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

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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Changes in blood-brain barrier, intestinal permeability found in individuals with autism

The group analyzed postmortem cerebral cortex and cerebellum tissues from 33 individuals - 8 with ASD, 10 with schizophrenia and 15 healthy controls. Altered expression of genes associated with blood-brain-barrier integrity and function and with inflammation was detected in ASD tissue samples, supporting the hypothesis that an impaired blood-brain barrier associated with neuroinflammation contributes to ASD.
In keeping with the hypothesis that the interplay within the gut-brain axis is a crucial component in the development of neurodevelopmental disorders, the group also analyzed intestinal epithelial tissue from 12 individuals with ASD and 9 without such disorders. That analysis revealed that 75 percent of the individuals affected by ASD had reduced expression of barrier-forming cellular components, compared with controls, and 66 percent showed a higher expression of molecules that increase intestinal permeability."


See also:-

The barrier, airway particle clearance, placental and detoxification functions of autism susceptibility genes.Pubmed

Antiviral compound may protect brain from pathogens, West Nile virus study shows

Studying West Nile virus infection in mice, scientists at Washington University School of
Medicine in St. Louis showed that interferon-lambda tightens the blood-brain barrier, making it harder for the virus to invade the brain.

The blood-brain barrier is a natural defense system that is supposed
to keep pathogens out of the brain. Sometimes, however, bacteria or
viruses circulating in the blood slip past the blood-brain barrier,
turning routine illnesses into serious infections.

Blood–brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment

Background

Functional loss of blood–brain barrier (BBB) is suggested to be pivotal to pathogenesis
and pathology of vascular-based neurodegenerative disorders such as Alzheimer’s disease.
We recently reported in wild-type mice maintained on standard diets, progressive deterioration
of capillary function with aging concomitant with heightened neuroinflammation. However,
the mice used in this study were relatively young (12 months of age) and potential
mechanisms for loss of capillary integrity were not investigated per se. The current study therefore extended the previous finding to investigate the effect
of aging on BBB integrity in aged mice at 24 months and its potential underlying molecular
mechanisms.

Results

Immunomicroscopy analyses confirmed significantly increased capillary permeability
with heightened neuroinflammation in naturally aged 24-month old mice compared to
young control at 3 months of age. Aged mice showed significant attenuation in the
expression of BBB tight junction proteins, occludin-1 and to lesser extent ZO-1 compared
to young mice. In addition, TNF-α in cerebral endothelial cells of aged mice was significantly
elevated compared to controls and this was associated with heightened peripheral inflammation.
The expression of ICAM-1 and VCAM-1 remained unelevated, and no sign of leukocyte
recruitment was observed in aged mice.

Conclusion

The BBB breakdown that occurs during ordinary aging is associated with inflammation
and disruption of tight junction complex assembly but not through leukocyte trafficking.

Blood vessels in older brains break down, possibly leading to Alzheimer's -- ScienceDaily

"University of Southern California (USC) neuroscientists may have unlocked another puzzle to preventing risks that can lead to Alzheimer's disease. Researchers at Keck Medicine of USC used high-resolution imaging of the living human brain to show for the first time that the brain's protective blood barrier becomes leaky with age, starting at the hippocampus, a critical learning and memory center that is damaged by Alzheimer's disease."

The gut microbiota influences blood-brain barrier permeability in mice

Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota–BBB communication is initiated during gestation and propagated throughout life.

Air Pollution and Children: Neural and Tight Junction Antibodies and Combustion Metals, the Role of Barrier Breakdown and Brain Immunity in Neurodegeneration.

Millions of children are exposed to concentrations of air pollutants, including fine particulate matter (PM2.5), above safety standards. Mexico City Metropolitan Area (MCMA) megacity children show an early brain imbalance in oxidative stress, inflammation, innate and adaptive immune response-associated genes, and blood-brain barrier breakdown. We investigated serum and cerebrospinal fluid (CSF) antibodies to neural and tight junction proteins and environmental pollutants in 139 children ages 11.91 ± 4.2 y with high versus low air pollution exposures. We also measured metals in serum and CSF. MCMA children showed significantly higher serum actin IgG, occludin/zonulin 1 IgA, IgG, myelin oligodendrocyte glycoprotein IgG and IgM (p < 0.01), myelin basic protein IgA and IgG, S-100 IgG and IgM, and cerebellar IgG (p < 0.001). Serum IgG antibodies to formaldehyde, benzene, and bisphenol A, and concentrations of Ni and Cd were significantly higher in exposed children (p < 0.001). CSF MBP antibodies and nickel concentrations were higher in MCMA children (p = 0.03). Air pollution exposure damages epithelial and endothelial barriers and is a robust trigger of tight junction and neural antibodies. Cryptic 'self' tight junction antigens can trigger an autoimmune response potentially contributing to the neuroinflammatory and Alzheimer and Parkinson's pathology hallmarks present in megacity children. The major factor determining the impact of neural antibodies is the integrity of the blood-brain barrier. Defining the air pollution linkage of the brain/immune system interactions and damage to physical and immunological barriers with short and long term neural detrimental effects to children's brains ought to be of pressing importance for public health.

Why inflammation leads to a leaky blood-brain barrier: MicroRNA-155

Until now, scientists have not known exactly how inflammation weakens
the Blood-Brain Barrier, allowing toxins and other molecules access to
the brain. A new research report appearing in the June 2014 issue of The FASEB Journal
solves this mystery by showing that a molecule, called "microRNA-155,"
is responsible for cleaving epithelial cells to create microscopic gaps
that let material through. Not only does this discovery help explain the
molecular underpinnings of diseases like multiple sclerosis, but it
also opens an entirely new avenue for developing therapies that can help
penetrate the Blood-Brain Barrier to deliver lifesaving drugs.

Drug shows potential to delay onset or progression of Alzheimer's disease

A research team led by Robert Nagele, PhD, of the New Jersey Institute for Successful Aging (NJISA) at the University of Medicine and Dentistry of New Jersey (UMDNJ)-School of Osteopathic Medicine, has demonstrated that the anti-atherosclerosis drug darapladib can significantly reduce leaks in the blood brain barrier. This finding potentially opens the door to new therapies to prevent the onset or the progression of Alzheimer's disease.

Research opens up possibility of therapies to restore blood-brain barrier

(Medical Xpress)—Research led by Queen Mary, University of London, has opened up the possibility that drug therapies may one day be able to restore the integrity of the blood-brain barrier, potentially slowing or even reversing the progression of diseases like multiple sclerosis (MS). The study, funded by the Wellcome Trust, is published in Proceedings of the National Academy of Sciences.

Read more at: http://medicalxpress.com/news/2013-01-possibility-therapies-blood-brain-barrier.html#jCp

New research investigates how the common 'cat parasite' gets into the brain

A new study demonstrates for the first time how the Toxoplasma gondii parasite enters the brain to influence its host's behavior. This research was led by researchers from the Karolinska Institute and Uppsala University in Sweden publishes today in the Open Access journal PLOS Pathogens.

Read more at: http://medicalxpress.com/news/2012-12-common-cat-parasite-brain.html#jCp

Chronic vascular risk factors (cholesterol, homocysteine, ethanol) impair spatial memory, decline cholinergic neurons and induce blood-brain barrier leakage in rats in vivo.

Epidemiological studies show that vascular risk factors (e.g. atherosclerosis, diabetes, homocysteine, hypertension or cholesterol) may play a role in the development of Alzheimer's disease. Animal models may help to discover the role of vascular risk factors on cognition. In the present project we treated male Sprague Dawley rats with a diet containing homocysteine (hyperhomocysteinemia) or cholesterol (hypercholesterolemia) for 5months or exposed the rats to ethanol (20% in drinking water) or a combination of cholesterol+ethanol (mix) for 12months. Our experiments show that all 3 treatments (homocysteine, cholesterol, ethanol) declined spatial memory in the 8-arm radial maze, reduced the number of cholinergic neurons and induced blood-brain barrier leakage in the cortex. Rats treated with cholesterol also displayed markedly enhanced inflammation in the cortex. Levels of amyloid precursor protein, beta-amyloid((1-42)), as well as tau and phospho-tau 181 were significantly enhanced in the cortex of cholesterol-fed rats. A combination of ethanol and cholesterol did not further potentiate the effects on spatial memory, cholinergic neurons and blood-brain barrier leakage.The data suggest that chronic mild vascular risk factors over months induce small
lesions of the brain capillaries in the cortex, which may contribute to the development of vascular dementia or also Alzheimer's disease.