PolygenicBlog: Alzheimers disease

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Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer | Scientific Reports

life cycle of Toxoplasma gondii (Photo credit: Wikipedia)

One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii. Approximately fifteen million of these have congenital toxoplasmosis. Although neurobehavioral disease is associated with seropositivity, causality is unproven. To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain: We identified susceptibility genes for congenital toxoplasmosis in our cohort of infected humans and found these genes are expressed in human brain. Transcriptomic and quantitative proteomic analyses of infected human, primary, neuronal stem and monocytic cells revealed effects on neurodevelopment and plasticity in neural, immune, and endocrine networks. These findings were supported by identification of protein and miRNA biomarkers in sera of ill children reflecting brain damage and T. gondii infection. These data were deconvoluted using three systems biology approaches: “Orbital-deconvolution” elucidated upstream, regulatory pathways interconnecting human susceptibility genes, biomarkers, proteomes, and transcriptomes. “Cluster-deconvolution” revealed visual protein-protein interaction clusters involved in processes affecting brain functions and circuitry, including lipid metabolism, leukocyte migration and olfaction. Finally, “disease-deconvolution” identified associations between the parasite-brain interactions and epilepsy, movement disorders, Alzheimer’s disease, and cancer. This “reconstruction-deconvolution” logic provides templates of progenitor cells’ potentiating effects, and components affecting human brain parasitism and diseases."

T. Gondii interactome

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Relationship between herpes simplex virus-1-specific antibody titers and cortical brain damage in Alzheimer’s disease and amnestic mild cognitive impairment

Alzheimer’s disease (AD) is a multifactorial disease with a still barely
understood etiology. Herpes simplex virus 1 (HSV-1) has long been
suspected to play a role in the pathogenesis of AD because of its
neurotropism, high rate of infection in the general population, and
life-long persistence in neuronal cells, particularly in the same brain
regions that are usually altered in AD. The goal of this study was to
evaluate HSV-1-specific humoral immune responses in patients with a
diagnosis of either AD or amnestic mild cognitive impairment (aMCI), and
to verify the possible relation between HSV-1-specific antibody (Ab)
titers and cortical damage; results were compared to those obtained in a
group of healthy controls (HC). HSV-1 serum IgG titers were measured in
225 subjects (83 AD, 68 aMCI, and 74 HC). HSV-specific Ab avidity and
cortical gray matter volumes analyzed by magnetic resonance imaging
(MRI) were evaluated as well in a subgroup of these individuals (44 AD,
23 aMCI, and 26 HC). Results showed that, whereas HSV-1 seroprevalence
and IgG avidity were comparable in the three groups, increased Ab titers
(p < 0.001) were detected in AD and aMCI compared to HC.
Positive significant correlations were detected in AD patients alone
between HSV-1 IgG titers and cortical volumes in orbitofrontal (region
of interest, ROI1 R_Sp0.56; p = 0.0001) and bilateral temporal cortices (ROI2 R_Sp0.57; p < 0.0001; ROI3 R_Sp0.48; p
= 0.001); no correlations could be detected between IgG avidity and MRI
parameters. Results herein suggest that a strong HSV-1-specific humoral
response could be protective toward AD-associated cortical damage.

PLoS ONE: Multivariate Protein Signatures of Pre-Clinical Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Plasma Proteome Dataset

Recent Alzheimer's disease (AD) research has focused on finding biomarkers to identify disease at the pre-clinical stage of mild cognitive impairment (MCI), allowing treatment to be initiated before irreversible damage occurs. Many studies have examined brain imaging or cerebrospinal fluid but there is also growing interest in blood biomarkers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has generated data on 190 plasma analytes in 566 individuals with MCI, AD or normal cognition. We conducted independent analyses of this dataset to identify plasma protein signatures predicting pre-clinical AD.

Role of amyloid beta as sensors and protectors in Alzheimer's and other diseases explored

Amyloid senses cellular environmental stress, such as elevation of 
reactive metabolites and oxidative products or metals, and then 
misfolds. This misfolding initiates a protective cellular response in 
the short term. Long-term or chronic stress such as metabolic 
dysfunction (diabetes) would lead to the pathological consequences of 
amyloid misfolding (as diabetes is a risk factor for Alzheimer's).

Age- and disease-related innate immunity of human leukocytes ex vivo.

Two mechanisms of innate immunity, i.e. resistance to viral infection and the production of cytokines by leukocytes, were compared in blood isolated from four groups of donors: healthy young (19-35 years old), healthy elderly (over 60), elderly Alzheimer's disease (AD) patients, and elderly patients with alimentary tract cancer (CA). Peripheral blood leukocytes (PBLs) were isolated by gradient centrifugation in Gradisol G. The degree of resistance was calculated from the kinetics of vesicular stomatitis virus (VSV) replication in the PBLs. Cytokine (TNFα, IFNα, IFNγ, IL-12, and IL-10) levels were determined by ELISA. The antiviral resistance of the PBLs varied, but a difference was observed only between the young and elderly groups and not between the healthy elderly controls and those with AD or cancer. Differences observed in all the groups concerned the ability and intensity of cytokine production. The most impressive results were obtained for spontaneous TNF and IFNα release. While TNF was released spontaneously by the PBLs of the elderly CA patients and the young healthy group, it was usually undetected in the AD and only sometimes in the healthy elderly group. Leukocytes isolated from the elderly groups responded to VSV infection with more intense IFNα and IFNγ production than the younger group.

Fast once or twice a week to improve brain health and prolong life

According to a team from the National Institute on Ageing in Baltimore, America, fasting for one or two days a week may protect against Alzheimer’s, Parkinson’s and other degenerative brain conditions.

Alzheimer's drugs (BACE inhibitors) may have adverse side effects

Alzheimer's disease drugs now being tested in clinical trials may have potentially adverse side effects, according to new Northwestern Medicine research. A study with mice suggests the drugs could act like a bad electrician, causing neurons to be miswired and interfering with their ability to send messages to the brain. Working with BACE1, Vassar discovered the animals' olfactory system – used for the sense of smell -- was incorrectly wired. The axons of the olfactory neurons were not wired properly to the olfactory bulb of the brain. The findings show the key role of BACE1 in axonal guidance.

Overeating may double risk of memory loss

New research suggests that consuming between 2,100 and 6,000 calories per day may double the risk of memory loss, or mild cognitive impairment (MCI), among people age 70 and older. The study was released today and will be presented at the American Academy of Neurology's 64th Annual Meeting in New Orleans April 21 to April 28, 2012. MCI is the stage between normal memory loss that comes with aging and early Alzheimer's disease.

Scientists uncover new clues in the early diagnosis of Alzheimer's

(Medical Xpress) -- Scientists in Nottingham have found abnormal levels of seven different proteins in spinal fluid could act as markers for detecting Alzheimer’s disease.
One protein in particular, called SPARCL1, was the strongest predictor for the disease. When the CSF samples were tested for changes in SPARCL1 alone, the researchers were able to detect whether a person had Alzheimer’s disease with 65 per cent accuracy. When they checked for abnormal levels of all seven proteins, accuracy improved to 95 per cent. The discovery of SPARCL1, amongst other proteins, resulted from the application of technologies developed at the John van Geest Cancer Research Centre.

Aberrant action of amyloidogenic host defense peptides: a new paradigm to investigate neurodegenerative disorders?

Host defense peptides (HDPs) are components of the innate immune system with activity against a broad range of microbes. In some cases, it appears that this activity is mediated by the ability of these peptides to permeabilize microbial membranes via the formation of amyloid associated structures. Recent evidence suggests that the naturally occurring function of the Aβ40 and Aβ42 peptides, which are causative agents of Alzheimer's disease, may be to serve as amyloidogenic HDPs. Here, it is hypothesized that the neurotoxicity of these peptides is related to aberrant use of their amyloid-mediated antimicrobial mechanisms, which provides the as yet unexplored paradigm of a relationship among HDPs, neurodegenerative disorders, and other conditions that could contribute to their understanding and remediation.-Harris, F., Dennison, S. R., Phoenix, D. A. Aberrant action of amyloidogenic host defense peptides: a new paradigm to investigate neurodegenerative disorders?

Amyloid precursor protein and proinflammatory changes are regulated in brain and adipose tissue in a murine model of high fat diet-induced obesity.

Abstract

BACKGROUND:

Middle age obesity is recognized as a risk factor for Alzheimer's disease (AD) although a mechanistic linkage remains unclear. Based upon the fact that obese adipose tissue and AD brains are both areas of proinflammatory change, a possible common event is chronic inflammation. Since an autosomal dominant form of AD is associated with mutations in the gene coding for the ubiquitously expressed transmembrane protein, amyloid precursor protein (APP) and recent evidence demonstrates increased APP levels in adipose tissue during obesity it is feasible that APP serves some function in both disease conditions.

METHODOLOGY/PRINCIPAL FINDINGS:

To determine whether diet-induced obesity produced proinflammatory changes and altered APP expression in brain versus adipose tissue, 6 week old C57BL6/J mice were maintained on a control or high fat diet for 22 weeks. Protein levels and cell-specific APP expression along with markers of inflammation and immune cell activation were compared between hippocampus, abdominal subcutaneous fat and visceral pericardial fat. APP stimulation-dependent changes in macrophage and adipocyte culture phenotype were examined for comparison to the in vivo changes.

CONCLUSIONS/SIGNIFICANCE:

Adipose tissue and brain from high fat diet fed animals demonstrated increased TNF-α and microglial and macrophage activation. Both brains and adipose tissue also had elevated APP levels localizing to neurons and macrophage/adipocytes, respectively. APP agonist antibody stimulation of macrophage cultures increased specific cytokine secretion with no obvious effects on adipocyte culture phenotype. These data support the hypothesis that high fat diet-dependent obesity results in concomitant pro-inflammatory changes in brain and adipose tissue that is characterized, in part, by increased levels of APP that may be contributing specifically to inflammatory changes that occur.

Alzheimer's: French scientists focus on key target

French scientists said on Tuesday that lack of a key brain protein was linked to Alzheimer's, a finding that threw up a tempting target for drugs to fight the disease.What we've found is a weapon for controlling and modifying tau," said Etienne-Emile Baulieu of France's National Institute of Health and Medical Research (Inserm), referring to a culprit involved in Alzheimer's.

Lifelong brain-stimulating habits linked to lower Alzheimer's protein levels

Brain scans revealed that people with no symptoms of Alzheimer's who engaged in cognitively stimulating activities throughout their lives had fewer deposits of beta-amyloid, a destructive protein that is the hallmark of the disease.

The plant sterol brassicasterol as additional CSF biomarker in Alzheimer's disease.

Comparison of lipid parameters per diagnosis based on relevant predictors revealed significantly lower concentrations of brassicasterol in the CSF of patients with Alzheimer's patients: Brassicasterol is synthesised by several unicellular algae (phytoplankton) and some terrestrial plants, e.g., oilseed rape.

Anti-ATP synthase autoantibodies from patients with Alzheimer's disease reduce extracellular HDL level.

Protein changes identified in early-onset Alzheimer's

(Medical Xpress) -- With a lack of effective treatments for Alzheimer's, most of us would think long and hard about whether we wanted to know years in advance if we were genetically predisposed to develop the disease. For researchers, however, such knowledge is a window into Alzheimer's disease's evolution.

Selective inhibition of the membrane attack complex of complement by low molecular weight components of the aurin tricarboxylic acid synthetic complex

English: A complement protein attacking an inv...

Image via Wikipedia

Aurin tricarboxylic acid, aurin quadracarboxylic acid, and aurin hexacarboxylic acid may be effective therapeutic agents in Alzheimer disease and other degenerative disorders where self damage from the membrane attack complex occurs.

Another potential risk factor for developing dementia and Alzheimer's disease in women

A hormone derived from visceral fat called adiponectin may play a role as a risk factor for development of all-cause dementia and Alzheimer disease in women, according to a study published Online First by the Archives of Neurology.

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