Indications why older people are more susceptible to Alzheimer's disease

July 8, 2019

Science Daily/DZNE - German Center for Neurodegenerative Diseases

The risk of developing Alzheimer's disease increases with age. Susanne Wegmann of the German Center for Neurodegenerative Diseases (DZNE) in Berlin and colleagues have uncovered a possible cause for this connection: Certain molecules involved in the disease, termed tau-proteins, spread more easily in the aging brain. This has been determined in laboratory experiments. The current study was carried out in close collaboration with researchers in the US at Harvard Medical School and Massachusetts General Hospital. The results were recently published in the journal Science Advances.

Alzheimer's disease usually begins with memory decline and later affects other cognitive abilities. Two different kinds of protein deposits in the patient's brain are involved in the disease: "Amyloid beta plaques" and "tau neurofibrillary tangles." The emergence of tau neurofibrillary tangles reflects disease progression: they first manifest in the brain's memory centers and then appear in other areas in the course of the disease. Tau proteins or tau aggregates probably migrate along nerve fibers and thereby contribute to the spreading of the disease throughout the brain.

Tau spreads more rapidly in aging brains

What is the role of aging in tau propagation? If the protein spread more easily in older brains, this could explain the increased susceptibility of older people to Alzheimer's disease. Wegmann and her colleagues tested this hypothesis.

Using a "gene vector" -- a tailored virus particle -- the scientists channeled the blueprint of the human tau protein into the brains of mice. Individual cells then began to produce the protein. Twelve weeks later, the researchers examined how far the tau protein had travelled from the production site. "Human tau proteins spread about twice as fast in older mice as compared to younger animals," Wegmann summarized the results.

The experimental part of the study was carried out in the laboratory of Bradley Hyman at Harvard Medical School in Boston, USA, where Susanne Wegmann worked for several years. In 2018, she moved to the DZNE's Berlin site, where her research group addresses various questions on tau-related disease mechanisms. Here, the major part of data analysis and summarizing the results took place.

Healthy and pathological tau

The experimental setting also allowed the scientists to analyze tau propagation in more detail. The protein exists in a healthy, soluble form in every neuron of the brain. However, in Alzheimer's disease, it can change its shape and convert into a pathological form prone to aggregate into fibrils. "It has long been thought that it is primarily the pathological form of tau that passes from one cell to the next. However, our results show that the healthy version of the protein also propagates in the brain and that this process increases in old age. Cells could also be harmed by receiving and accumulating large amounts of healthy tau," said Wegmann.

The findings from the study raise a number of questions that Wegmann will now tackle with her research group at the DZNE: Which processes underlie the increased spreading of tau in the aging brain? Is too much tau protein produced or too little defective protein removed? Answering these questions may open up new therapeutic options in the long term.

https://www.sciencedaily.com/releases/2019/07/190708135940.htm

New insight into aging

Plasticity is enhanced but dysregulated in the aging brain

September 19, 2018

Science Daily/McGill University

Researchers examined the effects of aging on neuroplasticity in the primary auditory cortex, the part of the brain that processes auditory information. Neuroplasticity refers to the brain's ability to modify its connections and function in response to environmental demands, an important process in learning.

They say you can't teach old dogs new tricks, but new research shows you can teach an old rat new sounds, even if the lesson doesn't stick very long.

Researchers at the Montreal Neurological Institute and Hospital (The Neuro) of McGill University examined the effects of aging on neuroplasticity in the primary auditory cortex, the part of the brain that processes auditory information. Neuroplasticity refers to the brain's ability to modify its connections and function in response to environmental demands, an important process in learning.

Plasticity in the young brain is very strong as we learn to map our surroundings using the senses. As we grow older, plasticity decreases to stabilize what we have already learned. This stabilization is partly controlled by a neurotransmitter called gamma-Aminobutyric acid (GABA), which inhibits neuronal activity. This role of GABA was discovered by K.A.C. Elliot and Ernst Florey at The Neuro in 1956.

First author Dr. Mike Cisneros-Franco and lab director Dr. Étienne de Villers-Sidani wanted to test the hypothesis that plasticity stabilization processes become dysregulated as we age. They ran an experiment where rats were exposed to audio tones of a specific frequency to measure how neurons in the primary auditory cortex adapt their responses to the tones.

They found that tone exposure caused neurons in older adult rats to become increasingly sensitized to the frequency, but this did not happen in younger adult rats. The effect in the older adult rats quickly disappeared after exposure, showing that plasticity was indeed dysregulated. However, by increasing the levels of the GABA neurotransmitter in another group of older rats, the exposure-induced plastic changes in the auditory cortex lasted longer.

These findings suggest the brain's ability to adapt its functional properties does not disappear as we age. Rather, they provide evidence that plasticity is, in fact, increased but dysregulated in the aged brain because of reduced GABA levels. Overall, the findings suggest that increasing GABA levels may improve the retention of learning in the aging brain.

"Our work showed that the aging brain is, contrary to a widely-held notion, more plastic than the young adult brain," says Cisneros-Franco. "On the flip side, this increased plasticity meant that any changes achieved through stimulation or training were unstable: both easy to achieve and easy to reverse."

"However, we also showed that it is possible to reduce this instability using clinically available drugs. Researchers and clinicians may build upon this knowledge to develop rehabilitation strategies to harness the full plastic potential of the aging brain."

https://www.sciencedaily.com/releases/2018/09/180919115827.htm

Older adults grow just as many new brain cells as young people

April 5, 2018

Science Daily/Cell Press

Researchers show for the first time that healthy older men and women can generate just as many new brain cells as younger people.

There has been controversy over whether adult humans grow new neurons, and some research has previously suggested that the adult brain was hard-wired and that adults did not grow new neurons. This study, to appear in the journal Cell Stem Cell on April 5, counters that notion. Lead author Maura Boldrini, associate professor of neurobiology at Columbia University, says the findings may suggest that many senior citizens remain more cognitively and emotionally intact than commonly believed.

"We found that older people have similar ability to make thousands of hippocampal new neurons from progenitor cells as younger people do," Boldrini says. "We also found equivalent volumes of the hippocampus (a brain structure used for emotion and cognition) across ages. Nevertheless, older individuals had less vascularization and maybe less ability of new neurons to make connections."

The researchers autopsied hippocampi from 28 previously healthy individuals aged 14-79 who had died suddenly. This is the first time researchers looked at newly formed neurons and the state of blood vessels within the entire human hippocampus soon after death. (The researchers had determined that study subjects were not cognitively impaired and had not suffered from depression or taken antidepressants, which Boldrini and colleagues had previously found could impact the production of new brain cells.)

In rodents and primates, the ability to generate new hippocampal cells declines with age. Waning production of neurons and an overall shrinking of the dentate gyrus, part of the hippocampus thought to help form new episodic memories, was believed to occur in aging humans as well.

The researchers from Columbia University and New York State Psychiatric Institute found that even the oldest brains they studied produced new brain cells. "We found similar numbers of intermediate neural progenitors and thousands of immature neurons," they wrote. Nevertheless, older individuals form fewer new blood vessels within brain structures and possess a smaller pool of progenitor cells -- descendants of stem cells that are more constrained in their capacity to differentiate and self-renew.

Boldrini surmised that reduced cognitive-emotional resilience in old age may be caused by this smaller pool of neural stem cells, the decline in vascularization, and reduced cell-to-cell connectivity within the hippocampus. "It is possible that ongoing hippocampal neurogenesis sustains human-specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience," she says.

Boldrini says that future research on the aging brain will continue to explore how neural cell proliferation, maturation, and survival are regulated by hormones, transcription factors, and other inter-cellular pathways.

https://www.sciencedaily.com/releases/2018/04/180405223413.htm

Powerful new data on the aging brain and traumatic brain injury

Latest data release also includes significant updates to Allen Cell Types Database and Allen Mouse Brain Connectivity Atlas

April 26, 2016

Science Daily/Allen Institute

The Allen Institute for Brain Science has announced major updates to its online resources available at brain-map.org, including a new resource on Aging, Dementia and Traumatic Brain Injury. The resource is the first of its kind to collect and share a wide variety of data modalities on a large sample of aged brains, complete with mental health histories and clinical diagnoses.

"The power of this resource is its ability to look across such a large number of brains, as well as a large number of data types," says Ed Lein, Ph.D., Investigator at the Allen Institute for Brain Science. "The resource combines traditional neuropathology with modern 'omics' approaches to enable researchers to understand the process of aging, look for molecular signatures of disease and identify hallmarks of brain injury."

The study samples come from the Adult Changes in Thought (ACT) study, a longitudinal research effort led by Dr. Eric B. Larson and Dr. Paul K. Crane of the Group Health Research Institute and the University of Washington to collect data on thousands of aging adults, including detailed information on their health histories and cognitive abilities. UW Medicine led efforts to collect post-mortem samples from 107 brains aged 79 to 102, with tissue collected from the parietal cortex, temporal cortex, hippocampus and cortical white matter.

"This collaborative research project aims to answer one of the most perplexing problems in clinical neuroscience," says Dr. Richard G. Ellenbogen, UW Chair and Professor, Department of Neurological Surgery. "If a person suffers a traumatic brain injury during his or her lifetime, what is the risk of developing dementia? We simply don't know the answer at this time, but some of the answers might be found in this comprehensive dataset by people asking the right kind of questions. This issue is important because of the inherent risk for everyone who plays sports, exercises or in general, participates in the activities of daily life."

"This study was made possible by the amazing generosity of the ACT participants and their families, incredible collaboration among our partners, and the generosity and vision of the Paul G. Allen Family Foundation," says Dr. Dirk Keene, co-principal investigator and Director, UW Neuropathology. "For the first time, scientists and clinicians from around the world will have access to this unique dataset, which will advance the study of brain aging and hopefully contribute to development of novel diagnostic and therapeutic strategies for neurodegenerative disease."

The final online resource includes quantitative image data to show the disease state of each sample, protein data related to those disease states, gene expression data and de-identified clinical data for each case. Because the data is so complex, the online resource also includes a series of animated "snapshots," giving users a dynamic sampling of the ways they can interrogate the data.

"There are many fascinating conclusions to be drawn by diving into these data," says Jane Roskams, Ph.D., Executive Director, Strategy and Alliances at the Allen Institute. "This is the first resource of its kind to combine a variety of data types and a large sample size, making it a remarkably holistic view of the aged brain in all its complexity."

Researchers focused on examining the impact of mild to moderate TBI on the aged brain, comparing samples from patients with self-reported loss of consciousness incidents against meticulously matched controls. "Interestingly, while we see many other trends in these data, we did not uncover a distinctive genetic signature or pathologic biomarker in patients with TBI and loss of consciousness in this population study," says Lein.

"This new resource is an exciting addition to our suite of open science resources," says Christof Koch, Ph.D., President and Chief Scientific Officer of the Allen Institute for Brain Science.

"Researchers around the globe will be able to mine the data and explore many facets of the aged brain, which we hope will accelerate discoveries about health and disease in aging."

Research to create this resource was funded with a $2.37 million grant from the Paul G. Allen Family Foundation to the University of Washington.

Two other resources have received significant updates in the latest data release. The Allen Cell Types Database now includes gene expression data on individual cells, in addition to shape, electrical activity and location in the brain. The number of cells in the database has also increased, and, in collaboration with the Blue Brain Project, a subset of cells are accompanied by a new robust biophysical model.

The Allen Mouse Brain Connectivity Atlas now includes its first public release of layer-specific connectivity in the visual cortex, including more specific targeting of cells using newly developed tracing methods.

https://www.sciencedaily.com/releases/2016/04/160426120104.htm

With beetroot juice before exercise, aging brains look 'younger'

April 19, 2017

Science Daily/Wake Forest University
Drinking a beetroot juice supplement before working out makes the brain of older adults perform more efficiently, mirroring the operations of a younger brain, according to a new study.

"We knew, going in, that a number of studies had shown that exercise has positive effects on the brain," said W. Jack Rejeski, study co-author. "But what we showed in this brief training study of hypertensive older adults was that, as compared to exercise alone, adding a beet root juice supplement to exercise resulted in brain connectivity that closely resembles what you see in younger adults."

While continued work in this area is needed to replicate and extend these exciting findings, they do suggest that what we eat as we age could be critically important to the maintenance of our brain health and functional independence.

Rejeski is Thurman D. Kitchin Professor and Director of the Behavioral Medicine Laboratory in the Department of Health & Exercise Science. The study, "Beet Root Juice: An Ergogenic Aid for Exercise and the Aging Brain," was published in the peer-reviewed Journals of Gerontology: Medical Sciences. One of his former undergraduate students, Meredith Petrie, was the lead author on the paper.

This is the first experiment to test the combined effects of exercise and beetroot juice on functional brain networks in the motor cortex and secondary connections between the motor cortex and the insula, which support mobility, Rejeski said.

The study included 26 men and women age 55 and older who did not exercise, had high blood pressure, and took no more than two medications for high blood pressure. Three times a week for six weeks, they drank a beetroot juice supplement called Beet-It Sport Shot one hour before a moderately intense, 50-minute walk on a treadmill. Half the participants received Beet-It containing 560 mg of nitrate; the others received a placebo Beet-It with very little nitrate.

Beets contain a high level of dietary nitrate, which is converted to nitrite and then nitric oxide (NO) when consumed. NO increases blood flow in the body, and multiple studies have shown it can improve exercise performance in people of various ages.

"Nitric oxide is a really powerful molecule. It goes to the areas of the body which are hypoxic, or needing oxygen, and the brain is a heavy feeder of oxygen in your body," said Rejeski.

When you exercise, the brain's somatomotor cortex, which processes information from the muscles, sorts out the cues coming in from the body. Exercise should strengthen the somatomotor cortex.

So, combining beetroot juice with exercise delivers even more oxygen to the brain and creates an excellent environment for strengthening the somatomotor cortex. Post-exercise analysis showed that, although the study groups has similar levels of nitrate and nitrite in the blood before drinking the juice, the beetroot juice group had much higher levels of nitrate and nitrite than the placebo group after exercise.

https://www.sciencedaily.com/releases/2017/04/170419091619.htm