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.

A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents | Adolescent Medicine | JAMA Psychiatry | JAMA Network

Infections have been associated with increased risks for
mental disorders, such as schizophrenia and depression. However, the
association between all infections requiring treatment and the wide
range of mental disorders is unknown to date.

To investigate the association between all treated infections
since birth and the subsequent risk of development of any treated mental
disorder during childhood and adolescence.

Design, Setting, and Participants
Population-based cohort study using Danish nationwide
registers. Participants were all individuals born in Denmark between
January 1, 1995, and June 30, 2012 (N = 1 098 930). Dates of analysis
were November 2017 to February 2018.

All treated infections were identified in a time-varying
manner from birth until June 30, 2013, including severe infections
requiring hospitalizations and less severe infection treated with
anti-infective agents in the primary care sector.

Main Outcomes and Measures
This study identified all mental disorders diagnosed in a
hospital setting and any redeemed prescription for psychotropic
medication. Cox proportional hazards regression was performed reporting
hazard rate ratios (HRRs), including 95% CIs, adjusted for age, sex,
somatic comorbidity, parental education, and parental mental disorders.

A total of 1 098 930 individuals (51.3% male) were followed up
for 9 620 807.7 person-years until a mean (SD) age of 9.76 (4.91)
years. Infections requiring hospitalizations were associated with
subsequent increased risk of having a diagnosis of any mental disorder
(n = 42 462) by an HRR of 1.84 (95% CI, 1.69-1.99) and with increased
risk of redeeming a prescription for psychotropic medication
(n = 56 847) by an HRR of 1.42 (95% CI, 1.37-1.46). Infection treated
with anti-infective agents was associated with increased risk of having a
diagnosis of any mental disorder (HRR, 1.40; 95% CI, 1.29-1.51) and
with increased risk of redeeming a prescription for psychotropic
medication (HRR, 1.22; 95% CI, 1.18-1.26). Antibiotic use was associated
with particularly increased risk estimates. The risk of mental
disorders after infections increased in a dose-response association and
with the temporal proximity of the last infection. In particular,
schizophrenia spectrum disorders, obsessive-compulsive disorder,
personality and behavior disorders, mental retardation, autistic
spectrum disorder, attention-deficit/hyperactivity disorder,
oppositional defiant disorder and conduct disorder, and tic disorders
were associated with the highest risks after infections.

Conclusions and Relevance
Although the results cannot prove causality, these findings
provide evidence for the involvement of infections and the immune system
in the etiology of a wide range of mental disorders in children and

Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. - PubMed - NCBI


The results from cross sectional
and 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.


chronic 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.


was 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


This study is the first to
show 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.

Host-parasite interaction associated with major mental illness. - PubMed - NCBI

Clinical studies frequently report that patients with major mental
illness such as schizophrenia and bipolar disorder have co-morbid
physical conditions, suggesting that systemic alterations affecting both
brain and peripheral tissues might underlie the disorders. Numerous
studies have reported elevated levels of anti-Toxoplasma gondii (T.
gondii) antibodies in patients with major mental illnesses, but the
underlying mechanism was unclear. Using multidisciplinary
epidemiological, cell biological, and gene expression profiling
approaches, we report here multiple lines of evidence suggesting that a
major mental illness-related susceptibility factor, Disrupted in
schizophrenia (DISC1), is involved in host immune responses against T.
gondii infection. Specifically, our cell biology and gene expression
studies have revealed that DISC1 Leu607Phe variation, which changes
DISC1 interaction with activating transcription factor 4 (ATF4),
modifies gene expression patterns upon T. gondii infection. Our
epidemiological data have also shown that DISC1 607 Phe/Phe genotype was
associated with higher T. gondii antibody levels in sera. Although
further studies are required, our study provides mechanistic insight
into one of the few well-replicated serological observations in major
mental illness.

Herpesvirus may lead to bipolar, depression

An international team of scientists led by Bhupesh Prusty — from the
Department of Microbiology at the University of Würzburg in Germany —
discovered that in the brains of people who lived with bipolar and major
depression, a class of neurons called Purkinje cells was infected with
the herpesvirus HHV-6A.
Purkinje neurons are inhibitory brain cells located in the human cerebellum, which is
the brain area responsible for controlling movement, muscles, balance,
and posture.
However, some research has also tied this brain region to language, cognition, and mood.

Active HHV-6 Infection of Cerebellar Purkinje Cells in Mood Disorders Frontiers in microbiology

Plastic chemical linked to smaller prefrontal cortex, reduced cognitive ability in rats: Findings demonstrate long-term influence of endocrine-disrupting compounds on brain development -- ScienceDaily

Adult rats that had been exposed before birth and during nursing to a
mixture of chemicals (Phthalates) found in a wide range of consumer products have a
smaller medial prefrontal cortex (mPFC) and perform worse on an
attention-switching task than rats not exposed to the chemicals early in
life. These findings, published in JNeurosci, demonstrate a long-term influence of endocrine-disrupting compounds on brain development.

Daniel G. Kougias, Elli P. Sellinger, Jari Willing, Janice M. Juraska. Perinatal
exposure to an environmentally relevant mixture of phthalates results
in a lower number of neurons and synapses in the medial prefrontal
cortex and decreased cognitive flexibility in adult male and female rats
. The Journal of Neuroscience, 2018; 0607-18 DOI: 10.1523/JNEUROSCI.0607-18.2018

Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models | PNAS

The gut microbiota regulates T cell functions throughout the body. We
hypothesized that intestinal bacteria impact the pathogenesis of
multiple sclerosis (MS), an autoimmune disorder of the CNS and thus
analyzed the microbiomes of 71 MS patients not undergoing treatment and
71 healthy controls. Although no major shifts in microbial community
structure were found, we identified specific bacterial taxa that were
significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus,
both increased in MS patients, induced proinflammatory responses in
human peripheral blood mononuclear cells and in monocolonized mice. In
contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10–expressing human CD4+CD25+ T cells and IL-10+FoxP3+
Tregs in mice. Finally, microbiota transplants from MS patients into
germ-free mice resulted in more severe symptoms of experimental
autoimmune encephalomyelitis and reduced proportions of IL-10+
Tregs compared with mice “humanized” with microbiota from healthy
controls. This study identifies specific human gut bacteria that
regulate adaptive autoimmune responses, suggesting therapeutic targeting
of the microbiota as a treatment for MS.

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
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.

Exposure to paint, varnish, other solvents linked to increased risk of MS -- ScienceDaily

People who have been exposed to paint, varnish and other solvents and
who also carry genes that make them more susceptible to developing
multiple sclerosis (MS) may be at much greater risk of developing the
disease than people who have only the exposure to solvents or the MS
genes, according to a study published in the July 3, 2018, online issue
of Neurology®, the medical journal of the American Academy of Neurology.

Anna Karin Hedström, Ola Hössjer, Michail Katsoulis, Ingrid Kockum, Tomas Olsson, Lars Alfredsson. Organic solvents and MS susceptibility Interaction with MS risk HLA genes. Neurology, 2018 DOI: 10.1212/WNL.0000000000005906

Exposure to fracking chemicals and wastewater spurs fat cell development: Researchers saw increases in the size and number of fat cells in laboratory models following exposure, even at diluted concentrations. -- ScienceDaily

Exposure to fracking chemicals and wastewater
promotes fat cell development, or adipogenesis, in living cells in a
laboratory, according to a new Duke University-led study.
Researchers observed increases in both the size and number of fat
cells after exposing living mouse cells in a dish to a mixture of 23
commonly used fracking chemicals. They also observed these effects after
exposing the cells to samples of wastewater from fracked oil and gas
wells and surface water believed to be contaminated with the wastewater.
The findings appear June 21 in Science of the Total Environment.

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.

NIH-supported researchers find link between allergen in red meat and heart disease | National Institutes of Health (NIH)

Only in recent years did scientists identify the main allergen in red
meat, called galactose-α-1,3-galactose, or alpha-Gal, a type of complex
sugar. They also found that a tick — the Lone Star tick — sensitizes
people to this allergen when it bites them. That is why red meat
allergies tend to be more common where these ticks are more prevalent,
such as the Southeastern United States, but also extending to other
areas, including Long Island, New York.

Researchers have suspected for some time that allergens can trigger
certain immunological changes that might be associated with plaque
buildup and artery blockages, but no one had identified a specific
substance that is responsible for this effect. In the current study,
researchers showed for the first time that a specific blood marker for
red meat allergy was associated with higher levels of arterial plaque,
or fatty deposits on the inner lining of the arteries. The blood marker
they identified is a type of antibody (immunoglobulin or IgE) that is
specific to the alpha-Gal allergen.

Bacteriophages: Are they an overlooked driver of Parkinson's disease? | EurekAlert! Science News

In the first study of its kind, researchers from the New York-based
Human Microbiology Institute have discovered the role certain
bacteriophages may play in the onset of Parkinson's disease (PD). The
research is presented at ASM Microbe, the annual meeting of the American
Society for Microbiology, held from June 7th to June 11th in Atlanta,
The researchers, led by George, Tetz, M.D., Ph.D., Human Microbiology Institute, showed that the abundance of lytic Lactococcus phages was higher in PD patients when compared to healthy individuals.This abundance led to a 10-fold reduction in neurotransmitter-producing Lactococcus,
suggesting the possible role of phages in neurodegeneration.
Comparative analysis of the bacterial component also revealed
significant decreases in Streptococcus spp. and Lactobacillus spp. in PD.
Lactococcus are regulators of gut permeability and are
enteric dopamine producers, which plays a primary role in PD. "The
depletion of lactococcus due to high numbers of strictly lytic phages in
PD patients might be associated with PD development and directly linked
to dopamine decrease as well as the development of gastrointestinal
symptoms of PD," said Dr. Tetz.

Drugs that suppress immune system may protect against Parkinson's: People who take immunosuppressants less likely to develop the disease -- ScienceDaily

Racette and colleagues analyzed Medicare Part D prescription drug
data on 48,295 people diagnosed with Parkinson's in 2009 and 52,324
people never diagnosed with Parkinson's. They identified 26 commonly
prescribed immunosuppressant drugs, representing six classes of
medications. The researchers determined which people in the data set had
been prescribed any of the drugs a year or more before the date of
diagnosis or by a pre-set cutoff date. Prescriptions written in the 12
months before diagnosis or by the cutoff were excluded to rule out any
chance that the prescriptions might have been linked to early signs of
the disease.
The researchers found that people taking drugs in either of two
classes were significantly less likely to develop Parkinson's than those
taking no immunosuppressants. People taking corticosteroids such as
prednisone were 20 percent less likely to be diagnosed with Parkinson's,
while those on inosine monophosphate dehydrogenase (IMDH) inhibitors
were about one-third less likely.

Here's the paper:-

Immunosuppressants and Risk of Parkinson Disease. Annals of Clinical and Translational Neurology, May 31, 2018

Convergence of placenta biology and genetic risk for schizophrenia | Nature Medicine

Defining the environmental context in which genes enhance disease
susceptibility can provide insight into the pathogenesis of complex
disorders. We report that the intra-uterine environment modulates the
association of schizophrenia with genomic risk (in this study,
genome-wide association study–derived polygenic risk scores (PRSs)). In
independent samples from the United States, Italy, and Germany, the
liability of schizophrenia explained by PRS is more than five times
greater in the presence of early-life complications (ELCs) compared with
their absence. Patients with ELC histories have significantly higher
PRS than patients without ELC histories, which is confirmed in
additional samples from Germany and Japan. The gene set composed of
schizophrenia loci that interact with ELCs is highly expressed in
placenta, is differentially expressed in placentae from complicated in
comparison with normal pregnancies, and is differentially upregulated in
placentae from male compared with female offspring. Pathway analyses
reveal that genes driving the PRS-ELC interaction are involved in
cellular stress response; genes that do not drive such interaction
implicate orthogonal biological processes (for example, synaptic
function). We conclude that a subset of the most significant genetic
variants associated with schizophrenia converge on a developmental
trajectory sensitive to events that affect the placental response to
stress, which may offer insights into sex biases and primary prevention.

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.

Cause of pesticide exposure, Parkinson's link: Low-level exposure to the pesticides disrupts cells in a way that mimics the effects of mutations known to cause Parkinson's disease -- ScienceDaily

Previous studies have found an association between two commonly used
agrochemicals (paraquat and maneb) and Parkinson's disease. Now a
professor has determined that low-level exposure to the pesticides
disrupts cells in a way that mimics the effects of mutations known to
cause Parkinson's disease. Adding the effects of the chemicals to a
predisposition for Parkinson's disease drastically increases the risk of
disease onset.

From this Paper:-
Nitration of microtubules blocks axonal mitochondrial transport in a human pluripotent stem cell model of Parkinson’s disease. The FASEB Journal, 2018; fj.201700759RR DOI: 10.1096/fj.201700759RR

Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia | Translational Psychiatry

The role of the human microbiome in health and disease is increasingly
appreciated. We studied the composition of microbial communities present
in blood across 192 individuals, including healthy controls and
patients with three disorders affecting the brain: schizophrenia,
amyotrophic lateral sclerosis, and bipolar disorder. By using
high-quality unmapped RNA sequencing reads as candidate microbial reads,
we performed profiling of microbial transcripts detected in whole
blood. We were able to detect a wide range of bacterial and archaeal
phyla in blood. Interestingly, we observed an increased microbial
diversity in schizophrenia patients compared to the three other groups.
We replicated this finding in an independent schizophrenia case–control
cohort. This increased diversity is inversely correlated with estimated
cell abundance of a subpopulation of CD8+ memory T cells in healthy controls, supporting a link between microbial products found in blood, immunity and schizophrenia.

Minimizing exposure to common hormone-disrupting chemicals may reduce obesity rates -- ScienceDaily

Everyday products carry environmental chemicals that may be making us
fat by interfering with our hormones, according to research presented in
Barcelona at the European Society of Endocrinology annual meeting, ECE
2018. Following recommendations on how to avoid these chemicals could
help minimise exposure and potentially reduce the risk of obesity and
its complications.

Most common childhood cancer 'partly caused by lack of infection' | Society | The Guardian

Clean modern homes, antiseptic wipes and the understandable desire to
protect small babies against any infection are all part of the cause of
the most common form of childhood cancer, a leading expert has
concluded after more than 30 years of research.

Childhood acute leukaemia, says the highly respected Prof Mel
Greaves, is nothing to do with power lines or nuclear fuel reprocessing
stations. Nor is it to do with hot dogs and hamburgers or the Vatican
radio mast, as have also been suggested. After the best part of a
century of speculation, some of it with little basis in science, Greaves
– who recently won the Royal Society’s prestigious Royal Medal – says
the cancer is caused by a combination of genetic mutations and a lack of
childhood infection.
The best news, says Greaves, is that the cancer is likely to be
preventable. And part of the answer could be to ensure children under
the age of one have social contact with others, possibly at daycare
Greaves, from the Institute of Cancer
Research in London, has compiled evidence from decades of work on acute
lymphoblastic leukaemia (ALL), which affects one in 2,000 children. In
the 1950s and 1960s, it was lethal. Today, 90% of children are cured,
although the treatment is lengthy and toxic and can have long-term