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NOVEMBER 7, 2016

Testosterone levels improve in overweight, obese men after 12-week exercise program
by American Physiological Society

Ball-and-stick model of the testosterone molecule, C19H28O2, as found in the crystal structure of testosterone monohydrate. Credit: Ben Mills/Wikipedia
Twelve weeks of aerobic exercise significantly boosted testosterone levels in overweight and obese men, with the greatest increases seen among vigorous exercisers, according to research presented today at the Integrative Biology of Exercise 7 meeting in Phoenix.

Researchers from Tsukuba University and Ryutsu Keizai University in Japan previously found that a combination of diet and exercise was effective in increasing the testosterone in this population. For this study, however, they looked specifically at the effect of regular aerobic exercise on testosterone levels.

"Testosterone is a male sex hormone, and low circulating testosterone levels lead to various health disorders in men. Obesity, one of the biggest problems in the world, results in reduction in circulating testosterone levels in men," the research team wrote. Fatigue, decreased sex drive and decreases in muscle and bone mass are some of the common symptoms of low testosterone in men.

The research team compared 16 normal weight men to 28 overweight/obese men. None of the men were regular exercisers. At baseline, the overweight/obese men had significantly lower total, free and bioavailable testosterone level than normal weight men. All of the study volunteers completed a 12-week aerobic exercise plan that entailed 40–60 minutes of walking or jogging on one to three days per week. Testosterone levels were also recorded at the end of the study.

While their testosterone was still at lower levels than the normal weight men at baseline, overweight and obese men saw a significant increase in all measured testosterone levels. This effect was particularly evident among the men who exercised vigorously. However, the exercise intervention had no significant effect on testosterone levels in the normal weight men.

Body weight also significantly decreased following the exercise intervention in the overweight/obese cohort. "I think decrease in body mass is one of the factors for increasing serum testosterone levels," said Hiroshi Kumagai, lead researcher on the study. "However, the degree of weight loss is small, and we found that the increase in vigorous physical activity was independently associated with the increase in serum testosterone levels. So, it seems the increase in physical activity, especially vigorous physical activity, is the main factor for increasing serum testosterone levels."

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Diabetes
AUGUST 25, 2016

Low testosterone thresholds established for type 2 diabetes
by Elliott Richardson, University of Western Sydney

Credit: University of Western Sydney
Research into type 2 diabetes conducted by Western Sydney University has for the first time established a range of clinical thresholds for testosterone levels in men associated with developing diabetes.

The link between low testosterone levels and risk of type 2 diabetes is well documented, and the new research pinpoints the level of risk to men according to their blood testosterone levels.

Research leader Dr Evan Atlantis says the findings indicate that men with decreasing testosterone levels have corresponding increasing risk of developing diabetes.

"For example, if you have a testosterone level of less than 16 nanomoles per litre, which is really common, you have a 13% chance of developing diabetes within 5 years.

"But if you have a level less than 10, which is found in about 8% of men in this age group, the chance of developing diabetes jumps to 20%," says Dr Atlantis.

Developed in collaboration with the University of Adelaide, the research gives general practitioners and diabetes specialists a better understanding about low testosterone levels in men to improve current type 2 diabetes screening programs..

"Low testosterone levels in men are associated with a range of medical conditions, including obesity, sexual dysfunction, depression and heart disease, as well as diabetes," he says.

However Dr Atlantis says all hope is not lost for men with low testosterone levels.

"Men with low testosterone levels can start by making small changes to their everyday lives, such as improving diet and exercise habits," he says.

"Lifestyle interventions that focus on achieving a healthy body weight are proven strategies for preventing diabetes".

And there is exciting new drug research underway to improve the benefits of lifestyle intervention.

"Currently, we are undertaking research to determine whether testosterone therapy with lifestyle intervention will reduce the rate of type 2 diabetes in men with both low testosterone and pre-diabetes or newly diagnosed type 2 diabetes more than lifestyle intervention alone over two years."

Low testosterone linked to adverse outcomes in T2DM
(HealthDay)—For men with type 2 diabetes, low serum testosterone seems to be implicated in adverse clinical outcomes, according to a review published online Nov. 3 in the Journal of Diabetes Investigation.

Kitty Kit Ting Cheung, from The Chinese University of Hong Kong, and colleagues conducted a systematic review of the literature to examine the evidence on low serum testosterone levels in patients with type 2 diabetes. The authors examined the implications of these levels on cardiovascular risk factors, metabolic syndrome, and adverse clinical outcomes.

The researchers note that there is accumulating evidence that low serum testosterone is associated with type 2 diabetes. Multiple lines of evidence indicate a possible causal role of low serum testosterone level in type 2 diabetes and obesity. Data from epidemiological studies, mainly in Caucasian populations, have confirmed inverse correlations between serum testosterone level and aging, metabolic syndrome, cardiovascular disease, and cardiovascular-disease-related and all-cause mortality.

"In conclusion, review of the literature has identified multiple mechanisms supportive of the effects of low serum testosterone level on causing insulin resistance, obesity, vascular dysfunction, and inflammation," the authors write. "At this moment, the results from these studies could not support checking testosterone level in asymptomatic men with type 2 diabetes, as an independent predictor effect of low testosterone on adverse clinical outcomes has not been clearly established."

Diabetic men with low testosterone run higher risk of developing atherosclerosis
Men who have low testosterone and Type 2 diabetes face a greater risk of developing atherosclerosis – a condition where plaque builds up in the arteries – than men who have diabetes and normal testosterone levels, according to a new study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism (JCEM).

Atherosclerosis occurs when fats, cholesterol and other substances build up in and on the walls of the body's arteries. This can restrict blood flow through the body's blood vessels. The plaques also can burst and cause blood clots.

"Our study indicates a strong association between low testosterone concentration and the severity of atherosclerotic plaques as well as other key atherosclerotic markers in middle-aged men with Type 2 diabetes," said one of the study's authors, Javier Mauricio Farias, MD, of the Hospital Universitario Sanatorio Guemes in Buenos Aires, Argentina. "The results of our study advance our understanding of the interplay between low testosterone and cardiovascular disease in patients with diabetes."

Several studies have raised concerns about the safety of testosterone therapy and the risk of cardiovascular complications. This has public health implications because the number of older men receiving testosterone replacement therapy has jumped sharply during the past decade. The Endocrine Society recommends that testosterone treatment should be reserved for men with clinical symptoms of hypogonadism and consistently low levels of testosterone. The Society also has called for large-scale, well-controlled trials to assess the long-term cardiovascular risks associated with testosterone therapy.

The cross-sectional prospective study published in JCEM examined testosterone levels and key atherosclerotic markers, including intimal media thickening of the layers in the carotid artery, the presence of atherosclerotic plaques, function of the endothelial cells that line the heart and blood vessels, and inflammatory markers in 115 men with Type 2 diabetes. The participants were younger than age 70 and had no history of cardiovascular disease. Researchers measured the levels of testosterone in each participant's blood. Among the participants, more than half of patients with diabetes were found to have low testosterone levels.

The study found men who had low testosterone and Type 2 diabetes were six times more likely to have increased thickness of the carotid artery and endothelium dysfunction compared to men with normal serum testosterone levels. A total of 54 percent of the men with low testosterone and 10 percent of the men with normal testosterone were found to be at higher risk for vascular disease.

"We still need to determine whether testosterone is directly involved in the development of atherosclerosis or if it is merely an indicator of advanced disease," Farias said. "This study is a stepping stone to better understanding the risks of cardiovascular events in men who have both low testosterone and Type 2 diabetes."

Testosterone promotes prostate cancer in rats
by The Endocrine Society

A researcher who found that testosterone raised the risk of prostate tumors and exacerbated the effects of carcinogenic chemical exposure in rats is urging caution in prescribing testosterone therapy to men who have not been diagnosed with hypogonadism, according to a new study published in the Endocrine Society's journal Endocrinology.

Testosterone use has soared in the last decade among older men seeking to boost energy and feel younger. One study published in The Journal of Clinical Endocrinology & Metabolism found that the number of American men who started testosterone therapy has nearly quadrupled since 2000, despite concerns about potential cardiovascular risks.

The Endocrine Society's Clinical Practice Guidelines on testosterone therapy in adult men recommend prescribing testosterone only to men who have unequivocally low levels of the hormone and decreased libido, erectile dysfunction or other symptoms of hypogonadism, a condition that results from low testosterone.

"This research demonstrates that testosterone on its own is a weak carcinogen in male rats," said the study's author, Maarten C. Bosland, DVSc, PhD, of the University of Illinois at Chicago. "When it is combined with cancer-causing chemicals, testosterone creates a hospitable environment for tumors to develop. If these same findings hold true in humans, there is serious cause for public health concern."

Two dose-response studies examined the incidence of prostate cancer in rats. The rats were given testosterone through slow-release implant devices. Before the rats were dosed with testosterone, some of the animals were given injections of the carcinogenic chemical N-nitroso-N-methylurea (MNU). These rats were compared to a control group that received MNU but had empty slow-release devices implanted.

Among the rats that received testosterone without the carcinogenic chemical, 10 to 18 percent developed prostate carcinomas. Testosterone treatment alone did not induce specific tumors at other sites, but compared with control rats, it caused a significant increase in the number of rats with malignant tumors at any site. When rats were exposed to testosterone and the carcinogen, the treatment caused prostate cancer in 50 to 71 percent of the rats. Even when the hormone dose was too low to elevate testosterone levels in the bloodstream, half of the rats developed prostate tumors. Animals that were exposed to the carcinogenic chemical but not testosterone did not develop prostate cancer.

"Since the growth of testosterone therapy is relatively recent and prostate cancer is a slow-moving disease, there are at present no data to determine if testosterone could heighten the risk of prostate cancer in humans," Bosland said. "While human studies are conducted, it would be prudent to limit testosterone prescriptions to men with symptomatic clinical hypogonadism and avoid testosterone use by men for non-medical purposes, including addressing normal signs of aging."

The study, "Testosterone Treatment is a Potent Tumor Promoter for the Rat Prostate," was published online, ahead of print.

Low testosterone levels may indicate worsening of disease for men with prostate cancer
by Wiley

Micrograph showing prostatic acinar adenocarcinoma (the most common form of prostate cancer) Credit: Wikipedia
For men with low-risk prostate cancer, low levels of testosterone may indicate a worsening of their disease. That's the conclusion of a new study published in BJU International. The findings may help physicians identify patients with low-risk prostate cancer who should receive aggressive anticancer treatment.

Men with prostate cancer that is not life threatening and is only slowly progressing, can often forego treatment and instead undergo active surveillance. This involves close monitoring to ensure that their disease does not become serious and jeopardize their health. Unfortunately, doctors currently have no reliable way of predicting which men will develop evidence of worsening or more aggressive disease during active surveillance.

Ignacio San Francisco, MD, of the Pontificia Universidad Católica de Chile, and his colleagues looked to see if testosterone levels might provide any indication. After following 154 men with low-risk prostate cancer for 38 months, the investigators found that low levels of free testosterone were significantly linked with an increased risk of developing more aggressive disease. They found no significant association with total testosterone concentrations, although there was a general trend towards increased risk with lower levels. Free testosterone comprises one to two percent of total testosterone and is considered a useful surrogate for the biologically active portion of circulating testosterone.

"These results suggest low levels of testosterone are associated with more aggressive prostate cancer. This contradicts long-held beliefs that high testosterone is risky for prostate cancer, and low testosterone is protective," said Dr. San Francisco.

The results of this study provide valuable information to clinicians and their patients concerning risk factors for prostate cancer progression in men undergoing active surveillance. "In borderline cases, the presence of low values of free testosterone may help determine whether it is more prudent to initiate treatment rather than continue observation," said Dr. San Francisco.

Researchers restore brain immune system function after prenatal exposure to environmental toxin
by University of Rochester Medical Center

Credit: Pixabay/CC0 Public Domain
New research shows that exposure to the industrial byproduct TCDD in utero could cause the brain's immune system to go array later in life, damaging important brain circuits, and potentially giving rise to neurodevelopmental disorders, such as autism and ADHD. TCDD is primarily released into the environment by vehicle exhaust and burning wood and low levels of the toxin are found in air, soil, and food. The most common way people are exposed is through meat, dairy, and fish.

In the same study, recently published in the journal Brain, Behavior, and Immunity, researchers also found that pharmacological manipulation could restore the function of microglia, important cells in the brain's immune system. "This suggests that defects in microglia function resulting from prenatal exposures can be reversed later in life, indicating a possible additional therapeutic avenue for neurodevelopmental disorders," said Rebecca Lowery, Ph.D., assistant research professor in the Del Monte Institute for Neuroscience at the University of Rochester, and co-first author of the study.

The research, which was conducted in mice, showed that when the brains of males were exposed to TCDD in utero, it caused inflammation which cause microglia to go array when responding to injury. While the microglia themselves appeared healthy, the cells became over activated while responding to injury in a way that could damage important brain circuits. But investigators found that by using the drug Pexidartinib (PLX3397) they could 'shut-off' the hyper-responsive microglia and those were replaced by new microglia that functioned normally.

This work offers new clues to when exposure to TCDD is most dangerous. Past research has found that adults exposed to TCDD did not have inflammation in the brain and there was no impact on microglia function. "Microglia are outside of the brain during pregnancy," said Ania Majewska, Ph.D., lead author on this study. "But after birth they are protected, possibly by the blood brain barrier, this barrier may be what prevents the harmful effects of TCDD from entering the brain." Researchers now want to understand if other environmental exposures impact microglia similarly, and whether these changes lead to long-term alterations in brain circuitry and function.

Ally and enemy? Scientists explore immune cell suspect in Alzheimer's disease
by Bill Hathaway, Yale University

Fig. 1: Characterization of microglia-like cells in mhCOs. a Schematic for generating mhCOs. 10% of PU.1-infected hESCs were mixed with 90% parental HES3 hESCs, and PU.1 priming and full induction were performed on day 2 and 18, respectively. b Expression of microglia-related genes from control hCOs and mhCOs (30-day and 70-day old). Gene expression was measured relative to control organoids on day 30 and normalized to β-Actin. Data represent the mean ± SEM (n = 5, three independent batches). c Left, immunostaining for IBA1 reveals the production of microglia-like cells in sectioned-mhCOs at days 30 and 70. IBA1+ cells were not found in control hCOs. Right, Sholl analysis of IBA1 + microglia-like cells from mhCOs at different time points. Data represent the mean ± SEM (n = 5 organoids from three independent differentiation replicates of two hESCs lines). d and e Immunostaining of mhCOs at day 70 and isolated microglia co-cultured with neurons (2D) for IBA1 and CSF1R (d) TMEM119 and P2RY12 (e). Representative images were shown (n = 5, from two independent batches). f Top, co-expression of PU.1 and IBA1 in hCOs and mhCOs at day 30 and 70. Bottom, quantification of Pu.1-derived IBA1 microglia-like cells. Data represent the mean ± SEM (n = 5 organoids from three independent differentiation replicates of two hESCs lines). Bottom, Pearson’s correlation coefficient of IBA1 with PU.1 in mhCOs at days 30 and 70. g Top, co-immunostaining for Ki67 and IBA1 in mhCOs at day 70. Bottom, quantification of proliferating IBA1 microglia-like cells. Data represent the mean ± SEM (n = 5 organoids from three independent differentiation replicates of two hESC lines). h Left, high-resolution imaging showed microglia isolated from mhCOs at day 90 and co-cultured D90 cortical neurons for 3 days contained inclusions of PSD95. Right, quantification of PSD95 particles in IBA1+ microglia-like cells. Data represent the mean ± SEM (n = 8, from three independent differentiation replicates of hESCs lines). The scale bar represents 50 μm in c–g and 20 μm in h. Credit: DOI: 10.1038/s41467-022-28043-y
As scientists search for the roots of Alzheimer's disease, they have had a hard time determining whether microglia, an immune system cell crucial to brain development and maintenance of the adult brain, is a friend or foe.

Evidence shows that a lack of microglia contributes to accumulation of amyloid plaques, a hallmark of Alzheimer's. Alternately, an excess of microglia has been implicated in the destruction of neurons and brain synapses which also characterizes neurodegeneration in the disease.

Now, Yale researchers have developed a way to tease out factors that may determine which of those roles microglia might play, they report in the journal Nature Communications.

"All microglia we possess as adults are created before we are born," said In-Hyun Park, associate professor of genetics at the Yale Stem Cell Center. "Microglia are crucial in neurogenesis because they do the synaptic pruning that allows neurons to communicate properly."

In adult brains, they act as a kind of cellular trash collector, identifying and disposing of debris from dead neurons.

But microglia have been a challenge to study because they form soon after conception and migrate quickly to the developing nervous system. Once they find a home in the developing brain, microglia are cut off from most interaction with other parts of the body by the blood-brain barrier, which protects the brain from pathogens. Dysfunction of microglia has been associated with neurodevelopmental and neurodegenerative diseases, but studying the link has been difficult due to the limited models of the human brain.

For the new study, Bilal Cakir and Yoshiaki Tanaka from Park's lab developed a method to generate functional microglia in human cortical organoids, which are small, three-dimensional replicas of the developing brain formed from early-stage stem cells. In laboratory tests, they identified an active gene created very early in development that is crucial to the birth of microglia. They were then able to activate the gene to coax the creation of microglia in the brain organoid.

In preliminary experiments, they found organoids lacking microglia were susceptible to accumulation amyloid, a protein that forms plaques linked with Alzheimer's disease. But organoids with functioning microglia were not. The findings suggest that in this case microglia play a protective role.

The organoids can be used to study effects of other genes linked to the development of Alzheimer's, the researchers said.

Microglial methylation "landscape" in human brain
by Elsevier

Credit: Unsplash/CC0 Public Domain
In the central nervous system, microglial cells play critical roles in development, aging, brain homeostasis, and pathology. Recent studies have shown variation in the gene-expression profile and phenotype of microglia across brain regions and between different age and disease states. But the molecular mechanisms that contribute to these transcriptomic changes in the human brain are not well understood. Now, a new study targets the methylation profile of microglia from human brain.

The study appears in Biological Psychiatry.

Microglia, the brain's own immune cells, were once thought of as a homogenous population that was either "activated" or "inactivated," with either pro-inflammatory or neuroprotective effects. But the cells are now recognized to have a vast array of phenotypes depending on environmental conditions with myriad functional consequences. Microglia are increasingly appreciated as critical players in neurologic and psychiatric disorders.

Fatemeh Haghighi, Ph.D., senior author of the new work, said that "to address this gap in knowledge, we set out to characterize the DNA methylation landscape of human primary microglia cells and factors that contribute to variations in the microglia methylome."

DNA methylation is the main form of epigenetic regulation, which determines the pattern of which genes are being turned "on" or "off" in various circumstances over time.

The researchers studied isolated microglia cells from post-mortem human brain tissue from 22 donors of various age, including 1 patient with schizophrenia, 13 with mood disorder, and 8 controls with no psychiatric disorder, taken from 4 brain regions. They analyzed the microglia using genome-scale methylation microarrays.

Unsurprisingly, microglia showed DNA methylation profiles that were distinct from other cells in the central nervous system. But less expected, said Haghighi, "we found that interindividual differences rather than brain region differences had a much larger effect on the DNA methylation variability." In addition, an exploratory analysis showed differences in the methylation profile of microglia from brains of subjects with psychiatric disorders compared to controls.

John Krystal, MD, Editor of Biological Psychiatry, said of the work, "These promising data point to pathology of the microglia, key immune cells of the brain, in the biology of depression."

Physical activity may improve Alzheimer's disease outcomes by lowering brain inflammation
by Society for Neuroscience

Conceptual diagram of moderated mediation models. Models examine the mediating effect of inferior temporal microglial activation (PAM IT) on the relationship between physical activity and global cognitive outcomes or synaptic integrity markers in the inferior temporal gyrus. Credit: Casaletto et al., JNeurosci 2021
No one will disagree that an active lifestyle is good for you, but it remains unclear how physical activity improves brain health, particularly in Alzheimer's disease. The benefits may come about through decreased immune cell activation, according to new research published in JNeurosci.

Microglia, the brain's resident immune cells, activate to clear debris and foreign invaders from the brain. But too much activation can trigger inflammation, damage neurons, and disrupt brain signaling. Exercise helps reduce aberrant activation in animals, but that link hadn't been established in humans.

Casaletto et al. examined the relationship between physical activity and microglia activation in 167 older adults across the spectrum of cognitive aging (majority nondemented) as part of the Rush Memory and Aging Project. The participants wore activity monitors 24 hours a day for up to ten days straight before annual cognitive exams. The researchers measured microglia activation and Alzheimer's disease (AD) pathology in postmortem brain tissue analyses. Greater physical activity was linked to lower microglial activation, particularly in the inferior temporal gyrus, a brain region hit the hardest by AD. Physical activity had a more pronounced effect on inflammation in people with more severe AD pathology.

Future research will examine if physical activity interventions can alter microglia activation in AD patients.

Do microglia hold the key to stop Alzheimer's disease?
by VIB (the Flanders Institute for Biotechnology)

Credit: CC0 Public Domain
A Leuven research team led by Prof. Bart De Strooper (VIB-KU Leuven, UK DRI) studied how specialized brain cells called microglia respond to the accumulation of toxic proteins in the brain, a feature typical of Alzheimer's. The three major disease risk factors for Alzheimer's—age, sex and genetics—all affect microglia response, raising the possibility that drugs that modulate this response could be useful for treatment.

One of the hallmarks of Alzheimer's disease is the presence of so-called amyloid plaques in the brain. Research suggests that these plaques trigger a series of processes in which microglia play a central role. Microglia are specialized brain cells that act as the first and main form of immune defense in the brain.

"The response of these important support cells to the accumulation of toxic amyloid beta may have a big effect on the disease process," says Alzheimer expert Bart De Strooper (VIB-KU Leuven, UK DRI). "That's why we wanted to understand better the microglial response to amyloid beta and how it may differ across individuals."

The activation state of 10,000 cells

"We know microglia get involved in Alzheimer's disease by switching into an activated mode," explains Dr. Carlo Sala Frigerio. "We were interested to know if aging in the presence or absence of amyloid beta deposition would affect this activation." Sala Frigerio worked in De Strooper's lab in Leuven and recently started his own group at the UK Dementia Research Institute in London.

The researchers used a genetic mouse model in which amyloid beta progressively accumulates, mimicking the disease process in human patients. The team analyzed the gene expression profiles of more than 10,000 individual microglia cells isolated from different brain regions of both male and female mice at different disease stages.

"We found that the microglial responses to amyloid beta were complex but could essentially be catalogued into two major activation states. The same two activation states that are found during normal ageing, but then activation was slower and less pronounced."

In female mice, the microglia reacted earlier to amyloid beta, especially if the mice were older. Similar findings resulted from analyzing the microglia in a different Alzheimer mouse model and in human brain tissue.

Targeting microglia activation

"Our data indicate that major Alzheimer risk factors, such as age, sex and genetic risk, affect the complex microglia response to amyloid plaques in the brain," says De Strooper. "In other words, different Alzheimer's risk factors converge on the activation response of microglia."

Both De Strooper and Sala Frigerio believe that the response of individual microglia will largely depend on their direct environment within the brain. "A particular challenge will be to dissect the distribution of microglia in different activation states across the brain. Such a detailed dissection could lead to a whole set of new drug targets that could be useful to tune the microglia response in a beneficial way."

New PET imaging biomarker could better predict progression of Alzheimer's disease
by Society of Nuclear Medicine and Molecular Imaging

Multimodal correlation analysis of cognitive testing with terminal PET and immunohistochemical results in PS2APP mice at study termination. Representative PET images (z score on MRI template), immunohistochemistry (fused methoxy-X04 [blue] and Iba1 [red]), and WM findings of individual mice, showing either low (orange) or high (magenta) markers of microglial activation at study termination. Credit: Focke C, Blume T, Zott B, Shi Y, et al.
Researchers have discovered a way to better predict progression of Alzheimer's disease. By imaging microglial activation levels with positron emission tomography (PET), researchers were able to better predict progression of the disease than with beta-amyloid PET imaging, according to a study published in the April issue of the Journal of Nuclear Medicine.

According to the Alzheimer's Association, an estimated 5.3 million Americans are currently living with Alzheimer's disease. By 2025, that number is expected to increase to more than seven million. The hallmark brain changes for those with Alzheimer's disease include the accumulation of beta-amyloid plaques. When microglial cells from the central nervous system recognize the presence of beta-amyloid plaques, they produce an inflammatory reaction in the brain.

"The 18-kD translocator protein (TSPO) is highly expressed in activated microglia, which makes it a valuable biomarker to assess inflammation in the brain," said Matthias Brendel, MD, MHBA, at Ludwig-Maximilians-University of Munich in Germany. "In our study, we utilized TSPO-PET imaging to determine whether microglial activation had any influence on cognitive outcomes in an amyloid mouse model."

In the study, researchers compiled a series of PET images for 10 transgenic mice with beta-amyloid proteins and seven wild-type mice. TSPO PET imaging of activated microglia was conducted at eight, 9.5, 11.5 and 13 months, and beta-amyloid PET imaging was performed at eight and 13 months. Upon completion of the imaging, researchers then subjected the mice to a water maze in which the mice were to distinguish between a floating platform that would hold their weight and one that would sink. The tasks were performed several times a day during a 1.5-week period. Memory performance in the water maze was assessed by measuring the average travel time from the start point to a platform each day of training and by calculating the traveled distance at the last day of training. After completing the water maze task, immunohistochemistry analyses were performed for microglia, amyloid and synaptic density.

Transgenic mice with the highest TSPO PET signal in the forebrain or other areas associated with spatial learning tended to have better cognitive performance in the water maze, while beta-amyloid signals in the same areas of the brain showed no correlation to cognitive outcomes in the maze. Researchers found that an earlier microglial response to amyloid pathology in transgenic mice also protected synaptic density at follow-up. Specifically, transgenic mice with higher TSPO expression at eight months had much better cognitive outcomes in the water maze and higher synaptic density as confirmed by immunochemistry analyses.

"This study provides the first evidence that the level of microglial activation could be a far better predictor of current and future cognitive performance than beta-amyloid levels," noted Brendel. "Keeping the limitations of mouse models in mind, it could be crucial to modify an individual's microglial activation state to ameliorate future cognitive decline. We believe that a balanced microglia activation is crucial for prevention of cognitive impairment."

The brain's immune system may be key to new Alzheimer's treatments
by Sanford-Burnham Prebys Medical Discovery Institute

Huaxi Xu, Ph.D., professor and director of SBP's Neuroscience Initiative. Credit: Sanford Burnham Prebys Medical Discovery Institute
Sanford Burnham Prebys Medical Research Institute (SBP) researchers have published two new studies in Neuron that describe how TREM2, a receptor found on immune cells in the brain, interacts with toxic amyloid beta proteins to restore neurological function. The research, performed on mouse models of Alzheimer's disease, suggests boosting TREM2 levels in the brain may prevent or reduce the severity of neurodegenerative disorders including Alzheimer's disease.

"Our first paper identifies how amyloid beta binds to TREM2, which activates neural immune cells called microglia to degrade amyloid beta, possibly slowing Alzheimer's disease pathogenesis," says Huaxi Xu, Ph.D., professor and director of SBP's Neuroscience Initiative, Jeanne and Gary Herberger Leadership Chair in Neuroscience Research and senior author of the study. "The second study shows that increasing TREM2 levels renders microglia more responsive and reduces Alzheimer's disease symptoms."

Alzheimer's disease affects more than 47 million people worldwide, a number expected to grow as the population ages. One of the hallmarks of the disease is the accumulation of amyloid plaques that form between neurons and interfere with brain function. Many drug companies have been working for years to reduce amyloid beta production to thwart Alzheimer's—but with minimal success.

"TREM2 offers a potential new strategy," says Xu."Researchers have known that mutations in TREM2 significantly increase Alzheimer's risk, indicating a fundamental role for this particular receptor in protecting the brain. This new research reveals specific details about how TREM2 works, and supports future therapeutic strategies to strengthen the link between amyloid beta and TREM2, as well as increasing TREM2 levels in the brain to protect against pathological features of the disease.

Xu led the first study (TREM2 is a receptor for β-amyloid which mediates microglial function), showing that TREM2 binds quite specifically to amyloid beta. In particular, it connects with amyloid beta oligomers (proteins that bind together to form a polymer), which are the protein's most toxic configuration. Without TREM2, microglia were much less successful at binding to, and clearing out, amyloid beta.

Further investigation showed that removing TREM2 downregulated microglial potassium ion channels, impairing the electrical currents associated with the activation of these immune cells. In addition, TREM2 turned on a number of mechanisms associated with the amyloid beta response in microglia.

The second study (TREM2 Gene Dosage Increase Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models), a collaboration led by with X. William Yang, M.D., Ph.D., professor in Jane and Terry Semel Institute for Neuroscience and Human Behavior, and Department of Psychiatry & Biobehavioral Sciences at David Geffen School of Medicine at UCLA, added TREM2 to a mouse model with aggressive Alzheimer's disease. They found that the added TREM2 signaling stopped disease progression and even restored cognitive function.

"These studies are important because they show that in addition to rescuing the pathology associated with Alzheimer's disease, we are able to reduce the behavioral deficits with TREM2," says Xu. "To our knowledge this provides convincing evidence that minimizing amyloid beta levels alleviates Alzheimer's disease symptoms." As they learn more about how TREM2 modulates the amyloid signals that put microglia to work, the Xu lab and other researchers have their work cut out for them.

"It could be beneficial in early stages to activate microglia to eat up amyloid beta," says Xu, "but if you over-activate them, they may release an overabundance of cytokines (causing extensive inflammation) damaging healthy synaptic junctions as a side-effect from overactivation."

Still, the ability to use the brain's existing immune mechanisms to clear amyloid offers intriguing possibilities.

"Going after microglia, rather than amyloid beta generation, may be a new research avenue for Alzheimer's disease," says Xu. "We could use brain immune cells to solve what's becoming a public health crisis."

One step closer to defeating Alzheimer's disease
by Rockefeller University Press

In mice with Alzheimer's-like disease, removal of TREM2 (right) decreased the formation of toxic plaques (arrows) that characterize the disease. Credit: Jay et al., 2015
Tackling brain inflammation ameliorates Alzheimer's disease (AD), according to a study published in The Journal of Experimental Medicine.

AD is characterized by the toxic build-up of a brain protein called beta-amyloid, and clearance of these protein "plaques" reduces disease. Immune cells called macrophages infiltrate the brain during AD and are thought to help clear away these toxic proteins, with the help of resident brain cells called microglia. Macrophages and microglia express a surface receptor called TREM2, and although debilitating mutations in TREM2 have been associated with AD, the function of the receptor is uncertain.

To decipher TREM2's role in AD, Bruce Lamb and colleagues from the Cleveland Clinic's Lerner Research Institute deleted the receptor in mice that develop an AD-like disease. Removal of TREM2 decreased plaque formation, reduced brain inflammation, and improved the survival of neurons. This protection was associated with fewer infiltrating macrophages. Macrophages lacking TREM2 were apparently better at engulfing beta-amyloid aggregates, suggesting that they might assist in the brain clean-up effort.

Although additional studies are needed to clarify the exact mechanism of TREM2's action in AD, these results suggest that toning down the receptor's activity may help put a stop to neurodegeneration in AD patients.

Targeting inflammatory pathway reduces Alzheimer's disease in mice
by Journal of Clinical Investigation

Alzheimer's disease (AD) is the most common form of dementia and is characterized by the formation of β-amyloid plaques throughout the brain. Proteins known as chemokines regulate inflammation and the immune response. In both patients with AD and mouse AD models, the chemokine CXCL10 is found in high concentrations in the brain and may contribute to AD.

A new study in the Journal of Clinical Investigation indicates that activation of the CXCL10 receptor, CXCR3, contributes to AD pathology. Using a murine model of AD, Michael Heneka and colleagues at the University of Bonn found that mice lacking CXCR3 had reduced β-amyloid plaque formation. Importantly, loss of CXCR3 signaling in AD mice attenuated behavioral deficits.

The results of this study suggest that CXCR3 should be explored as a potential therapeutic target for AD.

Drugs targeting blood vessels may be candidates for treating Alzheimer's
by University of British Columbia

(Medical Xpress)—University of British Columbia researchers have successfully normalized the production of blood vessels in the brain of mice with Alzheimer's disease (AD) by immunizing them with amyloid beta, a protein widely associated with the disease.

While AD is typically characterized by a build-up of plaques in the brain, recent research by the UBC team showed a near doubling of blood vessels in the brain of mice and humans with AD.

The new study, published online last week in Scientific Reports, a Nature journal, shows a reduction of brain capillaries in mice immunized with amyloid beta – a phenomenon subsequently corroborated by human clinical data – as well as a reduction of plaque build-up.

"The discovery provides further evidence of the role that an overabundance of brain blood vessels plays in AD, as well as the potential efficacy of amyloid beta as basis for an AD vaccine," says lead investigator Wilfred Jefferies, a professor in UBC's Michael Smith Laboratories.

"Now that we know blood vessel growth is a factor in AD, if follows that drugs targeting blood vessels may be good candidates as an AD treatment."

AD accounts for two-thirds of all cases of dementia. The number of Canadians living with dementia is expected to reach 1.4 million by 2013, according to the Alzheimer's Society of Canada.

Common epilepsy drug could prevent and treat Alzheimer's disease

The team led by UBC Psychiatry Prof. Weihong Song, who is also the Jack Brown and Family Professor and Chair in Alzheimer's Disease at UBC, found that if Valproic Acid (VPA) is used as a treatment in early stages of AD memory deficit is reversed.

The study, published in the Journal of Experimental Medicine, reveals that VPA works by inhibiting the activity of an enzyme that produces a neurotoxic protein called beta Amyloid. In doing so, plaque formation is discontinued. Amyloid beta-proteins are the central component of neurotoxic plaques in AD.

"We found that if we used VPA in the early stage of Alzheimer's disease, in model mice, it reduced plaque formation and further prevented brain cell death and axon damage," says Song, who is a Canada Research Chair in Alzheimer's disease and Director of the Townsend Family Laboratories in UBC's Faculty of Medicine. "The drug also improved performance in memory tests."

The results will help inform the design of human clinical trials because researchers now understand the mechanisms and pathology of VPA in AD animal models.

"We are very excited about these results because we now know when VPA should be administered to be most effective and we now know how VPA is working to prevent AD," says Song, who is also a member of the Brain Research Centre at UBC and VCHRI. "A small human clinical trial is currently underway and we expect results to be available in the next year."

AD is a neurodegenerative disorder characterized by progressive cognitive deterioration and is the most common form of dementia. The Alzheimer Society of Canada estimates that AD affects close to 300,000 Canadians and accounts for two-thirds of all cases of dementia. By 2031, about 750,000 Canadians will suffer from AD and related dementias.

Source: University of British Columbia

Researchers generate new neurons in brains, spinal cords of living adult mammals
by UT Southwestern Medical Center

UT Southwestern Medical Center researchers created new nerve cells in the brains and spinal cords of living mammals without the need for stem cell transplants to replenish lost cells.

Although the research indicates it may someday be possible to regenerate neurons from the body's own cells to repair traumatic brain injury or spinal cord damage or to treat conditions such as Alzheimer's disease, the researchers stressed that it is too soon to know whether the neurons created in these initial studies resulted in any functional improvements, a goal for future research.

Spinal cord injuries can lead to an irreversible loss of neurons, and along with scarring, can ultimately lead to impaired motor and sensory functions. Scientists are hopeful that regenerating cells can be an avenue to repair damage, but adult spinal cords have limited ability to produce new neurons. Biomedical scientists have transplanted stem cells to replace neurons, but have faced other hurdles, underscoring the need for new methods of replenishing lost cells.

Scientists in UT Southwestern's Department of Molecular Biology first successfully turned astrocytes – the most common non-neuronal brain cells – into neurons that formed networks in mice. They now successfully turned scar-forming astrocytes in the spinal cords of adult mice into neurons. The latest findings are published today in Nature Communications and follow previous findings published in Nature Cell Biology.

"Our earlier work was the first to clearly show in vivo (in a living animal) that mature astrocytes can be reprogrammed to become functional neurons without the need of cell transplantation. The current study did something similar in the spine, turning scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons," said Dr. Chun-Li Zhang, assistant professor of molecular biology at UT Southwestern and senior author of both studies.

"Astrocytes are abundant and widely distributed both in the brain and in the spinal cord. In response to injury, these cells proliferate and contribute to scar formation. Once a scar has formed, it seals the injured area and creates a mechanical and biochemical barrier to neural regeneration," Dr. Zhang explained. "Our results indicate that the astrocytes may be ideal targets for in vivo reprogramming."

The scientists' two-step approach first introduces a biological substance that regulates the expression of genes, called a transcription factor, into areas of the brain or spinal cord where that factor is not highly expressed in adult mice. Of 12 transcription factors tested, only SOX2 switched fully differentiated, adult astrocytes to an earlier neuronal precursor, or neuroblast, stage of development, Dr. Zhang said.

In the second step, the researchers gave the mice a drug called valproic acid (VPA) that encouraged the survival of the neuroblasts and their maturation (differentiation) into neurons. VPA has been used to treat epilepsy for more than half a century and also is prescribed to treat bipolar disorder and to prevent migraine headaches, he said.

The current study reports neurogenesis (neuron creation) occurred in the spinal cords of both adult and aged (over one-year old) mice of both sexes, although the response was much weaker in the aged mice, Dr. Zhang said. Researchers now are searching for ways to boost the number and speed of neuron creation. Neuroblasts took four weeks to form and eight weeks to mature into neurons, slower than neurogenesis reported in lab dish experiments, so researchers plan to conduct experiments to determine if the slower pace helps the newly generated neurons properly integrate into their environment.

In the spinal cord study, SOX2-induced mature neurons created from reprogramming of astrocytes persisted for 210 days after the start of the experiment, the longest time the researchers examined, he added.

Because tumor growth is a concern when cells are reprogrammed to an earlier stage of development, the researchers followed the mice in the Nature Cell Biology study for nearly a year to look for signs of tumor formation and reported finding none

Natural mineral may help reverse memory loss
by University of Queensland

Credit: Pixabay/CC0 Public Domain
Selenium—a mineral found in many foods—could reverse the cognitive impact of stroke and boost learning and memory in aging brains, according to University of Queensland research.

Queensland Brain Institute (QBI) lead researcher Dr. Tara Walker said studies on the impact of exercise on the aging brain found levels of a protein key to transporting selenium in the blood were elevated by physical activity.

"We've known for the last 20 years that exercise can create new neurons in the brain, but we didn't really understand how," Dr. Walker said.

The research team investigated whether dietary selenium supplements could replicate the effects of exercise.

"Our models showed that selenium supplementation could increase neuron generation and improve cognition in elderly mice," Dr. Walker said.

"The levels of new neuron generation decrease rapidly in aged mice, as they do in humans.

"When selenium supplements were given to the mice, the production of neurons increased, reversing the cognitive deficits observed in aging."

Selenium is an essential trace mineral absorbed from soil and water and is found in foods such as grains, meat and nuts, with the highest levels found in Brazil nuts.

The scientists also tested whether selenium would have an impact on the cognitive decline sometimes experienced following stroke, which can affect people's memory and ability to learn.

"Young mice are really good at the learning and memory tasks, but after a stroke, they could no longer perform these tasks," Dr. Walker said.

"We found that learning and memory deficits of stroke affected mice returned to normal when they were given selenium supplements."

Dr. Walker said the results opened a new therapeutic avenue to boost cognitive function in people who were unable to exercise due to poor health or old age.

"However, selenium supplements shouldn't be seen as a complete substitute for exercise, and too much can be bad for you," she said.

"A person who is getting a balanced diet of fruits, nuts, veggies and meat usually has good selenium levels.

"But in older people, particularly those with neurological conditions, selenium supplements could be beneficial."

Selenium status influence cancer risk
by Charité - Universitätsmedizin Berlin

As a nutritional trace element, selenium forms an essential part of our diet. In collaboration with the International Agency for Research on Cancer, researchers from Charité - Universitätsmedizin Berlin have been able to show that high blood selenium levels are associated with a decreased risk of developing liver cancer. In addition to other risk factors, the study also examines in how far selenium levels may influence the development of other types of cancer. Results from this study have been published in the American Journal of Clinical Nutrition.

Selenium (Se) is found in foods like fish, shellfish, meat, milk and eggs; certain South American nuts, such as Brazil nuts, are also good sources of selenium. It is a trace element that occurs naturally in soil and plants, and enters the bodies of humans and animals via the food they ingest. European soil has a rather low selenium concentration, in comparison with other areas of the world, especially in comparison to North America. Deficiencies of varying degrees of severity are common among the general population, and are the reason why German livestock receive selenium supplements in their feed.

While in Europe, neither a selenium-rich diet nor adequate selenium supplementation is associated with adverse effects, selenium deficiency is identified as a risk factor for a range of diseases. "We have been able to show that selenium deficiency is a major risk factor for liver cancer," says Prof. Dr. Lutz Schomburg of the Institute of Experimental Endocrinology, adding: "According to our data, the third of the population with lowest selenium status have a five- to ten-fold increased risk of developing hepatocellular carcinoma - also known as liver cancer."

In this case-control study, the team of European researchers investigated a cohort of 477,000 participants, and selected individuals who had developed hepatocellular carcinoma during a 10-year follow up. Blood samples were also chosen from healthy participants and subsequently analyzed to determine their selenium status. "Our study does not show that selenium supplementation has a direct protective effect against liver cancer. However, it does confirm the importance of a balanced diet, of which selenium forms an integral part," explains Prof. Schomburg. Previous studies had suggested a similar relationship between a person's selenium status and their risk of developing colon cancer, as well as their risk of developing autoimmune thyroid disease.