Tag Archives: #dementia

A Study Identified 15 Novel Biomarkers For Diseases Predisposing To Dementia (Neuroscience)

Study provides new data on potential aetiological mechanisms that are linked with dementia caused by diseases, such as Alzheimer’s and vascular dementia.

A study by an international research group identified 15 novel biomarkers that are linked to late-onset dementias. These biomarkers are proteins, which predict cognitive decline and subsequent increased risk of dementia already 20 years before the disease onset.

The proteins are related to immune system dysfunction, blood-brain-barrier dysfunction, vascular pathologies, and central insulin resistance. Six of these proteins can be modified with currently available medications prescribed for conditions other than dementia. 

“These findings provide novel avenues for further studies to examine whether drugs targeting these proteins could prevent or delay the development of dementia”, says lead author Joni Lindbohm MD, PhD from the University College London and University of Helsinki.

The results of the study have been published in the Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

New methods enable advances in dementia research

Amyloid beta and tau proteins have dominated pathophysiological research on dementia etiology, but to date prevention and treatment trials targeting these biomarkers have been unsuccessful. This has motivated researches to search also other potential mechanisms that could predispose to dementia. Recent development of scalable platforms has made it possible to analyze a wide range of circulating proteins, which may reveal novel biological processes linked to dementias.

In this study the authors were able to analyze proteins with novel large-scale protein panel from stored blood samples of the British Whitehall II and US Atherosclerosis Risk in Communities (ARIC) study collected 20 years ago. Using a panel of 5,000 proteins measured from plasma, the researchers identified proteins that predicted cognitive decline in 5-yearly screenings and subsequent onset of clinical dementia. The 15 proteins predicted dementia in both the British and US cohorts.

Further research will provide more information to find drug targets

“This new study is the first step in our 5-year Wellcome Trust funded research programme. We will next examine whether the identified proteins have a causal association with dementia, and whether they are likely to be modifiable, and druggable”, tells one of the authors, Professor Mika Kivimäki, Director of the Whitehall II study at University College London.

The ultimate aim of the research programme is to identify novel drug targets for dementia prevention.

Dementia rates and related cost are increasing

The global number of individuals living with dementia is approximately 45 million and the number is projected to two or three times higher in 2050. In USA the annual cost of care for those living with dementia have increased 35% since 2015 and are nearly one billion annually. It is the fifth leading cause of death globally and currently no cure for dementia causing diseases exist.

Featured image credit: Mostphotos

Original publication: Lindbohm JV, Mars N, Walker KA, Singh-Manoux A, Livingston G, Brunner EJ, Sipilä PN, Saksela K, Ferrie JE, Lovering R, Williams SA, Hingorani AD, Gottesman RF, Zetterberg H, Kivimäki M. Plasma proteins, cognitive decline and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies Alzheimer’s & Dementia 6/2021. DOI: doi.org/10.1002/alz.12419. 

Provided by University of Helsinki

Johns Hopkins Medicine Suggests Eliminating Nerve Cell Protein May Stop ALS, Dementia (Neuroscience)

Amyotrophic lateral sclerosis (ALS), commonly known as “Lou Gehrig’s disease,” is a devastating neurodegenerative illness that causes nerve cells in the brain and the spinal cord to atrophy (waste away), usually resulting in dementia. Ninety percent of ALS cases are sporadic, with no known genetic mutation responsible, while the remaining 10 percent are genetically passed from parent to child. Now, Johns Hopkins Medicine researchers have identified a defective cellular pathway that initiates nerve cell breakdown and may be tied to both forms of the disease. They also suggest that eliminating charge multivesicular body protein 7 (CHMP7), the wayward protein responsible for the broken pathway, might provide a future means of treating ALS and dementia.

Led by Jeffrey Rothstein M.D., Ph.D., director of the Pedersen Brain Science Institute and the Robert Packard Center for ALS Research, and professor of neurology and neuroscience at the Johns Hopkins University School of Medicine, and senior postdoctoral fellow Alyssa Coyne, Ph.D., the research team studied CHMP7 within an area of a nerve cell known as the nuclear pore. The nuclear pore — a large, highly organized complex of different proteins — serves as the gatekeeper for the nucleus, the cell’s control center, by governing the in-and-out movement of genetic material (RNA) and proteins. Previous studies by Rothstein’s team showed that when this process goes awry — which is said to be dysregulated — it can result in the development of either the familial or inherited forms of ALS and dementias.

However, it has remained unknown why this dysregulation occurs, how it starts the chain of events leading to ALS and if it occurs in the far more common sporadic forms of ALS and dementia.

The Johns Hopkins Medicine study, published July 28, 2021, in the journal Science Translational Medicine, evaluated why the nuclear pore starts to degrade in patients with ALS and dementia, and the role of CHMP7 in that destruction.

The researchers found that CHMP7 protein accumulates specifically within the nucleus of neurons, starting a cascade of events that leads to nuclear pore injury. This, in turn, causes dysregulation of essential proteins in the cell — including one called TAR DNA binding protein 43 (TDP-43), where the dysregulated form is seen in both sporadic and familial ALS — and ultimately, cell death.

“Think of it like an engine that’s starting to lose parts,” Rothstein says. “If CHMP7 is making the nuclear pore start to degrade, what would happen if we took that insult away?”

To find the answer, Rothstein and his colleagues eliminated the CHMP7 protein with antisense technology, a new and promising tool for controlling gene expression (production of a protein) in a cell. Using synthetic antisense oligonucleotides (fragments of genetic material), the researchers targeted the CHMP7 gene at the level of messenger RNA — which codes for CHMP7 protein to be made — rather than changing the DNA — which provides the code. This inhibited the CHMP7 gene from producing its protein, and in turn, the researchers found it prevented nuclear pore degradation, subsequent cellular dysfunction and cell death. With the pore stable, they believe that the conditions potentially leading to ALS cannot be triggered.

“We’re essentially preventing the biological events that give birth to ALS,” Rothstein says.

He says the next steps in the research are to determine if this discovery can be applied to a potential ALS therapy in humans. The team also hopes to learn what causes CHMP7 to become dysregulated in patients with ALS.

Featured image: Johns Hopkins Medicine researchers have shown that blocking production of a protein, CHMP7, in nerve cell nuclei enables other proteins (Nuc50 and Pom121) to keep nuclear pores (passageways in and out of the nucleus) functional and prevent nerve cell death — and perhaps prevent amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder. Graphic shows that as CHMP7 decreases, the levels of Nup50 and Pom121 increase (more green color indicates more protein). Credit: Robert Packard Center for ALS Research, Johns Hopkins Medicine

Reference: Alyssa Coyne et al., “Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS”, Science Translational Medicine  28 Jul 2021: Vol. 13, Issue 604, eabe1923 DOI: https://doi.org/10.1126/scitranslmed.abe1923

Provided by Johns Hopkins University School of Medicine

Evidence Of Sustained Benefits of Pimavanserin For Dementia-related Psychosis (Medicine)

Evidence of the sustained benefits of an investigational antipsychotic treatment for people with dementia-related psychosis has been published.

Up to half of the 45 million people worldwide who are living with Alzheimer’s disease will experience psychotic episodes, a figure that is even higher in some other forms of dementia. Psychosis is linked to a faster deterioration in dementia.

Despite this, there is no approved safe and effective treatment for these particularly distressing symptoms. In people with dementia, widely-used antipsychotics lead to sedation, falls and increased risk of deaths.

Pimavanserin works by blocking serotonin 5HT2A receptors, and doesn’t interact with the dopamine receptors. It is licensed in the US to treat hallucinations and delusions in people with Parkinson’s disease psychosis.

A new paper published in the New England Journal of Medicine outlines a clinical trial, conducted in 392 people with psychosis associated with Alzheimer’s disease, Parkinson’s disease, Lewy body, frontotemporal, or vascular dementia. All participants were given pimavanserin for 12 weeks. Those who met a threshold of symptom improvement were then assigned to pimavanserin or placebo for up to 26 weeks.

The trial was stopped early for positive efficacy results. Of the 351 participants, 217 (61.8%) had a sustained initial treatment benefit, of whom 112 were assigned to placebo and 105 to pimavanserin. Relapse occurred in 28/99 (28.3%) of the placebo group, compared to 12/95 (12.6%) of the pimvanserin group, with pimvanserin more than halving the relapse rate and significantly improving the sustained benefit.

Professor Clive Ballard, Executive Dean of the University of Exeter Medical School, said: “Psychosis affects up to half of all people with dementia, and it’s a particularly distressing symptom – yet there’s currently no safe and effective treatment. Currently used antipsychotics are known to cause harms, and best practice guidelines recommend prescribing for no longer than 12 weeks for people with dementia as a result. We urgently need alternatives. It’s exciting that the relapse rate in the pimavanserin group was lower than the placebo group, indicating that the treatment benefits may be sustained over time. We now need longer and larger scale trials to explore this further.”

The trial found headache, urinary tract infection and constipation occurred more frequently in the pimavanserin group, but there was no increase in mortality or the other serious events, such as stroke, which are known to increase with other antipsychotics.

The full paper is entitled ‘Trial of Pimavanserin in Dementia-related psychosis‘, published in the New England Journal of Medicine.

Provided by University of Exeter

Success in Reversing Dementia in Mice Sets the Stage for Human Clinical Trials (Neuroscience)

Researchers have identified a new treatment candidate that appears to not only halt neurodegenerative symptoms in mouse models of dementia and Alzheimer’s disease, but also reverse the effects of the disorders.

The team, based at Tohoku University, published their results on June 8 in the International Journal of Molecular Sciences. The treatment candidate has been declared safe by Japan’s governing board, and the researchers plan to begin clinical trials in humans in the next year.

“There are currently no disease-modifying therapeutics for neurodegenerative disorders such as Alzheimer’s disease, Lewy body dementia, Huntington disease and frontotemporal dementia in the world,” said paper author Kohji Fukunaga, professor emeritus in Tohoku University’s Graduate School of Pharmaceutical Sciences. “We discovered the novel, disease-modifying therapeutic candidate SAK3, which, in our studies, rescued neurons in most protein-misfolding, neurodegenerative diseases.”

In a previous study, the team found that the SAK3 molecule – the base structure of which is found in the enhancement of T-type Ca2+ channel activity – appeared to help improve memory and learning in a mouse model of Alzheimer’s disease.

According to previous studies, SAK3 enhances the function of a cell membrane channel thereby promoting neuronal activity in the brain. Typically, SAK3 promotes neurotransmitter releases of acetylcholine and dopamine that are significantly reduced in Alzheimer’s disease and Lewy body dementia. The Ca2+ channel enhancement is thought to trigger a change from resting to active in neuronal activity. When the Ca2+ channel is dysregulated in the brain, the acetylcholine and dopamine releases are reduced. The result is a dysregulated system that a person experiences as cognitive confusion and uncoordinated motor function.

Neurodegenerative diseases such as Alzheimer’s disease and dementia with Lewy body (DLB) are caused by the accumulation of aggregated amyloid beta and α-synucelin, respectively. The aggregated proteins impaired the proteasome activity, thereby exacerbating neuronal death. On the other hand, we developed a novel T-type calcium channel enhancer SAK3 in 2017. Since T-type calcium channel is critical for neurotransmitter release, SAK3 enhanced the acetylcholine release in the brain thereby improving learning and memory. We here found that calcium entry through T-type calcium channel activates protein kinase (CaMKII), thereby promoting Rpt-6 phosphorylation. The Rpt-6 phosphorylation promoted the degradation of aggregated amyloid beta and α-synucelin in neurons. This is the first disease modifying therapeutics in most neurodegenerative diseases such as Alzheimer’s disease, dementia with Lewy body (DLB), Huntington disease (HD) and frontotemporal dementia (FTD). © Kohji Fukunaga

SAK3 directly binds to the subunit of this channel, resulting in the enhancement of neurotransmission thereby improving cognitive deficits. The researchers found that the same process also appeared to work in a mouse model of Lewy body dementia, which is characterized by a build-up of proteins known as Lewy bodies.

“Even after the onset of cognitive impairment, SAK3 administration significantly prevented the progression of neurodegenerative behaviors in both motor dysfunction and cognition,” Fukunaga said.

In comparison, Aduhelm, the Alzheimer’s drug recently approved by the U.S. Food and Drug Administration, reduces the number of amyloid plaques in the brain, but it is not yet known if the amyloid reduction actually prevents further cognitive or motor decline in patients. According to Fukunaga, SAK3 helps destroy amyloid plaque – at least in mice.

SAK3 also helps manage the destruction of misfolded alpha-synuclein. Normal alpha-synuclein helps regulate neurotransmitter transmission in the brain. The protein can misfold and aggregate, contributing to what researchers suspect may be an underlying cause of neurodegenerative symptoms. This aggregation can also lead to the loss of dopamine neurons, which help with learning and memory.

“We found that chronic administration of SAK3 significantly inhibited the accumulation of alpha-synuclein in the mice,” Fukunaga said, noting that the mice received a daily oral dose of SAK3.

According to Fukunaga, SAK3 enhances the activity of the system that identifies and destroys misfolded proteins. In neurodegenerative diseases, this system is often dysfunctional, leaving misfolded proteins to muck up the cell’s machinery.

“SAK3 is the first compound targeting this regulatory activity in neurodegenerative disorders,” Fukunaga said. “SAK3 administration promotes the destruction of misfolded proteins, meaning the therapeutic has the potential to solve the problems of diverse protein misfolding diseases such as Parkinson’s disease, Lewy body dementia and Huntington disease, in addition to Alzheimer’s disease.”

Publication Details:

  • Title: T-type Ca2+ enhancer SAK3 activates CaMKII and proteasome activities in Lewy body dementia mice model
  • Authors: Jing Xu, Ichiro Kawahata, Hisanao Izumi and Kohji Fukunaga
  • Journal: International Journal of Molecular Sciences
  • DOI: 10.3390/ijms22126185

Provided by Tohoku University

Protein Linked to Heart Health, Disease A Potential Therapeutic Target For Dementia (Neuroscience)

Brain protein reduces Alzheimer’s-like brain damage in mice

By the time people with Alzheimer’s disease start exhibiting difficulty remembering and thinking, the disease has been developing in their brains for two decades or more, and their brain tissue already has sustained damage. As the disease progresses, the damage accumulates, and their symptoms worsen.

Researchers at Washington University School of Medicine in St. Louis have found that high levels of a normal protein associated with reduced heart disease also protect against Alzheimer’s-like brain damage – at least in mice. The findings, published June 21 in Neuron, suggest that raising levels of the protein — known as low-density lipoprotein receptor (LDL receptor) — could potentially be a way to slow or stop cognitive decline.

The discovery of LDL receptor as a potential therapeutic target for dementia is surprising since the protein is much better known for its role in cholesterol metabolism. Statins and PCSK9 inhibitors, two groups of drugs widely prescribed for cardiovascular disease, work in part by increasing levels of LDL receptor in the liver and some other tissues. It is not known whether they affect LDL receptor levels in the brain.

“There are not yet clearly effective therapies to preserve cognitive function in people with Alzheimer’s disease,” said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “We found that increasing LDL receptor in the brain strongly decreases neurodegeneration and protects against brain injury in mice. If you could increase LDL receptor in the brain with a small molecule or other approach, it could be a very attractive treatment strategy.”

The key to the importance of LDL receptor lies in a different protein, APOE, that also is linked to both cholesterol metabolism and Alzheimer’s disease. High cholesterol in the blood is associated with increased risk of Alzheimer’s disease, although the exact nature of the association is unclear.

During the long, slow development of Alzheimer’s disease, plaques of a protein called amyloid gradually accumulate in the brain. After many years, another brain protein called tau starts forming tangles that become detectable just before Alzheimer’s symptoms arise. The tangles are thought to be toxic to neurons, and their spread through the brain foretells the death of brain tissue and cognitive decline. First author Yang Shi, PhD, a postdoctoral researcher, and Holtzman previously showed that APOE drives tau-mediated degeneration in the brain by activating microglia, the brain’s cellular janitorial crew. Once activated, microglia can injure neural tissue in their zeal to clean up molecular debris.

Higher levels of LDL receptor limit the damage APOE can do in part by binding to APOE and degrading it. Higher levels of LDL receptor in the brain, therefore, should pull more APOE out of the fluid surrounding brain cells and mitigate damage even further, the researchers reasoned.

As part of this study, Shi, Holtzman and colleagues including co-senior author Jason Ulrich, PhD, an associate professor of neurology, studied mice predisposed to develop Alzheimer’s-like neurodegeneration because they had been genetically modified to develop tau buildup in the brain, much like people with Alzheimer’s disease and other forms of dementia. The researchers bred the tau mice with mice genetically modified to express high levels of LDL receptor in their brains. The resulting offspring had high levels of LDL receptor and a propensity to develop Alzheimer’s-like brain damage by the time they were 9 months old, which is similar to middle age in a person.

Then, the researchers compared the four groups: normal mice, tau mice, mice with high levels of LDL receptor, and tau mice with high levels of LDL receptor. At 9 months, the normal mice and the mice with high levels of LDL receptor had healthy looking brains. The tau mice had severe brain atrophy and neurological damage. In comparison, the tau mice with high levels of LDL receptor were in much better shape. They had significantly less brain shrinkage and damage, their levels of certain forms of tau and APOE were significantly lower, and their microglia were shifted toward a less damaging pattern of activation.

“Alzheimer’s develops slowly through multiple phases, and the degeneration phase when tau is building up is when the symptoms arise and worsen,” Holtzman said. “In terms of quality of life for people with Alzheimer’s, this is a phase in which it would be great if we could intervene. I think this LDL receptor pathway is a good candidate because it has a strong effect, and we know it can be targeted in other parts of the body. This has motivated us over the last few years to try to develop programs to modulate the receptor in other ways.”

This study was funded by the National Institutes of Health (NIH), grant numbers NS090934 and AG047644; the Tau Consortium; and the JPB Foundation. The EM study was supported by the DRC grant.

Featured image: Mice prone to developing Alzheimer’s-like brain damage have potentially damaging activated immune cells in their brains (above). Researchers at Washington University School of Medicine in St. Louis have found that high levels of a normal protein associated with reduced heart disease also protect against Alzheimer’s-like damage in mice, opening up new approaches to slowing or stopping brain damage and cognitive decline in people with Alzheimer’s. © Yang Shi

Reference: Shi Y, Andhey PS, Ising C, Wang K, Snipes LL, Boyer K, Lawson S, Yamada K, Qin W, Manis M, Serrano JR, Benitez BA, Schmidt RE, Artyomov M, Ulrich JD, Holtzman JD. Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms. Neuron. June 21, 2021. DOI: 10.1016/j.neuron.2021.05.034

Provided by WUSTL

Will Reduction in Tau Protein Protect Against Parkinson’s and Lewy Body Dementias? (Neuroscience)

New results suggest the answer is no, implying that the role of tau in the pathogenesis of Lewy body dementias is distinct from Alzheimer’s disease.

Will a reduction in tau protein in brain neurons protect against Parkinson’s disease and Lewy body dementias? 

A new study, published in the journal eNeuro, suggests the answer is no. If this is borne out, that result differs from Alzheimer’s disease, where reducing endogenous tau levels in brain neurons is protective for multiple models of the disease — which further suggests that the role of tau in the pathogenesis of Lewy body dementias is distinct from Alzheimer’s disease.

Both Parkinson’s disease dementia and Lewy body dementia are characterized by intracellular aggregates of misfolded alpha-synuclein protein in brain neurons, and the two diseases together are the second most common cause of neurodegenerative dementia after Alzheimer’s.

University of Alabama at Birmingham researchers, led by Laura Volpicelli-Daley, Ph.D., associate professor of neurology, used a Parkinson’s disease model she developed 11 years ago. Volpicelli-Daley applies very low concentrations of altered alpha-synuclein, which has taken on a pathologic conformation, to either in vitro or in vivo neurons. The nerve cells take up some of the fibrils. Inside the cells, the altered alpha-synuclein acts as a seed to attract the soluble alpha-synuclein that is naturally present in neurons. This transforms soluble alpha-synuclein into pathological, insoluble aggregates that impair neuron function and lead to cell death. These modified alpha-synuclein inclusions share morphology with those found in the Parkinson’s disease brains after death.

This disease model — termed templated alpha-synuclein inclusion formation — was used to compare neurons that produce the normal amount of tau protein, against mutant neurons that lack one or both genes for tau, and thus have less or no tau protein. If endogenous tau contributes to disease progression, the heterozygous or knockout tau mutants were expected to show protection. However, the UAB researchers found no difference from the wild-type control.

In their results, the researchers first showed that there was indeed an interaction between tau and alpha-synuclein in the cells — both proteins localized in presynaptic terminals of primary culture neurons, and in the cortex of the mouse brain, which is consistent with previous findings from preparations of human brains, and with several in vitro studies showing that the two proteins interact with each other.

However, the reduction or complete absence of tau did not prevent fibril-induced alpha-synuclein inclusion formation in primary hippocampal neurons growing in vitro. In mice, reduction or absence of tau also did not prevent fibril-induced alpha-synuclein formation in the motor control or limbic areas of the brain, including the cortex, amygdala, hippocampus and the substantia nigra pars compacta, as measured six weeks or six months after fibril injections.

Laura Volpicelli-Daley, Ph.D., associate professor of neurology (Photo by: Lexi Coon)
Laura Volpicelli-Daley, Ph.D., associate professor of neurology (Photo by: Lexi Coon)

Finally, while the alpha-synuclein fibrils in the mouse model caused the death of half of the wild-type neurons that produce the neurotransmitter dopamine, the dopaminergic neurons in tau-heterozygous or tau-knockout mice showed the same amount of neuron death, which meant no protection. In addition, reducing tau did not have any major impact on behavioral phenotypes of mice with fibril-induced α-synuclein inclusions.

“Here, we have shown that reduction of endogenous tau did not influence formation of templated alpha-synuclein inclusion formation or the loss of dopamine neurons,” Volpicelli-Daley said. “This suggests that therapeutics directed to tau for Parkinson’s disease may be more complicated than tau reduction. This is unlike Alzheimer’s disease, where tau reduction has been suggested as a possible therapy.”

Co-authors with Volpicelli-Daley of the study, “Templated alpha-synuclein inclusion formation is independent of endogenous tau,” are Lindsay E. Stoyka, Casey L. Mahoney, Drake R. Thrasher, Drèson L. Russell, Anna K. Cook, Anner T. Harris, Ashwin Narayanan, Tiara P. Janado, David G. Standaert and Erik D. Roberson, UAB Center for Neurodegeneration and Experimental Therapeutics.

Support came from the Department of Defense Parkinson’s Research Program grant PD15032, and from National Institutes of Health grants NS102257, NS075487, NS108675, AG058458 and GM008361.

Reference: Lindsay E. Stoyka, Casey L. Mahoney, Drake R. Thrasher, Drèson L. Russell, Anna K. Cook, Anner T. Harris, Ashwin Narayanan, Tiara P. Janado, David G. Standaert, Erik D. Roberson and Laura A. Volpicelli-Daley, “Templated α-Synuclein Inclusion Formation Is Independent of Endogenous Tau”, eNeuro 10 May 2021, 8 (3) ENEURO.0458-20.2021; DOI: https://doi.org/10.1523/ENEURO.0458-20.2021

Provided by UAB

New Drug To Halt Dementia After Multiple Head Injuries (Medicine)

A world-first international study led by the University of South Australia has identified a new drug to stop athletes developing dementia after sustaining repeated head injuries in their career.

The link between concussion and neurogenerative diseases is well established, but new research findings could halt the progression of chronic traumatic encephalopathy (CTE) in sportspeople who sustain repeated blows to the head.

CTE is a progressive and fatal brain disease associated with the accumulation of a protein known as hyperphosphorylated tau which affects cognition and behaviour.

In a paper published in Scientific ReportsUniSA Emeritus Professor Bob Vink and colleagues show how repeated concussions can cause CTE and a way to block it with a specially developed drug.

The findings will potentially have significant implications for athletes who play contact sports – such as boxers and footballers – as well as military veterans sustaining head injuries in conflict.

The team of researchers from Adelaide, Melbourne and the United States say the brain releases a neurotransmitter called substance P in the event of a head injury, causing abnormal amounts of the tau protein to collect inside neurons.

Professor Robert Vink © UNISA

“Tau protein tangles are a feature of CTE, which reportedly leads to memory problems, confusion, personality changes, aggression, depression and suicidal thinking,” Prof Vink says.

“Our research shows that by blocking substance P with a specific drug, we can prevent the tau protein tangles from developing in the brain and causing neurological problems.”

The treatment was successfully tested in animal models, giving hope that CTE can be prevented in humans.

Prof Vink says the next step is human clinical trials, but that could take several years given that currently CTE can only be diagnosed post-mortem.

study of 14,000 Americans over 25 years, published in Alzheimer’s and Dementia in March, showed that people who sustained even one head injury were 25 per cent more likely to develop dementia later in life. This risk increased with multiple traumatic brain injuries.

The Guardian also reported in April that an analysis of late AFLW player Jacinta Barclay’s brain uncovered neurological damage at age 29, highlighting the risks of repeated concussions to both sexes. Previous research has focused on the impact of brain injuries in male athletes, but females are more likely to sustain concussions.

Featured image: Red area shows where the brain is inflamed after concussion © UNISA

Reference: Corrigan, F., Cernak, I., McAteer, K. et al. NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury. Sci Rep 11, 8861 (2021). https://doi.org/10.1038/s41598-021-88237-0

Provided by University of South Australia

Changes in How Cholesterol Breaks Down in the Body May Accelerate Progression of Dementia (Neuroscience)

Study suggests that some cholesterol medications may impact signaling pathways in the brain, particularly in men

The blood-brain barrier is impermeable to cholesterol, yet high blood cholesterol is associated with increased risk of Alzheimer’s disease and vascular dementia. However, the underlying mechanisms mediating this relationship are poorly understood. A study published in the open-access journal PLOS Medicine by Vijay Varma and colleagues at the National Institute on Aging, part of the National Institutes of Health, in Baltimore, Maryland, suggests that disturbances in the conversion of cholesterol to bile acids (called cholesterol catabolism) may play a role in the development of dementia.

Little is known about how high blood cholesterol may lead to an increased risk of Alzheimer’s and dementia, yet understanding the underlying processes may lay the foundation for discovering effective therapeutics. To investigate whether abnormalities in cholesterol catabolism through its conversion to bile acids is associated with development of dementia, researchers drew on more than 1800 participants from two prospective studies: the Baltimore Longitudinal Study of Aging (BLSA) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

First, the research team investigated whether cholesterol catabolism was associated with brain abnormalities typical of Alzheimer’s and vascular dementia. They next tested whether exposure to cholesterol medications that block bile acid absorption into the bloodstream was associated with an increased risk of dementia among more than 26,000 patients from general practice clinics in the United Kingdom. Finally, they examined 29 autopsy samples from the BLSA to determine whether people with Alzheimer’s disease tend to have altered levels of bile acids in their brains.

The authors found that the risk of vascular dementia increased for males, but not females, with greater number of prescriptions of bile acid blocking drugs. Their findings suggest that cholesterol catabolism and bile acid synthesis may impact dementia progression through sex-specific effects on brain signaling pathways. However, additional studies are needed as the research was limited by the relatively small numbers of autopsy samples. In addition, experimental studies are required to better understand the role of cholesterol breakdown in dementia.

“To further extend these findings, we are now testing whether approved drugs for other diseases that may correct bile acid signaling abnormalities in the brain could be novel treatments for Alzheimer’s disease and related dementias,” said senior author Madhav Thambisetty, M.D., Ph.D., investigator and chief of the Unit of Clinical and Translational Neuroscience in the NIA’s Laboratory of Behavioral Neuroscience. “These analyses are being pursued in the Drug Repurposing for Effective Alzheimer’s Medicines (DREAM) study.”

Research Article

Peer reviewed; Observational; Humans

In your coverage please use this URL to provide access to the freely available paper: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003615

Funding: This research was supported in part by the intramural program of the National Institute on Aging (NIA) and the National Cancer Institute (NCI). ROSMAP is supported by NIA grants P30AG10161, R01AG15819, R01AG17917, and U01AG61356. The ADMC is supported by National Institute on Aging (NIA): grant R01AG046171, a component of the Accelerated Medicines Partnership for AD (AMP-AD) Target Discovery and Preclinical Validation Project; grant RF1 AG0151550, a component of the M2OVE-AD Consortium (Molecular Mechanisms of the Vascular Etiology of AD-Consortium; and RF1AG057452, R01AG059093, RF1AG058942, U01AG061359, U19AG063744 and FNIH: #DAOU16AMPA. Specific authors, indicated in parentheses, were supported by additional grants: NIA RF1 AG058942 and R01 AG057452 (RKD); NLM R01 LM012535 and NIA R03 AG054936 (KN). MT is grateful for funding support from the Andrew and Lillian A. Posey foundation to the Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, NIA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DFW has prior contracts with Roche Neuroscience, AVID pharma, Lundbeck.

Featured image: Investigators with the National Institute on Aging, part of the National Institutes of Health, are searching for drug candidates that may correct the brain’s metabolic abnormalities, such as cholesterol breakdown © Dr. Vijay R. Varma

Reference: Varma VR, Wang Y, An Y, Varma S, Bilgel M, Doshi J, et al. (2021) Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study. PLoS Med 18(5): e1003615. https://doi.org/10.1371/journal.pmed.1003615

Provided by PLOS

New Insight Into Protein Production in Brain Could Help Tackle Dementia (Neuroscience)

A pioneering new study led by UCL scientists has revealed, for the first time, a layer of genetic material involved in controlling the production of tau; a protein which plays a critical role in serious degenerative conditions, such as Parkinson’s and Alzheimer’s disease.

The international research, conducted in mice and cells, also revealed this material is part of a larger family of non-coding genes* which control and regulate other similar brain proteins, such as beta amyloid associated with Alzheimer’s and alpha-synuclein implicated in Parkinson’s disease and Lewy body dementia.

Researchers say the breakthrough findings, published in Nature, shed an important new light on how proteins linked to neurological conditions are produced and controlled, and could pave the way for new treatments for a wide range of dementia related diseases.

Lead author, Dr Roberto Simone (UCL Queen Square Institute of Neurology), said: “Tau plays a vital role inside our brain cells: It helps to stabilise and maintain the cytoskeletal structures that allow different materials to be transported to where they need to be. We know that too much tau is detrimental – the excess unused tau converts into toxic species that may be responsible for damaging cells and driving the spread and progression of degenerative disease. However, despite the fact that tau has been studied for more than three decades, until now we did not know how tau protein production is controlled.”

For the laboratory-based study, researchers identified a section of genetic material known as ‘antisense long non-coding RNA’ (lncRNA). They discovered this material does not make tau directly but helps to regulate, fine-tune and repress the production of the protein inside brain cells. This precision provided by antisense lncRNA in tau regulation could be crucial for smooth functioning of the brain’s nerve cells.

Research group leader, Professor Rohan de Silva (UCL Queen Square Institute of Neurology) said: “Excitingly, we found that the lncRNA that controls tau is not unique. Other key proteins we know to be involved in neurological conditions, including alpha-synuclein in Parkinson’s disease and beta-amyloid in Alzheimer’s disease, are controlled by very similar lncRNAs. This means we may have found the key to regulating the production of a whole range of proteins involved in brain function and the development of these devastating conditions.

“It’s early days but we hope that these exciting new insights will lead to the development of drugs that can keep tau and other proteins under control, and that these therapies could be life-changing for degenerative brain conditions that as yet, have no treatments to halt, let alone slow their progression.”

Other neurological conditions associated with the tau protein include corticobasal degeneration and progressive supranuclear palsy.

Targeting tau to create new treatments

Professor de Silva said: “Genetic studies have previously shown that people who have a particular form of the tau gene – called H1 – are more likely to get Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy. We know that people with the H1 form of the gene produce more tau. We also know the lncRNA we’ve identified helps to limit tau production, and that studies using post-mortem brain tissue show this lncRNA may be reduced in people with Parkinson’s disease.

“So, if we can find a way to boost the levels of this lncRNA, we might be able to reduce the production of tau protein which could help to slow or stop the damage to cells inside the brain.”

He added: “That’s exactly what we are working on now. Specifically, we are developing a gene therapy to deliver this lncRNA to brain cells and we’re currently testing whether this approach can reduce tau levels in mice and other animal models. If it’s successful, we hope to take this approach forward to be developed as a new therapy that can one day be tested in people.”

Professor David Dexter, Associate Director of Research at Parkinson’s UK, said: “This important research provides fantastic new insights into how tau production is controlled inside brain cells, and presents an exciting new opportunity for developing therapies that target this. It’s especially exciting to see that similar mechanisms may be involved in controlling the production of many other key proteins implicated in other neurological conditions, as it suggests strategies targeting these mechanisms could be effective across many conditions.”

This research has involved collaborations within UCL and with research groups at the Francis Crick Institute, UK Dementia Research Institute, St George’s University of London, Karolinska Institute, Sweden and the University of Trento, Italy.

Funding for this study came from Reta Lila Weston Trust, Wellcome Trust, Medical Research Council (MRC), Parkinson’s UK, CBD Solutions, PSP Association and CurePSP.

* Non-coding DNA: Our genome contains coding genes, the parts of our DNA that contain instructions for making proteins, the building blocks of our bodies. However, these coding genes make up only a small part of our genome – a mere 3% of the 3 billion letters (the nucleotides) of our genetic material. Until recently, the remainder of the genome (non-coding) was regarded as junk DNA, without known function. However, it is now clear that the DNA that lies in-between the coding genes is emerging as crucially important not only in human evolution but also in regulating function of cells and influencing the way coding genes produce proteins.


Featured Image

  • Beta-Amyloid Plaques (seen in brown) and Tau (seen in blue) in the Brain. Credit: National Institute on Aging, NIH, on Flickr

Provided by University College London