tau proteins

Discovery of Neurotransmission Gene May Pave Way for Early Detection of Alzheimer's Disease

A new Tel Aviv University study identified a gene coding for a protein that turns off neurotransmission signaling, which contributes to Alzheimer’s disease (AD).

The gene, called RGS2 (Regulator of Protein Signaling 2), has never before been implicated in AD. The researchers report that lower RGS2 expression in AD patient cells increases their sensitivity to toxic effects of amyloid-β. The study, published in Translational Psychiatry, may lead to new avenues for diagnosing Alzheimer’s disease — possibly a blood test — and new therapies to halt the progression of the disease.

The research was led by Dr. David Gurwitz of the Department of Human Molecular Genetics and Biochemistry at TAU’s Sackler School of Medicine and Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU’s Sackler School of Medicine; and a member of TAU’s Adams Super Center for Brain Studies and TAU’s Sagol School of Neuroscience. Also participating in the research were their PhD student Adva Hadar and postgraduate student Dr. Elena Milanesi, in collaboration with Dr. Noam Shomron of the Department of Cell and Developmental Biology at TAU’s Sackler Faculty of Medicine and his postgraduate student Dr. Daphna Weissglas; and research teams from Italy and the Czech Republic.

Identifying the suspect

“Alzheimer’s researchers have until now zeroed in on two specific pathological hallmarks of the chronic neurodegenerative disease: deposits of misfolded amyloid-β (Aβ) peptide plaques, and phosphorylated tau protein neurofibrillary tangles found in diseased brains,” Dr. Gurwitz said. “But recent studies suggest amyloid-β plaques are also a common feature of healthy older brains. This raises questions about the central role of Aβ peptides in Alzheimer’s disease pathology.”

The researchers pinpointed a common suspect — the RGS2 gene — by combining genome-wide gene expression profiling of Alzheimer’s disease blood-derived cell lines with data-mining of previously published gene expression datasets. They found a reduced expression of RGS2 in Alzheimer’s disease blood-derived cell lines, then validated the observation by examining datasets derived from blood samples and post-mortem brain tissue samples from Alzheimer’s patients.

“Several genes and their protein products are already known to be implicated in Alzheimer’s disease pathology, but RGS2 has never been studied in this context,” Dr. Gurwitz said. “We now propose that whether or not Aβ is a primary culprit in Alzheimer’s disease, neuroprotective mechanisms activated during early disease phases lead to reduced RGS2 expression.”

Sensitizing brain neurons to potential damage

The new TAU study furthermore proposes that reduced RGS2 expression increases the susceptibility of brain neurons to the potentially damaging effects of Aβ.

“We found that reduced expression of RGS2 is already noticeable in blood cells during mild cognitive impairment, the earliest phase of Alzheimer’s,” Dr. Gurwitz observed. “This supported our theory that the reduced RGS2 expression represents a ‘protective mechanism’ triggered by ongoing brain neurodegeneration.”

The team further found that the reduced expression of RGS2 was correlated with increased Aβ neurotoxicity. It acted like a double-edged sword, allowing the diseased brain to function with fewer neurons, while increasing damage to it by accumulating misfolded Aβ.

“Our new observations must now be corroborated by other research groups,” Dr. Gurwitz concluded. “The next step will be to design early blood diagnostics and novel therapeutics to offset the negative effects of reduced expression of the RGS2 protein in the brain.”

Genetically Engineered Mice Suggest New Model for How Alzheimer’s Disease Causes Dementia

Using a novel, newly developed mouse model that mimics the development of Alzheimer’s disease in humans, Johns Hopkins researchers say they have been able to determine that a one-two punch of major biological “insults” must occur in the brain to cause the dementia that is the hallmark of the disease. A description of their experiments is published online in the journal Nature Communications.

For decades, Alzheimer’s disease, the most common cause of dementia, has been known to be associated with the accumulation of so-called neurofibrillary tangles, consisting of abnormal clumps of a protein called tau inside brain nerve cells, and by neuritic plaques, or deposits of a protein called beta-amyloid outside these cells along with dying nerve cells, in brain tissue.

In Alzheimer’s disease, tau bunches up inside the nerve cells and beta-amyloid clumps up outside these cells, mucking up the nerve cells controlling memory, notes Philip C. Wong, Ph.D., professor of pathology at the Johns Hopkins University School of Medicine.

What hasn’t been clear is the relationship and timing between those two clumping processes, since one is inside cells and one is outside cells, says lead and corresponding study author Tong Li, Ph.D., an assistant professor of pathology at Johns Hopkins. Prior studies of early-onset Alzheimer’s disease have suggested that the abnormal accumulation of beta-amyloid in the brain somehow triggers the aggregation of tau leading directly to dementia and brain cell degeneration. But the new research from Li, Wong and colleagues suggests that the accumulation of beta-amyloid in and of itself is insufficient to trigger the conversion of tau from a normal to abnormal state. Instead, their studies show, it may set off a chain of chemical signaling events that lead to the “conversion” of tau to a clumping state and subsequent development of symptoms.

“For the first time, we think we understand that the accumulation of amyloid plaque alone can damage the brain, but that’s actually not sufficient to drive the loss of nerve cells or behavioral and cognitive changes,” Wong says. “What appears to be needed is a second insult — the conversion of tau — as well.”

In humans, the lag between development of the beta-amyloid plaques and the tau tangles inside brain nerve cells can be 10 to 15 years or more, Li says, but because the lifetime of a mouse is only two to three years, current animal models that successfully mimic the appearance of beta-amyloid plaques did not offer enough time to observe the changes in tau.

To address that problem, the Johns Hopkins researchers genetically engineered a mouse model that used a tau fragment to promote the clumping of normal tau protein. They then cross-bred these mice with mice engineered to accumulate beta-amyloid. The result was a mouse model that developed dementia in a manner more similar to what happens in humans, Li says.

The researchers found during brain dissections of the animals that the presence of beta-amyloid plaque alone was not sufficient to cause the biochemical conversion of tau, the repeat domain of tau — the part of tau protein that is responsible for the conversion of normal tau to an abnormal state — alone was insufficient for the conversion of tau, beta-amyloid plaques must be present in the brain for the conversion of tau and the tau fragments could “seed” the plaque-dependent pathological conversion of tau.

One implication of the new research, Wong says, is to possibly explain why some drugs designed to attack the disease after the conversion of tau haven’t worked. “The timing may be off,” he says. “If you were to intervene in the time period before the conversion of tau, you might have a good chance of ameliorating the deficits, brain cell loss and ensuing consequence of the disease.”

The work also suggests that combination therapy designed to prevent both the beta-amyloid plaque formation as well as pathological conversion of tau may provide optimal benefit for Alzheimer’s disease, the researchers say. Their mouse model could be used to test new therapies.

An estimated 5.4 million Americans are living with Alzheimer’s disease, according to 2016 statistics from the Alzheimer’s Association. There is no cure, but there are some medications that may help stabilize cognition for a limited time or help with related depression, anxiety or hallucinations.

Alzheimer’s Researchers Creating “Designer Tracker” to Quantify Elusive Brain Protein, Provide Earlier Diagnosis

One of the biggest challenges with Alzheimer’s disease (AD) is that by the time physicians can detect behavioral changes, the disease has already begun its irreversibly destructive course. Scientists know toxic brain lesions created by amyloid beta and tau proteins are involved. Yet, emerging therapies targeting these lesions have failed in recent clinical trials. These findings suggest that successful treatments will require diagnosis of disease at its earliest stages.

Now, by using computer-aided drug discovery, an Ohio State University molecular biochemist and molecular imaging chemist are collaborating to create an imaging chemical that attaches predominantly to tau-bearing lesions in living brain. Their hope is that the “designer” tracer will open the door for earlier diagnosis – and better treatments for Alzheimer’s, frontal temporal dementia and traumatic brain injuries like those suffered by professional athletes, all conditions in which tangled tau filaments accumulate in brain tissue.

“We’re creating agents that are specifically engineered to bind the surface of aggregated tau proteins so that we can see where and how much tau is collecting in the brain,” said Jeff Kuret, professor of molecular and cellular biochemistry at The Ohio State University College of Medicine. “We think the “tau signature” can be used to improve diagnosis and staging of disease.”

The study’s co-investigator, Michael Tweedle, a professor of radiology at Ohio State’s College of Medicine, notes that there may be more advantages to being able to image tau.

“Unlike beta amyloid, tau appears in specific brain regions in Alzheimer’s,” said Tweedle. “With a better view of how tau is distinct from amyloid, we’ll be able to create a much more accurate view of disease staging, and do a much better job getting the right therapeutics into the right populations at the right time.”

Tweedle notes that there are no drugs currently available that target tau, but that several are in development. Both investigators emphasized that being able to image tau in a living brain could be critical for identifying individuals that could benefit from tau-tackling drugs as they move into clinical trials.

The search for tau selective neuroimaging agents is proceeding with the help of a pilot grant awarded to the team by Ohio State’s Center for Clinical and Translational Science (CCTS). The award provided them with the funds needed to synthesize candidate radiotracers for testing. The team then received funding from the Alzheimer’s Drug Discovery Foundation to test how the compounds distribute throughout the body. This work also leverages several CCTS-funded core resources. So far, the team has prepared 12 ligands that have promising binding affinity for tau aggregates.

“It’s an iterative process, and each step gives us new information on what we need to be looking for,” said Tweedle. “Now we know what parts of the molecule to alter while trying to retain other good qualities.”

Tauopathies are neurodegenerative diseases associated with the accumulation of tau protein “tangles” in the human brain. Alzheimer’s disease is one of the most common tauopathies, but tau aggregates are also found in certain forms of frontal temporal dementia as well as traumatic brain injuries. Alzheimer’s disease has become one of the most common disorders in the aging population, and is predicted to be a major driver of health care costs in the coming decades.

Scientists Develop Antibody to Treat Traumatic Brain Injury and Prevent Long-Term Neurodegeneration

New research led by investigators at Beth Israel Deaconess Medical Center (BIDMC) provides the first direct evidence linking traumatic brain injury to Alzheimer’s disease and chronic traumatic encephalopathy (CTE) – and offers the potential for early intervention to prevent the development of these debilitating neurodegenerative diseases. TBI can result from repetitive contact sport injuries or from exposure to military blasts, and is one of the most significant risk factors for both Alzheimer’s disease and CTE.

In a study published in the online edition of the journal Nature, the researchers found that a misshapen isoform of the tau protein can develop as soon as 12 hours after TBI, setting in motion a destructive course of events that can lead to widespread neurodegeneration. Importantly, the researchers have developed a potent antibody that can selectively detect and destroy this highly toxic protein.

“TBI is a leading cause of death and disability in children and young adults and also affects approximately 20 percent of the more than two million troops who have deployed to Iraq and Afghanistan,” said co-senior author Kun Ping Lu, MD, PhD, Chief of the Division of Translational Therapeutics in the Department of Medicine at BIDMC and Professor of Medicine at Harvard Medical School (HMS). “Our study shows that an early neurodegenerative process induced by the toxic tau protein can begin just hours after a traumatic brain injury. In both cell models of stress and in mouse models simulating sport- and military-related TBI, the production of this pathogenic protein, called cis P-tau, disrupts normal neurological functioning, spreads to other neurons and leads to widespread neuronal death. We have developed a potent monoclonal antibody that can prevent the onset of widespread neurodegeneration by identifying and neutralizing this toxic protein and restoring neurons’ structural and functional abilities.”

Alzheimer’s disease is the most common form of dementia in older individuals and currently affects more than 5 million Americans and 30 million people worldwide. Chronic traumatic encephalopathy is a degenerative brain disease associated with a number of neurological symptoms including risk-taking, aggression and depression. CTE can also lead to progressive dementia.

Previous research has shown that abnormal phosphorylation of the tau protein underlies Alzheimer’s and other neurodegenerative diseases. In recent years, the Lu laboratory discovered that tau exists in two isoforms, or shapes – one functioning and one disease-causing.

“Healthy tau protein is found in the brain and serves to assemble and support microtubules, the ‘scaffolding systems’ that give neurons their unique shape and are integral to memory and normal brain functioning,” explained Lu. But in Alzheimer’s, CTE and other neurodegenerative diseases, collectively called tauopathies, tau becomes tangled and unable to function properly.

“Recent studies of CTE in the brains of boxers, American football players and blast-exposed veterans have identified extensive neurofibrillary tau tangles,” he said. “But, because these tangles were not detected until months or, more likely, years after TBI, it has not been known whether tauopathy is a cause or a consequence of TBI-related neurodegenerative disease. We have now shown that it is a cause of these diseases.”

Co-senior author of the new study Xiao Zhen Zhou, MD, also an investigator in BIDMC’s Division of Translational Therapeutics and Assistant Professor of Medicine at HMS, had previously developed polyclonal antibodies capable of distinguishing between two distinct isoforms of the phosphorylated tau protein. The isoform known as trans is in a relaxed shape and is important for normal brain functioning. The other isoform, known as cis, is in a twisted shape and is prone to becoming tangled. Cis P-tau is an early pathogenic protein leading to tauopathy and memory loss in Alzheimer’s disease.

“In this new study, we wanted to find out whether cis P-tau is present following TBI and, if so, how to eliminate it from the brain without disrupting the healthy functioning of trans P-tau,” said Zhou. “We generated a monoclonal antibody able to detect and eliminate cis P-tau very early in the disease process.”

Monoclonal antibody technology is a popular drug development approach. Working like a lock and key, it enabled the investigators to both detect and neutralize only the toxic cis P-tau.

After confirming the existence of this toxic cis tau isoform in the brain tissue of humans who had died of CTE, the authors simulated contact-sport and blast-related injuries in mouse models, and found that the brain’s induction of cis P-tau is dependent on injury severity and frequency.

“Mild TBI, also known as a concussion, results in moderate and transient cis P-tau induction,” explained Lu. “However, repetitive concussions, as might occur in contact sports, can result in robust and persistent cis P-tau induction. This is similar to what is produced following a single severe TBI caused by a blast or impact.”
Subsequent experiments revealed that the cis P-tau protein disrupts the brain’s microtubule scaffolding systems and the transport of mitochondria, the powerhouse that provides energy for neuronal function, and eventually leads to neuron death by apoptosis. The research also showed that, over time, cis P-tau progressively spreads throughout the brain. Treating TBI with cis antibody eliminated the toxic cis P-tau, prevented widespread tauopathy and neuron death and restored brain structure and function.

“These experiments told us that cis P-tau has the ability to kill one neuron after another, eventually leading to widespread neurofibrillary tangles and brain atrophy, which are the hallmark lesions of both Alzheimer’s disease and CTE,” said Lu. “We have determined that cis P-tau is an early driver of neurodegenerative disease after brain injury and that tauopathy it is a cause of TBI-related Alzheimer’s disease and CTE. We have also determined that the cis antibody can treat TBI and prevent its long-term consequences in mouse models. The next important steps will be to establish cis P-tau as a new biomarker to help enable early detection, and to humanize the cis antibody for treating patients with TBI.”

“Alzheimer’s disease and chronic traumatic encephalopathy are terrible diseases that progressively rob individuals of their memory, judgment and ability to function,” said study coauthor Alvaro Pascual-Leone, MD, PhD, Chief of the Division of Cognitive Neurology at BIDMC and Professor of Neurology at HMS. Pascual-Leone also serves as Associate Director of the Football Players Health Study (FPHS) at Harvard University, a multi-year initiative to discover new approaches to diagnose, treat and prevent injuries in professional football players.

“High-profile cases of CTE, such as that of the late football player Junior Seau, have vividly demonstrated the tragic consequences of this affliction,” he added. “We need to learn more about CTE’s causes in order to develop better ways of diagnosing and treating it, and this study offers us a promising early intervention to prevent the pathologic consequences of this disease. These findings additionally offer us a new way to approach Alzheimer’s disease, which poses a staggering unsustainable burden throughout the world. Alzheimer’s afflicts both individuals and their families and, it deprives society of the contributions of experienced and wise elders.”

Skin Test May Shed New Light on Alzheimer’s and Parkinson’s Diseases

Scientists have discovered a skin test that may shed new light on Alzheimer’s and Parkinson’s diseases, according to a study released today will be presented at the American Academy of Neurology’s 67th Annual Meeting in Washington, D.C., April 18 to 25, 2015.

The study showed that skin biopsies can be used to detect elevated levels of abnormal proteins found in the two diseases.

“Until now, pathological confirmation was not possible without a brain biopsy, so these diseases often go unrecognized until after the disease has progressed,” said study author Ildefonso Rodriguez-Leyva, MD, at Central Hospital at the University of San Luis Potosi in San Luis Potosi, Mexico. “We hypothesized that since skin has the same origin as brain tissue while in the embryo that they might also show the same abnormal proteins. This new test offers a potential biomarker that may allow doctors to identify and diagnose these diseases earlier on.”

For the study, researchers took skin biopsies from 20 people with Alzheimer’s disease, 16 with Parkinson’s disease and 17 with dementia caused by other conditions and compared them to 12 healthy people in the same age group. They tested these skin samples to see if specific types of altered proteins were found—ones that indicate a person has Alzheimer’s or Parkinson’s.

As compared to healthy patients and ones with dementia caused by other conditions, those with both Alzheimer’s and Parkinson’s had seven times higher levels of the tau protein. People with Parkinson’s also had an eight times higher level of alpha-synuclein protein than the healthy control group.

Alzheimer’s disease is ranked as the sixth leading cause of death in the United States, and 5.4 million Americans are currently diagnosed with Alzheimer’s disease. Parkinson’s disease affects one million Americans, with at least 60,000 new cases reported annually each year.

“More research is needed to confirm these results, but the findings are exciting because we could potentially begin to use skin biopsies from living patients to study and learn more about these diseases. This also means tissue will be much more readily available for scientists to study,” said Rodriguez-Leyva. “This procedure could be used to study not only Alzheimer’s and Parkinson’s, but also other neurodegenerative diseases.”