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. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1–42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1–42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer’s disease.
Showing posts with label Alzheimer's disease. Show all posts
Showing posts with label Alzheimer's disease. Show all posts
Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits | Nature Communications
Bloodborne infections with Candida albicans are an increasingly
recognized complication of modern medicine. Here, we present a mouse
model of low-grade candidemia to determine the effect of disseminated
infection on cerebral function and relevant immune determinants. We show
that intravenous injection of 25,000 C. albicans cells causes a
highly localized cerebritis marked by the accumulation of activated
microglial and astroglial cells around yeast aggregates, forming
fungal-induced glial granulomas. Amyloid precursor protein accumulates
within the periphery of these granulomas, while cleaved amyloid beta
(Aβ) peptides accumulate around the yeast cells. CNS-localized C. albicans
further activate the transcription factor NF-κB and induce production
of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor (TNF), and Aβ
peptides enhance both phagocytic and antifungal activity from BV-2
cells. Mice infected with C. albicans display mild memory
impairment that resolves with fungal clearance. Our results warrant
additional studies to understand the effect of chronic cerebritis on
cognitive and immune function.
recognized complication of modern medicine. Here, we present a mouse
model of low-grade candidemia to determine the effect of disseminated
infection on cerebral function and relevant immune determinants. We show
that intravenous injection of 25,000 C. albicans cells causes a
highly localized cerebritis marked by the accumulation of activated
microglial and astroglial cells around yeast aggregates, forming
fungal-induced glial granulomas. Amyloid precursor protein accumulates
within the periphery of these granulomas, while cleaved amyloid beta
(Aβ) peptides accumulate around the yeast cells. CNS-localized C. albicans
further activate the transcription factor NF-κB and induce production
of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor (TNF), and Aβ
peptides enhance both phagocytic and antifungal activity from BV-2
cells. Mice infected with C. albicans display mild memory
impairment that resolves with fungal clearance. Our results warrant
additional studies to understand the effect of chronic cerebritis on
cognitive and immune function.
Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. - PubMed - NCBI
BACKGROUND:
The results from cross sectionaland longitudinal studies show that periodontitis is closely associated
with cognitive impairment (CI) and Alzhemer's Disease (AD). Further,
studies using animal model of periodontitis and human post-mortem brain
tissues from subjects with AD strongly suggest that a gram-negative
periodontal pathogen, Porphyromonas gingivalis
(Pg) and/or its product gingipain is/are translocated to the brain.
However, neuropathology resulting from Pg oral application is not known.
In this work, we tested the hypothesis that repeated exposure of wild
type C57BL/6 mice to orally administered Pg results in
neuroinflammation, neurodegeneration, microgliosis, astrogliosis and
formation of intra- and extracellular amyloid plaque and neurofibrillary
tangles (NFTs) which are pathognomonic signs of AD.
METHODS:
Experimentalchronic periodontitis was induced in ten wild type 8-week old C57BL/6
WT mice by repeated oral application (MWF/week) of Pg/gingipain for 22
weeks (experimental group). Another 10 wild type 8-week old C57BL/6 mice
received vehicle alone (control group) MWF per week for 22 weeks. Brain
tissues were collected and the presence of Pg/gingipain was determined
by immunofluorescence (IF) microscopy, confocal microscopy, and
quantitative PCR (qPCR). The hippocampi were examined for the signs of
neuropathology related to AD: TNFα, IL1β, and IL6 expression
(neuroinflammation), NeuN and Fluoro Jade C staining (neurodegeneration)
and amyloid beta1-42 (Aβ42) production and phosphorylation of tau
protein at Ser396 were assessed by IF and confocal microscopy. Further,
gene expression of amyloid precursor protein (APP), beta-site APP
cleaving enzyme 1 (BACE1), a disintegrin and metalloproteinase
domain-containing protein10 (ADAM10) for α-secretase and presenilin1
(PSEN1) for ɣ-secretase, and NeuN (rbFox3) were determined by RT-qPCR.
Microgliosis and astrogliosis were also determined by IF microscopy.
RESULTS:
Pg/gingipainwas detected in the hippocampi of mice in the experimental group by
immunohistochemistry, confocal microscopy, and qPCR confirming the
translocation of orally applied Pg to the brain. Pg/gingipain was
localized intra-nuclearly and peri-nuclearly in microglia (Iba1+),
astrocytes (GFAP+), neurons (NeuN+) and was evident extracellularly.
Significantly greater levels of expression of IL6, TNFα and IL1β were
evident in experimental as compared to control group (p<0.01,
p<0.00001, p<0.00001 respectively). In addition, microgliosis and
astrogliosis were evident in the experimental but not in control group
(p <0.01, p<0.0001 respectively). Neurodegeneration was evident in
the experimental group based on a fewer number of intact neuronal cells
assessed by NeuN positivity and rbFOX3 gene expression, and there was a
greater number of degenerating neurons in the hippocampi of
experimental mice assessed by Fluoro Jade C positivity. APP and BACE1
gene expression were increased in experimental group compared with
control group (p<0.05, p<0.001 respectively). PSEN1 gene
expression was higher in experimental than control group but the
difference was not statistically significant (p = 0.07). ADAM10 gene
expression was significantly decreased in experimental group compared
with control group (p<0.01). Extracellular Aβ42 was detected in the
parenchyma in the experimental but not in the control group (p<
0.00001). Finally, phospho-Tau (Ser396) protein was detected and NFTs
were evident in experimental but not in the control group
(p<0.00001).
CONCLUSIONS:
This study is the first toshow neurodegeneration and the formation of extracellular Aβ42 in young
adult WT mice after repeated oral application of Pg. The
neuropathological features observed in this study strongly suggest that
low grade chronic periodontal pathogen infection can result in the
development of neuropathology that is consistent with that of AD.
Pathway of Alzheimer's degeneration discovered: Finding is key for future treatment and earlier diagnosis -- ScienceDaily
Scientists at the Montreal Neurological
Institute and Hospital (The Neuro) of McGill University have used a
unique approach to track brain degeneration in Alzheimer's disease,
uncovering a pathway through which degeneration spreads from one region
to another.
Individuals in the early stages of Alzheimer's disease (AD) were Institute and Hospital (The Neuro) of McGill University have used a
unique approach to track brain degeneration in Alzheimer's disease,
uncovering a pathway through which degeneration spreads from one region
to another.
scanned using both structural magnetic resonance imaging (sMRI) and
positron emission tomography (PET). The scientists were interested in
how AD affects the basal forebrain -- a deep brain structure that
supplies the outer cortex with acetylcholine, a neurotransmitter that is
critical for maintaining normal brain function. They found that as
cholinergic neurons in the basal forebrain degenerate, the areas in the
cortex which receive their cholinergic inputs also degenerate.
Herpes Viruses Implicated in Alzheimer’s Disease
The brains of Alzheimer’s disease patients have an abnormal build up of amyloid-β proteins and tau tangles, which, according to many researchers, drives the ultimately fatal cognitive disease. This theory is being amended to a newer one, which posits that microbes may trigger Alzheimer’s pathology. Two new studies, using different approaches, further bolster this pathogen theory. Analyzing the transcriptomes of post-mortem brain samples from patients with Alzheimer’s disease, one group of researchers finds that two strains of human herpes virus (Roseoloviruses HHV-6 and HHV-7) are significantly more abundant than in the brains of people of the same age without Alzheimer’s disease. Gene networks in the brains of Alzheimer’s patients with these strains are also rewired such that disease-related genes are differentially expressed compared to controls.
In the other study, another team of investigators observed in mouse models and in a three-dimensional human neuronal cell culture that a Herpesviridae infection could seed amyloid-β plaques.
In the other study, another team of investigators observed in mouse models and in a three-dimensional human neuronal cell culture that a Herpesviridae infection could seed amyloid-β plaques.
Infection of Fungi and Bacteria in Brain Tissue From Elderly Persons and Patients With Alzheimer’s Disease | Frontiers in Aging Neuroscience
Alzheimer’s disease (AD) is the leading cause of dementia in elderly
people. The etiology of this disease remains a matter of intensive
research in many laboratories. We have advanced the idea that
disseminated fungal infection contributes to the etiology of AD. Thus,
we have demonstrated that fungal proteins and DNA are present in nervous
tissue from AD patients. More recently, we have reported that bacterial
infections can accompany these mycoses, suggesting that polymicrobial
infections exist in AD brains. In the present study, we have examined
fungal and bacterial infection in brain tissue from AD patients and
control subjects by immunohistochemistry. In addition, we have
documented the fungal and bacterial species in brain regions from AD
patients and control subjects by next-generation sequencing (NGS). Our
results from the analysis of ten AD patients reveal a variety of fungal
and bacterial species, although some were more prominent than others.
The fungal genera more prevalent in AD patients were Alternaria, Botrytis, Candida, and Malassezia.
We also compared these genera with those found in elderly and younger
subjects. One of the most prominent genera in control subjects was Fusarium.
Principal component analysis clearly indicated that fungi from frontal
cortex samples of AD brains clustered together and differed from those
of equivalent control subjects. Regarding bacterial infection, the
phylum Proteobacteria was the most prominent in both AD patients and controls, followed by Firmicutes, Actinobacteria, and Bacteroides. At the family level, Burkholderiaceae and Staphylococcaceae
exhibited higher percentages in AD brains than in control brains. These
findings could be of interest to guide targeted antimicrobial therapy
for AD patients. Moreover, the variety of microbial species in each
patient may constitute a basis for a better understanding of the
evolution and severity of clinical symptoms in each patient.
people. The etiology of this disease remains a matter of intensive
research in many laboratories. We have advanced the idea that
disseminated fungal infection contributes to the etiology of AD. Thus,
we have demonstrated that fungal proteins and DNA are present in nervous
tissue from AD patients. More recently, we have reported that bacterial
infections can accompany these mycoses, suggesting that polymicrobial
infections exist in AD brains. In the present study, we have examined
fungal and bacterial infection in brain tissue from AD patients and
control subjects by immunohistochemistry. In addition, we have
documented the fungal and bacterial species in brain regions from AD
patients and control subjects by next-generation sequencing (NGS). Our
results from the analysis of ten AD patients reveal a variety of fungal
and bacterial species, although some were more prominent than others.
The fungal genera more prevalent in AD patients were Alternaria, Botrytis, Candida, and Malassezia.
We also compared these genera with those found in elderly and younger
subjects. One of the most prominent genera in control subjects was Fusarium.
Principal component analysis clearly indicated that fungi from frontal
cortex samples of AD brains clustered together and differed from those
of equivalent control subjects. Regarding bacterial infection, the
phylum Proteobacteria was the most prominent in both AD patients and controls, followed by Firmicutes, Actinobacteria, and Bacteroides. At the family level, Burkholderiaceae and Staphylococcaceae
exhibited higher percentages in AD brains than in control brains. These
findings could be of interest to guide targeted antimicrobial therapy
for AD patients. Moreover, the variety of microbial species in each
patient may constitute a basis for a better understanding of the
evolution and severity of clinical symptoms in each patient.
Reaction of Amyloid-β Peptide Antibody with Different Infectious Agents Involved in Alzheimer’s Disease - IOS Press
As early as the 1980s, molecular virologist Ruth Itzhaki began to
investigate if there was a causal connection between infections and
neurodegenerative disorder. Although the theory has yet to be
universally embraced, in 2016 Itzhaki and 33 other scientists from all
over the world published a review
article in this very journal presenting evidence for the causal role of
pathogens in Alzheimer’s disease (AD). Exactly how and in what way
pathogens affect the induction of AD has yet to be determined, but one
possible answer may involve the cross-reactivity of different pathogens
with amyloid-β (Aβ). Aβ autoantibodies have been detected in the serum
and cerebrospinal fluid of AD patients and in some healthy individuals.
In the present study our major goal was to investigate whether
antibodies made against Aβ would react both with other brain proteins as
well as pathogens associated with AD as a result of molecular mimicry
or the binding of bacterial toxins to Aβ42. Our study used a specific
monoclonal antibody made against Aβ42, which not only reacted strongly
with Aβ42, tau protein, and α-synuclein, but also had from weak to
strong reactions with 25 different pathogens or their molecules, some of
which have been associated with AD. The homology between peptide
stretches of microbial origin and proteins involved in AD could be a
mechanism by which antibodies to homologous peptides mount attacks
against autoantigens in AD. We concluded that bacterial molecules bind
to Aβ protein, forming small oligomers, then encasing pathogens and
their molecules to form amyloid plaques, the tell-tale markers of AD.
Conversely, these same Aβ peptides induce the production of antibodies
to both Aβ42 and bacterial molecules, which may inhibit bacterial
pathogenesis, but in the process may promote amyloid plaque formation.
investigate if there was a causal connection between infections and
neurodegenerative disorder. Although the theory has yet to be
universally embraced, in 2016 Itzhaki and 33 other scientists from all
over the world published a review
article in this very journal presenting evidence for the causal role of
pathogens in Alzheimer’s disease (AD). Exactly how and in what way
pathogens affect the induction of AD has yet to be determined, but one
possible answer may involve the cross-reactivity of different pathogens
with amyloid-β (Aβ). Aβ autoantibodies have been detected in the serum
and cerebrospinal fluid of AD patients and in some healthy individuals.
In the present study our major goal was to investigate whether
antibodies made against Aβ would react both with other brain proteins as
well as pathogens associated with AD as a result of molecular mimicry
or the binding of bacterial toxins to Aβ42. Our study used a specific
monoclonal antibody made against Aβ42, which not only reacted strongly
with Aβ42, tau protein, and α-synuclein, but also had from weak to
strong reactions with 25 different pathogens or their molecules, some of
which have been associated with AD. The homology between peptide
stretches of microbial origin and proteins involved in AD could be a
mechanism by which antibodies to homologous peptides mount attacks
against autoantigens in AD. We concluded that bacterial molecules bind
to Aβ protein, forming small oligomers, then encasing pathogens and
their molecules to form amyloid plaques, the tell-tale markers of AD.
Conversely, these same Aβ peptides induce the production of antibodies
to both Aβ42 and bacterial molecules, which may inhibit bacterial
pathogenesis, but in the process may promote amyloid plaque formation.
Hallmarks of Alzheimer disease are evolving relentlessly in Metropolitan Mexico City infants, children and young adults. APOE4 carriers have higher suicide risk and higher odds of reaching NFT stage V at ≤ 40 years of age - ScienceDirect
Exposures to fine particulate matter (PM2.5) and ozone (O3)
above USEPA standards are associated with Alzheimer's disease (AD)
risk. Metropolitan Mexico City (MMC) residents have life time exposures
to PM2.5 and O3 above USEPA standards. We
investigated AD intra and extracellular protein aggregates and
ultrastructural neurovascular pathology in 203 MMC residents age
25.36 ± 9.23 y. Immunohistochemical methods were used to identify AT8
hyperphosphorilated tau (Htau) and 4G8 (amyloid β 17-24). Primary
outcomes: staging of Htau and amyloid, per decade and cumulative PM2.5 (CPM2.5) above standard. Apolipoprotein E allele 4 (APOE4), age and cause of death were secondary outcomes.
above USEPA standards are associated with Alzheimer's disease (AD)
risk. Metropolitan Mexico City (MMC) residents have life time exposures
to PM2.5 and O3 above USEPA standards. We
investigated AD intra and extracellular protein aggregates and
ultrastructural neurovascular pathology in 203 MMC residents age
25.36 ± 9.23 y. Immunohistochemical methods were used to identify AT8
hyperphosphorilated tau (Htau) and 4G8 (amyloid β 17-24). Primary
outcomes: staging of Htau and amyloid, per decade and cumulative PM2.5 (CPM2.5) above standard. Apolipoprotein E allele 4 (APOE4), age and cause of death were secondary outcomes.
Subcortical
pretangle stage b was identified in an 11month old baby. Cortical tau
pre-tangles, neurofibrillary tangles (NFT) Stages I-II, amyloid phases
1–2, Htau in substantia nigrae, auditory, oculomotor, trigeminal and
autonomic systems were identified by the 2nd decade. Progression to NFT
stages III-V was present in 24.8% of 30–40 y old subjects. APOE4
carriers have 4.92 times higher suicide odds (p = 0.0006), and 23.6
times higher odds of NFT V (p < 0.0001) v APOE4 non-carriers having
similar CPM2.5 exposure and age. Age (p = 0.0062) and CPM2.5 (p = 0.0178) were significant for developing NFT V. Combustion-derived nanoparticles
were associated with early and progressive damage to the neurovascular
unit. Alzheimer's disease starting in the brainstem of young children
and affecting 99.5% of young urbanites is a serious health crisis. Air pollution control
should be prioritised. Childhood relentless Htau makes a fundamental
target for neuroprotective interventions and the first two decades are
critical. We recommend the concept of preclinical AD be revised and
emphasize the need to define paediatric environmental, nutritional,
metabolic and genetic risk factor interactions of paramount importance
to prevent AD. AD evolving from childhood is threating the wellbeing of
our children and future generations.
pretangle stage b was identified in an 11month old baby. Cortical tau
pre-tangles, neurofibrillary tangles (NFT) Stages I-II, amyloid phases
1–2, Htau in substantia nigrae, auditory, oculomotor, trigeminal and
autonomic systems were identified by the 2nd decade. Progression to NFT
stages III-V was present in 24.8% of 30–40 y old subjects. APOE4
carriers have 4.92 times higher suicide odds (p = 0.0006), and 23.6
times higher odds of NFT V (p < 0.0001) v APOE4 non-carriers having
similar CPM2.5 exposure and age. Age (p = 0.0062) and CPM2.5 (p = 0.0178) were significant for developing NFT V. Combustion-derived nanoparticles
were associated with early and progressive damage to the neurovascular
unit. Alzheimer's disease starting in the brainstem of young children
and affecting 99.5% of young urbanites is a serious health crisis. Air pollution control
should be prioritised. Childhood relentless Htau makes a fundamental
target for neuroprotective interventions and the first two decades are
critical. We recommend the concept of preclinical AD be revised and
emphasize the need to define paediatric environmental, nutritional,
metabolic and genetic risk factor interactions of paramount importance
to prevent AD. AD evolving from childhood is threating the wellbeing of
our children and future generations.
Neuroscientists say daily ibuprofen can prevent Alzheimer's disease -- ScienceDaily
A Vancouver-based research team led by Canada's most cited
neuroscientist, Dr. Patrick McGeer, has successfully carried out studies
suggesting that, if started early enough, a daily regimen of the
non-prescription NSAID (nonsteroidal anti-inflammatory drug) ibuprofen
can prevent the onset of Alzheimer's disease. This means that by taking
an over-the-counter medication, people can ward off a disease that,
according to Alzheimer's Disease International's World Alzheimer Report
2016, affects an estimated 47 million people worldwide, costs health
care systems worldwide more than US$818 billion per year and is the
fifth leading cause of death in those aged 65 or older.
Here's the paper:-
neuroscientist, Dr. Patrick McGeer, has successfully carried out studies
suggesting that, if started early enough, a daily regimen of the
non-prescription NSAID (nonsteroidal anti-inflammatory drug) ibuprofen
can prevent the onset of Alzheimer's disease. This means that by taking
an over-the-counter medication, people can ward off a disease that,
according to Alzheimer's Disease International's World Alzheimer Report
2016, affects an estimated 47 million people worldwide, costs health
care systems worldwide more than US$818 billion per year and is the
fifth leading cause of death in those aged 65 or older.
Here's the paper:-
Conquering Alzheimer’s Disease by Self Treatment JAD
Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections—a Nationwide, Population-Based Cohort Study in Taiwan
This retrospective cohort study is to investigate the association
between herpes simplex virus (HSV) infections and dementia, and the
effects of anti-herpetic medications on the risk involved, using
Taiwan’s National Health Insurance Research Database (NHIRD). We
enrolled a total of 33,448 subjects, and identified 8362 with newly
diagnosed HSV infections and 25,086 randomly selected sex- and
age-matched controls without HSV infections in a ratio of 1:3, selected
from January 1, to December 31, 2000. A multivariable Cox proportional
hazards regression model was used to evaluate the risk of developing
dementia in the HSV cohort. This analysis revealed an adjusted hazard
ratio of 2.564 (95% CI: 2.351-2.795, P < 0.001)
for the development of dementia in the HSV-infected cohort relative to
the non-HSV cohort. Thus, patients with HSV infections may have a
2.56-fold increased risk of developing dementia. A risk reduction of
dementia development in patients affected by HSV infections was found
upon treatment with anti-herpetic medications (adjusted HR = 0.092 [95%
CI 0.079-0.108], P < 0.001).
Theusage of anti-herpetic medications in the treatment of HSV infections
was associated with a decreased risk of dementia. These findings could
be a signal to clinicians caring for patients with HSV infections.
Further research is, therefore, necessary to explore the underlying
mechanism(s) of these associations.
between herpes simplex virus (HSV) infections and dementia, and the
effects of anti-herpetic medications on the risk involved, using
Taiwan’s National Health Insurance Research Database (NHIRD). We
enrolled a total of 33,448 subjects, and identified 8362 with newly
diagnosed HSV infections and 25,086 randomly selected sex- and
age-matched controls without HSV infections in a ratio of 1:3, selected
from January 1, to December 31, 2000. A multivariable Cox proportional
hazards regression model was used to evaluate the risk of developing
dementia in the HSV cohort. This analysis revealed an adjusted hazard
ratio of 2.564 (95% CI: 2.351-2.795, P < 0.001)
for the development of dementia in the HSV-infected cohort relative to
the non-HSV cohort. Thus, patients with HSV infections may have a
2.56-fold increased risk of developing dementia. A risk reduction of
dementia development in patients affected by HSV infections was found
upon treatment with anti-herpetic medications (adjusted HR = 0.092 [95%
CI 0.079-0.108], P < 0.001).
Theusage of anti-herpetic medications in the treatment of HSV infections
was associated with a decreased risk of dementia. These findings could
be a signal to clinicians caring for patients with HSV infections.
Further research is, therefore, necessary to explore the underlying
mechanism(s) of these associations.
Half of all dementias start with damaged 'gatekeeper cells': Once the cells are compromised, the brain's protective fort becomes leaky and allows blood toxins to trespass into the brain, damaging critical connections between brain areas, esearchers say. -- ScienceDaily
Half of all dementias start with damaged 'gatekeeper cells', or Pericytes: Once the cells are compromised, the brain's protective fort becomes leaky and allows blood toxins to trespass into the brain, damaging critical connections between brain areas, researchers say. -- ScienceDaily
$1 Million Prize for Alzheimer’s Disease Germ Announced by Dr. Leslie Norins on ALZgerm.org
Leslie Norins, MD, PhD, CEO of Alzheimer’s Germ Quest, Inc., announces a
$1 million challenge award for the scientist who provides persuasive
evidence that an infectious agent is the root cause of Alzheimer’s
disease. The three-year contest begins January 16, 2018. Details are
provided at ALZgerm.org..
$1 million challenge award for the scientist who provides persuasive
evidence that an infectious agent is the root cause of Alzheimer’s
disease. The three-year contest begins January 16, 2018. Details are
provided at ALZgerm.org..
Frontiers | The Porphyromonas gingivalis/host interactome shows enrichment in GWASdb genes related to Alzheimer’s disease, diabetes and cardiovascular diseases | Frontiers in Aging Neuroscience
Periodontal disease is of established aetiology in which polymicrobial
synergistic ecology has become dysbiotic under the influence of
Porphyromonas gingivalis. Following breakdown of the host’s protective
oral tissue barriers, P. gingivalis migrates to developing inflammatory
pathologies that associate with Alzheimer’s disease (AD). Periodontal
disease is a risk factor for cardiovascular disorders (CVD), type II
diabetes mellitus (T2DM), AD and other chronic diseases, whilst T2DM
exacerbates periodontitis. This study analysed the relationship between
the P. gingivalis/host interactome and the genes identified in
genome-wide association studies (GWAS) for the aforementioned conditions
using data from GWASdb (P<1E-03) and, in some cases, from the
NCBI/EBI GWAS database (P< 1E-05). Gene expression data from
periodontitis or P. gingivalis microarray was compared to microarray
datasets from the AD hippocampus and/or from carotid artery plaques. The
results demonstrated that the host genes of the P. gingivalis
interactome were significantly enriched in genes deposited in GWASdb
genes related to cognitive disorders, AD and dementia, and its co-morbid
conditions T2DM, obesity, and CVD. The P. gingivalis/host interactome
was also enriched in GWAS genes from the more stringent NCBI-EBI
database for AD, atherosclerosis and T2DM. The misregulated genes in
periodontitis tissue or P. gingivalis infected macrophages also matched
those in the AD hippocampus or atherosclerotic plaques. Together, these
data suggest important gene/environment interactions between P.
gingivalis and susceptibility genes or gene expression changes in
conditions where periodontal disease is a contributory factor.
synergistic ecology has become dysbiotic under the influence of
Porphyromonas gingivalis. Following breakdown of the host’s protective
oral tissue barriers, P. gingivalis migrates to developing inflammatory
pathologies that associate with Alzheimer’s disease (AD). Periodontal
disease is a risk factor for cardiovascular disorders (CVD), type II
diabetes mellitus (T2DM), AD and other chronic diseases, whilst T2DM
exacerbates periodontitis. This study analysed the relationship between
the P. gingivalis/host interactome and the genes identified in
genome-wide association studies (GWAS) for the aforementioned conditions
using data from GWASdb (P<1E-03) and, in some cases, from the
NCBI/EBI GWAS database (P< 1E-05). Gene expression data from
periodontitis or P. gingivalis microarray was compared to microarray
datasets from the AD hippocampus and/or from carotid artery plaques. The
results demonstrated that the host genes of the P. gingivalis
interactome were significantly enriched in genes deposited in GWASdb
genes related to cognitive disorders, AD and dementia, and its co-morbid
conditions T2DM, obesity, and CVD. The P. gingivalis/host interactome
was also enriched in GWAS genes from the more stringent NCBI-EBI
database for AD, atherosclerosis and T2DM. The misregulated genes in
periodontitis tissue or P. gingivalis infected macrophages also matched
those in the AD hippocampus or atherosclerotic plaques. Together, these
data suggest important gene/environment interactions between P.
gingivalis and susceptibility genes or gene expression changes in
conditions where periodontal disease is a contributory factor.
Selective Activation of Basal Forebrain Cholinergic Neurons Attenuates Polymicrobial Sepsis-Induced Inflammation via the Cholinergic Anti-Inflammat... - PubMed - NCBI
OBJECTIVES:
Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored.
SUBJECTS:
Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice.
INTERVENTIONS:
The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used.
MEASUREMENTS AND MAIN RESULTS:
Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation.
CONCLUSIONS:
These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis."
'via Blog this'
Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored.
SUBJECTS:
Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice.
INTERVENTIONS:
The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used.
MEASUREMENTS AND MAIN RESULTS:
Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation.
CONCLUSIONS:
These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis."
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Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease - IOS Press
Diverse pathogens are detected in Alzheimer’s disease (AD) brains. A bioinformatics survey showed that AD genome-wide association study (GWAS) genes (localized in bone marrow, immune locations and microglia) relate to multiple host/pathogen interactomes (Candida albicans, Cryptococcus neoformans, Bornavirus, Borrelia burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, Chlamydia pneumoniae, Porphyrymonas gingivalis, Helicobacter pylori, Toxoplasma gondii, Trypanosoma cruzi). These interactomes also relate to the AD hippocampal transcriptome and to plaque or tangle proteins. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi, or protozoa in immunocompetent cells. AD genes are enriched in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance, as supported by the old age of AD patients, implying resistance to earlier infections. APOE4 is concentrated in regions of high parasitic burden and protects against childhood tropical infections and hepatitis C. Immune/inflammatory gain of function applies to APOE4, CR1, and TREM2 variants. AD genes are also expressed in the blood-brain barrier (BBB), which is disrupted by AD risk factors (age, alcohol, aluminum, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) and by pathogens, directly or via olfactory routes to basal-forebrain BBB control centers. The BBB benefits from statins, NSAIDs, estrogen, melatonin, memantine, and the Mediterranean diet. Polymicrobial involvement is supported by upregulation of bacterial, viral, and fungal sensors/defenders in the AD brain, blood, or cerebrospinal fluid. AD serum amyloid-β autoantibodies may attenuate its antimicrobial effects favoring microbial survival and cerebral invasion leading to activation of neurodestructive immune/inflammatory processes, which may also be augmented by age-related immunosenescence. AD may thus respond to antibiotic, antifungal, or antiviral therapy."
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Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APP SWE /PS1 ΔE9 murine model of Alzheimer’s disease | Scientific Reports
Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer’s disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APPSWE/PS1ΔE9 mouse model of amyloidosis is commensurate with reductions in amyloid-β (Aβ) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APPSWE/PS1ΔE9 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long-term alterations of gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduction in brain Aβ deposition in aged APPSWE/PS1ΔE9 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3+ T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX-induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD.
Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies | Journal of Neurology, Neurosurgery & Psychiatry
Objectives Increasing evidence suggests that inflammation is involved in Alzheimer’s disease (AD) pathology. This study quantitatively summarised the data on peripheral inflammatory markers in patients with AD compared with healthy controls (HC).
Methods Original reports containing measurements of peripheral inflammatory markers in AD patients and HC were included for meta-analysis. Standardised mean differences were calculated using a random effects model. Meta-regression and exploration of heterogeneity was performed using publication year, age, gender, Mini-Mental State Examination (MMSE) scores, plasma versus serum measurements and immunoassay type.
Results A total of 175 studies were combined to review 51 analytes in 13 344 AD and 12 912 HC patients. Elevated peripheral interleukin (IL)-1β, IL-2, IL-6, IL-18, interferon-γ, homocysteine, high-sensitivity C reactive protein, C-X-C motif chemokine-10, epidermal growth factor, vascular cell adhesion molecule-1, tumour necrosis factor (TNF)-α converting enzyme, soluble TNF receptors 1 and 2, α1-antichymotrypsin and decreased IL-1 receptor antagonist and leptin were found in patients with AD compared with HC. IL-6 levels were inversely correlated with mean MMSE scores.
Conclusions These findings suggest that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment. Further studies are needed to determine the clinical utility of these markers."
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Methods Original reports containing measurements of peripheral inflammatory markers in AD patients and HC were included for meta-analysis. Standardised mean differences were calculated using a random effects model. Meta-regression and exploration of heterogeneity was performed using publication year, age, gender, Mini-Mental State Examination (MMSE) scores, plasma versus serum measurements and immunoassay type.
Results A total of 175 studies were combined to review 51 analytes in 13 344 AD and 12 912 HC patients. Elevated peripheral interleukin (IL)-1β, IL-2, IL-6, IL-18, interferon-γ, homocysteine, high-sensitivity C reactive protein, C-X-C motif chemokine-10, epidermal growth factor, vascular cell adhesion molecule-1, tumour necrosis factor (TNF)-α converting enzyme, soluble TNF receptors 1 and 2, α1-antichymotrypsin and decreased IL-1 receptor antagonist and leptin were found in patients with AD compared with HC. IL-6 levels were inversely correlated with mean MMSE scores.
Conclusions These findings suggest that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment. Further studies are needed to determine the clinical utility of these markers."
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Lithium in Drinking Water May Lower Dementia Risk
"Higher long-term lithium exposure from drinking water may be associated with a lower incidence of dementia, a large population-based study suggests.
"This is the first study ever investigating the association between lithium in drinking water and onset of dementia," Lars Vedel Kessing, MD, DMSc, from the University of Copenhagen, Denmark, told Medscape Medical News.
"If confirmed by others, tablets of lithium in microdose could be used among individuals at high risk of developing Alzheimer's disease, including those with a family history or certain genetic variations," Dr Kessing added.
The study was published online August 23 in JAMA Psychiatry."
However, Lithium in drug form does not appear to affect Alzheimer's disease
See:-
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"This is the first study ever investigating the association between lithium in drinking water and onset of dementia," Lars Vedel Kessing, MD, DMSc, from the University of Copenhagen, Denmark, told Medscape Medical News.
"If confirmed by others, tablets of lithium in microdose could be used among individuals at high risk of developing Alzheimer's disease, including those with a family history or certain genetic variations," Dr Kessing added.
The study was published online August 23 in JAMA Psychiatry."
However, Lithium in drug form does not appear to affect Alzheimer's disease
See:-
Association Between Lithium Use and Risk of Alzheimer's Disease.
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Polymicrobial Infections In Brain Tissue From Alzheimer's Disease Patients.
Several studies have advanced the idea that the etiology of Alzheimer's disease (AD) could be microbial in origin. In the present study, we tested the possibility that polymicrobial infections exist in tissue from the entorhinal cortex/hippocampus region of patients with AD using immunohistochemistry (confocal laser scanning microscopy) and highly sensitive (nested) PCR. We found no evidence for expression of early (ICP0) or late (ICP5) proteins of herpes simplex virus type 1 (HSV-1) in brain sections. A polyclonal antibody against Borrelia detected structures that appeared not related to spirochetes, but rather to fungi. These structures were not found with a monoclonal antibody. Also, Borrelia DNA was undetectable by nested PCR in the ten patients analyzed. By contrast, two independent Chlamydophila antibodies revealed several structures that resembled fungal cells and hyphae, and prokaryotic cells, but most probably were unrelated to Chlamydophila spp. Finally, several structures that could belong to fungi or prokaryotes were detected using peptidoglycan and Clostridium antibodies, and PCR analysis revealed the presence of several bacteria in frozen brain tissue from AD patients. Thus, our results show that polymicrobial infections consisting of fungi and bacteria can be revealed in brain tissue from AD patients."
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Frontiers | 16S rRNA Next Generation Sequencing Analysis Shows Bacteria in Alzheimer’s Post-Mortem Brain | Frontiers in Aging Neuroscience
The neurological deterioration associated with Alzheimer’s disease (AD), involving accumulation of amyloid-beta peptides and neurofibrillary tangles, is associated with evident neuroinflammation. This is now seen to be a significant contributor to pathology. Recently the tenet of the privileged status of the brain, regarding microbial compromise, has been questioned, particularly in terms of neurodegenerative diseases. It is now being considered that microbiological incursion into the central nervous system could be either an initiator or significant contributor to these. This is a novel study using 16S ribosomal gene-specific Next generation sequencing (NGS) of extracted brain tissue. A comparison was made of the bacterial species content of both frozen and formaldehyde fixed sections of a small cohort of Alzheimer-affected cases with those of cognitively unimpaired (normal). Our findings suggest an increase in bacterial populations in Alzheimer brain tissue compared with normal."
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