlying mechanism of the pathogenesis, which relies on the interplay between two virulence factors of the bacterium, namely gingipain R and the bacterial peptidyl arginine deiminase. - Gingipain R cleaves host proteins to expose the C-terminal arginines for peptidyl arginine deiminase to citrullinate and generate #Citrullinated Proteins. - Citrullinating proteins present in the host synovial tissues, atherosclerotic plaques and neurons. - both virulence factors are the key factors that trigger distal effects mediated by citrullination, leading to the development of some non-communicable diseases, such as #Rheumatoid Arthritis, #Atherosclerosis, and Alzheimer’s disease. [#Grape seed] - the production of bioactive #Phenolic acids derived from the anthocyanin-rich GSPE is dependent on the microbiota, and two of the microbiota-derived metabolites 3-hydroxybenzoic acid and 3-(3′-hydroxyphenyl) #Propionic acid accumulate in micromolar concentrations in the brain where they can interfere with the assembly of #Amyloid-beta peptides. - microbial-derived #Urolithins are neuroprotective and pomegranate’s anti- AD’s neuroprotective ability was attributed to the production of microbial-derived #Urolithins. [1.71] [#Periodontal disease] - In patients with AD, oral bacteria were detected in brain tissues, and increased levels of pro-inflammatory cytokines were also detected. [1.72] [#Amyotrophic lateral sclerosis] - extracellular #Glutamate leads to excitotoxicity in vitro and in vivo in astrocytes and neurons through the overactivation of ionotropic #Glutamate receptors. - Chronic excitotoxicity is hypothesized to play a role in numerous neurodegenerative disorders, including AD, ALS, and #Huntington’s Disease [#Amyotrophic lateral sclerosis, #Multiple Sclerosis] - ALS appeared to be less associated with microbial dysbiosis compared to MS and AD, with only one microbe genus, #Methanobrevibacter and #Ruminococcaceae being commonly present under elevated conditions, respectively. - in a mouse model of Alzheimer’s disease, increased gut microbiota-produced #Propionate correlates with neuroinflammation and cognitive decline - In AD, the levels of #Putrescine are increased by 70 percent. At the same time, #Spermidine concentration is decreased in the temporal cortex of AD patients. [1.73] [#Cognitive impairment, #Mild Cognitive Impairment] [#Mediterranean Ketogen Diet] - Participants with MCI on the MMKD had lower levels of #GABA-producing microbes #Alistipes sp. CAG:514 and #GABA, and higher levels of #GABA-regulating microbes #Akkermansia muciniphila. [1.74] [#Adult] - A 15 mg/dL increase in high density lipoprotein (HDL) #Cholesterol was associated with decreased AD risk during earlyand middle adulthood. - A 15 mg/dL increase in #Glucose measured during middle adulthood was associated with 14.5% increased AD risk . [1.75] - higher tissue #Polyamine levels have been reported in various diseases like #Dementia due to Alzheimer’s disease (AD), #Parkinson’s Disease, #Cancer, and mental disorders like #Depression. - Urinary #Polyamine levels in AD patients were significantly elevated compared to healthy individuals. - Elevated #Spermidine plasma levels are associated with advanced brain #Aging and might serve as potential early biomarker for AD and vascular brain pathology. [1.76] [#Mild Cognitive Impairment] [#Aging, #Mediterranean Ketogen Diet] - feeding modified Mediterranean-ketogenic diet (MMKD) increased production of #Butyrate, which was associated with reduced AD markers in the cerebrospinal fluid of older adults with MCI [1.77] [#Amyloid-beta, #Phenolic acids] [#Olive] - oral administration of EVOO and specific EVOO phenolic compounds, in particular, can reduce the accumulation of β-#Amyloid (Aβ) deposits and tau neuropathologies in mouse models of AD, resulting in improved memory and cognition. [#Olive] - #Lactobacilli and #Bifidobacterium are often greatly reduced in patients with AD. - Both of these bacterial types, populations of which are elevated with EVOO consumption, can produce γ-aminobutyric acid (#GABA), the main inhibitory neurotransmitter, likely influencing GABAergic firing in the brain via the enteric and vagal nervous systems. - Extra-virgin #Olive oil (EVOO)-rich #Mediterranean diet can significantly reduce the risk of AD. [#Olive] - In several rodent studies, EVOO, especially the EVOO #Secoiridoid #Oleocanthal, aided the prevention and halted the progression of AD [#Olive] - #Oleocanthal-rich EVOO given to TgSwDI mice at an advanced stage of AD resulted in significantly reduced NLRP3 inflammasome activation and increased Aβ clearance by stimulating autophagy through the AMPK− Unc-51-like kinase 1 (ULK1) pathway. [1.78] [#Amyloid-beta] - Aβ was associated with increased plasma phosphorylated tau and #Cognitive impairment only in those who tested positive for astrocyte reactivity (Ast+). [1.79] [#Amyloid-beta] - #Cocoa extracts are effective in preventing the oligomerization of Aβ, with Lavado extract being most effective. - Increased proportions of #Odoribacter and #Barnesiella and decreased proportions of #Eubacterium , #Roseburia , #Lachnoclostridium and #Collinsella were seen in elders with other #Dementia types than AD. [#Enterobacteriaceae bacterium] - AD elders were also depleted in #Adlercreutzia equolifaciens, an #Equol-producing bacterium, which has beneficial effects in reducing experimental cutaneous inflammation in mice and the loss of which has been associated with the neurodegenerative disorder #Multiple Sclerosis. - Increased proportions of #Bacteroides, #Alistipes, #Odoribacter, and #Barnesiella and decreased proportions of #Lachnoclostridium were present in AD elders. - #Bacteroides vulgatushe is a predictor of AD dementia which cause inflammatory states. [1.81] - The microbial pathways most associated with preclinical AD status in regression models share #Succinate as a product. - #Succinate, known largely as an intermediate of the tricarboxylic acid cycle, is also a bacterial metabolite produced in the gut that has been associated with #Obesity and inflammatory bowel disease and is increasingly appreciated as immunomodulatory. - #Alistipes, #Barnesiella, and #Odoribacter were previously found in symptomatic individuals with AD. - Distinct Bacteroides species were highly associated with preclinical AD and healthy groups (#Bacteroides intestinalis and #Bacteroides caccae, respectively) [#Short Chain Fatty Acid] - #Methanobrevibacter smithii was associated with preclinical AD and was negatively correlated with fecal concentrations of #Butyrate, a SCFA that attenuated Aβ plaque deposition and neuroinflammation in a mouse model of AD. [#Short Chain Fatty Acid] - #Succinate is a major precursor for the short-chain fatty acid (SCFA) #Propionate, which has previously been found to be elevated in symptomatic individuals with AD, as well as in AD mouse models, compared with healthy controls. - In a phase 2 randomized trial, #Sodium oligomannate (a marine algae–derived oligosaccharide) improved outcomes in cognitive function in AD [1.82] [#Diabetes Type 2] - genus Actinobacterium #Collinsella was confirmed to be associated with Alzheimer’s disease, as well as #Rheumatoid Arthritis, #Atherosclerosis, and type 2 diabetes. [1.83] - #Spermidine-induced autophagy slows the rate of cognitive decline due to its ability to clear #Amyloid-beta plaques in the brain. [1.84] - #Constipation significantly correlated with a steeper decline in cognitive function and greater increase in DWML volume in patients with AD and aMCI. - higher level of serum #Homocysteine was observed in those with #Constipation. - patients with #Constipation experienced cognitive decline at a rate over twice that experienced by patients without #Constipation. [1.85] [#β-hydroxy β-methylbutyrate] - Muscle-building supplement β-hydroxy β-methylbutyrate binds to PPARα to improve hippocampal functions in mice [1.86] [1.87] [#Mushroom] [1.88] - the whole #Coffee extract, #Caffeine, and #Genistein have biological properties in preventing aggregation, condensation, and seeding activity of the repeat region of #Tau. - a set of #Coffee compounds capable of binding to preformed #Tau fibrils. [1.89] - administrating feces of AD transgenic mice to wild-type mice resulted in AD-associated gut microbiota dysbiosis, #Tau phosphorylation, and #Cognitive impairment in the wild-type mice. - The oral and gut microbiota of AD patient partners resembled that of AD patients but differed from healthy controls, indicating the transmission of microbiota. - #Butyric acid-mediated acetylation of GSK3β at lysine 15 regulated its phosphorylation at serine 9, consequently impacting #Tau phosphorylation. - In AD > Gavage with #Lactobacillus and #Bifidobacterium restored these changes in the wild-type mice. [1.91] - The increased intestinal permeability in C3GnT−/− mice as compared to C3GnT+/+ mice may facilitate the passage of gut-microbe signals/metabolites to the brain, especially those derived from mucus-associated microbes which are in close proximity to the underlying mucosa. - the caecal content of C3GnT−/− mice exhibited altered levels of metabolites linked with Alzheimer’s disease (AD) and #Depression such as #N-acetyl-lysine derived metabolites, #Acetyl-carnitines, #Dimethylglycine and #Acetyl-L-Tyrosine. [1.92] [#Blood Brain Barrier Integrity] - Pericyte degeneration leads to BBB breakdown causing brain accumulation of blood-derived neurotoxic molecules. - Pericyte ischemic injury results in contractile rigor and obstruction of capillary blood flow. - Pericyte-specific genetic defects lead to primary familial brain calcification or Fahr’s disease. - Pericytes degenerate and likely play a role in cerebrovascular dysfunction in complex neurological diseases such as AD [1.93] [#Parkinson’s Disease] [#Campylobacter rectus, #Porphyromonas gingivalis, #Prevotella melaninogenica] - C. rectus has been associated with the symptoms of Alzheimer’s disease along with P. gingivalis and P. melaninogenica. - increase in C. rectus as well as P. gingivalis and P. melaninogenica in the PA+PD group. [#Treponema socranskii] - The spirochete T. socranskii is known to interact directly with target cells using their endotoxins and degradation products to invade tissues. - This is one of the most abundant spirochetes, found in sites with severe periodontal destruction and associated with #Periodontal disease. - This species was found in the trigeminal ganglions of patients with Alzheimer’s disease, indicating that T. socranskii may have access to neuronal axons. [1.94] [#Amyloid-beta] [#Fasting] - TRF (time-restricted feeding) had the remarkable capability of simultaneously reducing #Amyloid deposition, increasing Aβ42 clearance, improving #Sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. - TRF had a major impact on neuropathology, with treated APP23 TG mice displaying a significant reduction in plaque burden and #Amyloid deposition and a reversal of circulating biomarkers of AD. - TRF protocol was effective in reducing #Amyloid burden and improving memory in the APP knockin (APP-KI) mouse model. [1.95] [#Vitamin D] - Higher brain 25(OH)D3 concentrations were associated with a 25% to 33% lower odds of dementia or mild cognitive impairment (MCI) at the last visit before death [1.96] [#Dementia] - 4 essential-oil odorants twice a day for 5 months > significant 226% improvement was observed in the enriched group compared to the control group on the Rey Auditory Verbal Learning Test and improved functioning was observed in the left uncinate fasciculus [1.97] - Ferroptosis appears to be a major mechanism of white matter injury in Alzheimer’s disease and vascular #Dementia. - fragments of myelin are themselves rich in #Iron > degeneration > #Iron toxicity causing microglial degeneration in the brain > advancing cognitive decline in Alzheimer’s disease and vascular #Dementia. [1.98] - 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. - #Butyric acid-mediated acetylation of GSK3β at lysine 15 regulated its phosphorylation at #Serine, consequently impacting #Tau phosphorylation. [1.99] - The higher rate of mTOR and HIF-1α signals occurred with a reduction in O2 consumption and an enhancement in extracellular acidification, thus shifting the glycolytic balance in microglia [#Amyloid-beta] - supplementation of #Acetate to the diet of a mouse model for AD induced the pro-inflammatory phenotype of microglia with elevated cytokine expression > suppress the phagocytosis by microglia in the presence of Aβ. - #Acetate regulate the release of #Neurotransmitters including #Glutamate, #Glutamine, and γ-amino butyric acid in the hypothalamus and increase the neuropeptide expression. - #Acetate, as a signaling metabolite that can enhance the maturation of microglia, maintain the homeostatic metabolic state, and regulate microglial phagocytosis and AD pathological progression during neurodegeneration [#Keto diet] - high-ketogenic diet is the most promising therapeutic method for mitigating AD because it may restore the metabolic imbalance caused due to the occurrence of aerobic glycolysis in the neurons and the microglia. - The proposed high-ketogenic diet with low carbohydrates enhanced the supply of ketone bodies biosynthesized in the liver using free fatty acids as a substitute for those cells with a high demand for #Glucose [#Parkinson’s Disease] - several studies have consistently reported a greater abundance of #Akkermansia in the fecal samples of PD and AD patients than that in healthy controls [1.101] - A neurotoxic substance called #N-methylamino-L-alanine, generated by an intestinal bacterium called #Cyanobacteria, disrupts the N-methyl-D-aspartate glutamate receptor and contributes to signal dysfunction in AD. [1.102] - #Cutibacterium acnes and #Methylobacterium spp > co-occurrence in the brains of the AD cohort, primarily in the frontal lobe, suggests possible pathogenicity. [1.103] - Human neurons up-regulated the neuron-specific maternally expressed gene 3 (MEG3) in response to #Amyloid plaques. - MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. - Down-regulation of MEG3 protected the neurons from dying in the xenograft model of Alzheimer’s disease. [1.104] - milk and #Dairy product intake significantly reduced the risk of developing Alzheimer’s #Dementia but not vascular #Dementia [1.105] [#Mild Cognitive Impairment] - decreased #Formate among individuals with AD and MCI suggests alterations in #Tryptophan degradation in AD. [#Amyloid-beta] - #Tryptophan metabolites have been shown to regulate the cerebral activity of #Neprilysin, a metalloproteinase that controls the degradation and clearance of Aβ peptides in the brain. - #Formate metabolism is altered in individuals with AD also due to genetic variations, which could lead to changes in #Formate urine secretion in addition to microbial #Formate production. - urinary #Formate has been already suggested as a new potential biomarker for Alzheimer’s disease. - diminished #Formate microbial secretion > decreased #Formate and #Fumarate concentrations in AD. - #Tryptophan depletion increases cognitive deficits among people with AD and the bioavailability of metabolites in the #Serotonin and #kynurenine pathways are altered in both the urine and serum of AD patients [1.106] [#Trigonelline] - TG promotes the regeneration of dendrites and axons in cortical neurons and inhibits the formation of advanced glycation end products in vitro, and improves learning and memory impairment in the in vivo models of Alzheimer’s disease and neuroinflammation [1.107] [#Amyotrophic lateral sclerosis, #Multiple Sclerosis, #Parkinson’s Disease] - #Ferulic acid (FA), which occurs naturally as the feruloylated #Sugar ester in grains, fruits, and vegetables, is critical for combating #Oxidative stress and alleviating neurodegenerative diseases resulting from free radical-generated protein aggregates in brain cells. - #Ferulic acid esterases (FAE) of the gut microbiota are critical enzymes that facilitate FA release from feruloylated #Sugar ester conjugates and influence systemic health. [1.108] [#Amyotrophic lateral sclerosis, #Parkinson’s Disease] - the abundance of bacteria from the #Prevotella genus negatively correlates with the pathogenicity and prevalence of different PCDs, including ALS, PD, and a mouse AD model > neuroprotective role of #Prevotella spp. [#Prevotella corporis, #Prevotella disiens] - specific species (p. disiens and p. corporis) decrease toxic polyglutamine (polyQ) aggregation in #Caenorhabditis elegans [1.109] - Blockade of the IL-1 receptor with anakinra resulted in a significant increase in cognitive capacity in healthy mice as well as in the APP/PS1 model of Alzheimer´s disease. - repeated short exposures to #Menthol odor enhanced the immune response against ovalbumin immunization. - #Menthol inhalation also improved the cognitive capacity of immunocompetent mice but not in immunodeficient NSG mice, which exhibited very poor fear-conditioning. - Exposure to #Menthol for 6 months (1 week per month) prevented the #Cognitive impairment observed in the APP/PS1 mouse model of Alzheimer. - this improvement was also observed by the depletion or inhibition of T regulatory cells. [#Porphyromonas gingivalis] - patients with AD exhibited higher blood levels of anti-P. gingivalis IgG > is associated with specific #Cognitive impairment [#Actinomyces meyeri] - #Actinomycetia, a class-level bacteria of A. meyeri, and #Actinomyces, a genus-level bacteria of A. meyeri, have been found to be increased in the brain of AD patients [#Aggregatibacter actinomycetemcomitans] [#Amyloid-beta, #Lipopolysaccharide] - LPS from serotype B of A. actinomycetemcomitans, > trigger high levels of proinflammatory cytokine production in microglia and an increase the secretion of the Aβ1-42 peptide > AD [#Porphyromonas gingivalis] [#Lipopolysaccharide] - intraperitoneally injection of P. gingivalis LPS led to a reduction in the expression of #Neprilysin in the hippocampus > lower levels of #Neprilysin have been associated with increased Aβ accumulation in AD - #Streptococcus bacteria have been detected in the brain microbiome from AD patients - #Treponema species have been identified in the brains of patients with AD [1.111] [#Blood Brain Barrier Integrity] [#Candida albicans] [#Amyloid-beta] - C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted #Aspartic proteinases (Saps) and #Candidalysin. - Saps disrupt tight junction proteins of the blood-brain barrier (BBB) to permit fungal brain invasion. - Saps also hydrolyze amyloid precursor protein (APP) into amyloid b (Ab)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while #Candidalysin engages the integrin CD11b (Mac-1) on microglia. [1.112] [#Proton pump inhibitors] - PPIs can affect brain cells through various mechanisms, for example, by increasing beta-#Amyloid levels, involved in the development of AD. [1.113] the transplantation of human gut microbiota from Alzheimer’s patients is sufficient to produce core cognitive symptoms of Alzheimer’s disease coupled with an impairment in adult hippocampal neurogenesis (AHN), in healthy young adult rats. - decreased neurogenesis in human-derived HPCs treated with blood serum from Alzheimer’s patients - AD > lower proportion of bacteria with the potential to synthetize #Butyrate, a microbial metabolite negatively associated with cortical #Amyloid accumulation. - reduced abundance of #Clostridium sensu stricto 1 is associated with adverse outcomes in Alzheimer’s disease. - Reduced abundance of the genus #Coprococcus in Alzheimer’s disease, which is associated with #Amyloid accumulation. - the percentage of DCX-positive neuroblasts inversely correlated with parabiont genera #Desulfovibrio and #Dialister, and the percentage of Map2-positive cells inversely correlated with genera #Desulfovibrio, #Dialister and #Eisenbergiella. [#Fecal Microbiota Transplantation] - one of the genera that was increased at Day 59 post Alzheimer’s-FMT compared to Day 10 was #Desulfovibrio, a genus that was also significantly enriched in Alzheimer’s participants. [#Short Chain Fatty Acid] - The parabiont #Desulfovibrio has also been found to be enriched in other Alzheimer’s cohorts and is associated with reduced caecal levels of SCFAs and with inflammation in mice. [#Fecal Microbiota Transplantation] - young adult rats induced by gut microbiota from Alzheimer’s patients are reliant on AHN. Our analysis of AHN in recipient rats revealed that the survival of new neurons and the number of newly born neurons was decreased after Alzheimer’s-FMT, which supports our behavioural observations. [#Fecal Microbiota Transplantation] - the free amino acid #Taurine was decreased in the hippocampus of Alzheimer’s-FMT rats. - #Taurine administration has repeatedly been shown to increase hippocampal neural stem and progenitor cell proliferation, survival and neurogenesis both in vivo and in vitro. [1.114] [#Atopobium rimae, #Bacteroides-Prevotella group, #Prevotella nigrescens, #Prevotella oulorum, #Treponema socranskii, #prevotella salivae] - subgingival samples of the AD group showed significant increases in the abundance of bacterial species potentially linked with periodontitis, such as A. rimae, #Saccharibacteria (#TM7) HMT 348, #Selenomonas sp. HMT 442, T. socranskii and various #Prevotella spp., such as P. maculosa, P. multiformis, P. nigrescens, P. oulorum and P. salivae, which could aggravate systemic diseases. - potential periodontal pathogens such as #Prevotella, #Saccharibacteria (#TM7), #Treponema and #Selenomonas spp. were significantly more abundant in the AD group, especially in subgingival plaque. - #Prevotella spp. were densely interconnected with various oral microbiome. [1.115] [#Helicobacter pylori] - 11% increase in the risk of AD associated with exposure to CAHPI (clinically apparent #Helicobacter pylori infection) among subjects aged at least 50 years. - The increase in the risk of AD reached a peak of 24% roughly a decade after the onset of CAHPI > statistical significance roughly 8 years following CAHPI onset, peaked 2 years later, and decreased afterwards. [1.116] [#Parkinson’s Disease] [#Tryptophan] - Part of #kynurenine can also be converted to #3-hydroxykynurenine (3-HK) by the #kynurenine-3-monooxygenase (KMO). 3-HK is further converted to 3-hydroxyanthranilic (3-HAA) via the enzyme kynureninase. Both 3-HK and 3-HAA are neurotoxic and oxidative mediators. - 3-HK has been shown to induce endogenous oxidative stress and neuronal cell apoptosis and has been linked to a series of neurodegenerative disorders [1.117] [#β-hydroxybutyrate] [#Keto diet] - Alzheimer disease > KD’s ‘main actor’ is thought to be Beta-Hydroxy-butyrate (BHB) whose levels rose significantly in KD vs. CD mice, and BHB itself significantly rescued LTP in APP/PS1 hippocampi. - KD’s 6 most significant pathways induced in brains by RNAseq all related to Synaptic Plasticity. - KD induced significant increases in synaptic plasticity enzymes p-ERK and p-CREB in both sexes, and of brain-derived neurotrophic factor (#BDNF) in APP/PS1 females. [1.118] [#Amyloid-beta] - Early stage ovariectomy (OVX) leads to a reduction of plasma #Estradiol that is correlated with a significant alteration of gut microbiome composition and reduction in Aβ pathology. - supplementation of OVX-treated animals with #Estradiol restores Aβ burden and influences gut microbiome composition. [1.119] - #Anthocyanins were also able to mitigate #Oxidative stress and neurodegeneration in a mouse model of AD by modulating the PI3K/Akt/Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) axis - The #Flavonoid #Baicalein has also shown to inhibit microglia-induced neuroinflammation in a mouse model of AD by suppressing NLRP3 activation and the TLR4/NF-kB pathway - #Resveratrol, which is currently under investigation in several clinical trials for AD, has demonstrated to possess remarkable immunomodulatory properties in immune cell populations highly relevant in the context of the disease. It inhibited microglia activation, proliferation and cytokine production (#IL-6 and TNF-α) [#Parkinson’s Disease] [#Gingipains] - #Porphyromonas gingivalis (P. gingivalis), a pathogen of oral dysbiosis, plays an important role in PD, whose lysine-gingipain (Kgp) could lead to AD-type pathologies. [1.121] [#Retinoic acid] - RA, have been suggested to exhibit beneficial effects in Alzheimer’s disease by mechanisms that involve inhibiting the formation, elongation, and destabilizing effects of β-#Amyloid fibrils [1.122] - that microbial #Formate secretion capacity was lower in AD microbiomes. - changes in microbial #Formate production, due to differences in microbiome composition, would be responsible for the reduced urine #Formate secretion in AD patients - microbial-derived #Tryptophan degradation as one of the primary microbial sources of #Formate. - #Tryptophan depletion increases cognitive deficits among people with AD and the bioavailability of metabolites in the #Serotonin and #kynurenine pathways are altered in both the urine and serum of AD patients [1.123] - #Acetate treatment exacerbated Aβ plaque deposition and neuroinflammation in GF 5×FAD mice - dietary supplementation with high #Acetate and #Butyrate (HAMSAB) may attenuate cognitive decline in 5×FAD mice - #Butyrate, acting as a histone deacetylase inhibitor, has demonstrated the ability to elevate the expression of genes associated with learning, restore histone acetylation, and markedly enhance learning and memory ability in AD mice - AD patients > DCA and its conjugated forms with #Glycine and #Taurine increased, and #Deoxycholic acid was associated with decreased cognitive abilities [#Reactive Oxygen Species, #Ursodeoxycholic acid] - UDCA reduces the levels of ROS, tumor necrosis factor alpha (TNFα), and interleukin-1 beta (IL-1β), exerting anti-apoptotic, #Oxidative stress and inflammatory effects in AD [1.124] [#Amyloid-beta] - neuritin (NRN1), a neurotrophic factor previously linked to cognitive resilience > provided dendritic spine resilience against amyloid-β (Aβ) and blocked Aβ-induced neuronal hyperexcitability in cultured neurons. [1.125] - Orphan OPN4, related to disruption of circadian rhythm in AD, is significantly down-regulated in human AD hippocampus - C3AR and p-#Tau were reduced by #Agmatine, which has been reported to improve cognitive decline in AD rats. [#Bacteroides thetaiotaomicron] - L-#Phenylalanine was produced by B. theta C34 as an agonist for GPR56 (AGRG1) and GPR97 (AGRG3) [#Eubacterium rectale] - GPR183, an immunomodulatory EBI2 receptor, was recently reported to be antagonized by a gut metabolite #Lauroyl tryptamine derived from E. rectale. - two naturally occurring compounds (#Kaempferol and #Rhapontigenin) have been shown to increase the survival and functionality of glutamatergic and cholinergic neurons and improve animal memory. [#Niacin] - HCAR2 (GPR109A), a microglial receptor playing a protective role in AD, was activated by nicotinic acid derived from R. guavus. - N6-carboxymethyllysine has been linked to increased #Oxidative stress and mitochondrial dysfunction in microglia from the brains of aged mice. - #Phenethylamine reduced the p-#Tau levels in AD patient iPSC-derived neurons. #Phenethylamine, a trace amine, has been associated with reduced risk of AD. [#Phylloquinone ] - elevated dietary phylloquinone (vitamin K1) has been associated with better cognitive function in patients with AD.References Notes[ ]
