Pick Disease of the Brain

A spectrum of neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are due to the accumulation of abnormal, misfolded tau proteins in the brain. Scientists have now found potential ways to interrupt this process by targeting 'sticky' sites along the long form of mutated tau, preventing the misfolding and spreading of the neurofibrillary tangles. A spectrum of neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are due to the accumulation of abnormal, misfolded tau proteins in the brain. A team of researchers led by UC Santa Barbara scientists has found potential ways to interrupt this process by targeting "sticky" sites along the long form of mutated tau, preventing the misfolding and spreading of the neurofibrillary tangles. "This is a true collaboration of biology and chemistry," said UCSB neuroscientist Kenneth S. Kosik, who with chemistry professors Songi Han, Joan-Emma Shea and chemical engineering professor Scott Shell, presents findings in the Proceedings of the National Academy of Sciences. The study presents molecular-level insights on the way pathological tau spreads, and according to the researchers, this understanding could lead toward "a therapeutic intervention potentially capable of disaggregating tau or preventing its aggregation" in the long form of tau accumulates. A sticky hairpin Tau is an essential structural protein in the brain, giving cells form and stability and allowing the transport of necessary nutrients. However, when it mutates and misfolds, it can get sticky and tangled. Moreover, this error in folding can become a template for faulty instructions that direct normal tau proteins to misfold and collect until the condition spreads over wide regions of the brain, interfering with brain functions. The specific locations where these neurofibrillary tangles occur in the brain differ among the neurodegenerative disorders. There are two particular forms of tau, which serve as the starting point for this category of neurodegenerative diseases, called tauopathies, and for which Alzheimer's is the most well-known. Tau is produced in both a short "three-repeat" version and a longer "four-repeat" version; the latter the focus of this research. Tauopathies far less common than Alzheimer's such as FTD, PSP and CBD are exclusively tauopathies of the 4R type, though neurodegenerative diseases can also be associated with the 3R form, or, as in the case of Alzheimer's, a combination of both. The discoveries in this research pertain to diseases that accumulate 4R tau. Merging advanced techniques such as transmission electron microscopy and molecular dynamics simulations with in-vitro experiments involving cell cultures, the research team was able to get a sense of the conditions under which pathological 4R tau begins to misfold, template other tau proteins, and aggregate. "Tau folds in a unique way in each of these diseases," Kosik explained. "One part of it folds into a hairpin structure only in the 4R tau." Within the hairpin, he explained, is a sticky segment called PHF6 that can bind and stack up other tau proteins into large aggregations. But what if it were possible to induce tau aggregation in cell culture and use the system to interfere with this sticky site? "Creating conditions for tau propagation serves as a high throughput system for the discovery of compounds that may interfere with tau aggregation," Kosik commented. They found, for instance, that a single amino acid substitution along the protein adjacent to the sticky region was enough to prevent tau aggregation by weakening access to the vulnerable portion of the peptide. In other investigations the researchers also found that nanobodies -- fragments of antibodies -- synthesized from the blood of camelids (camels, llamas and other members of the Camelidae family) were able to bind to the PHF6 region, inhibiting aggregation of tau. Whatever the therapy, the region encompassing the hairpin segment of 4R tau is the apparent active zone to target. The researchers still have a long way before targeted therapeutics can be developed and approved to inhibit the formation of the neurofibrillary tangles that characterize tauopathies. But the findings in this paper unveil exciting potential pathways to arresting critical steps toward the accumulation of mutant tau. "We would want to continue to test this technology in animal models," Kosik said, crediting postdoctoral researcher and lead author Andrew Longhini for his "enormous contributions" to ideas and the experiments reported. On the chemistry side, the work of graduate student researchers Austin DeBose and Samuel Lobo in engineering protein interactions and doing the computational heavy lifting was also essential to the project, he said. "It's so interdisciplinary, it's amazing," Kosik said. "I learned so much from this project." In addition to advancing research on some forms of neurodegenerative disease, these findings can serve as a jumping-off point for potential clues toward therapies for the 3R Pick's disease and for the more complex Alzheimer's disease. Kosik is optimistic. "We'll try to apply our findings to the more complicated forms," he said. "We'll get there." Research in this project was supported by the Keck Foundation.

– Performances by Jay Allen and Kylie Morgan, Melinda Doolittle, Charles Esten, Paul Freeman, Paul Greene, Ginna Claire Mason, MaRynn Taylor, Noah Thompson, Alicia Witt, and more covering hits from the early 2000s – – Event raises awareness and funds for the Alzheimer's Association research grant program – *Photos available* NASHVILLE, Tenn., Nov. 13, 2023 /PRNewswire/ -- Hallmark stars Ashley Williams and Nikki DeLoach hosted the sixth annual Dance Party to End ALZ on Sunday, November 12 at Nashville's Wildhorse Saloon, which raised more than $300,000 for the Alzheimer's Association research grant program. The event founded by Kimberly Williams-Paisley was emceed by Apple Music radio host Kelleigh Bannen. Williams and DeLoach opened the evening with a surprise performance of "Party In the U.S.A." The dynamic duo welcomed guests and shared why co-hosting the event meant so much to them after both losing a parent to dementia. Williams' mom, Linda, passed away with Alzheimer's in 2016, and DeLoach's dad, David, passed away with Pick's disease, a rare form of dementia, in 2021. Dressed in 2000s fashion, performers took to the stage covering throwback hits from the era. Accompanied by Wildhorse Saloon's house band Three Lane, performances included: Jay Allen's take on "Kryptonite." Allen was then joined by wife and country music artist Kylie Morgan to perform his song on "No Present Like The Time" Melinda Doolittle's versions of "Crazy In Love" and "Since You've Been Gone" Charles Esten's channeled Billie Joe Armstrong for "Wake Me Up When September Ends" Paul Freeman's rendition of "Mr. Brightside" Paul Greene's spin on "Seven Nation Army" Ginna Claire Mason's version of "Before He Cheats" MaRynn Taylor's rendition of "Complicated" Noah Thompson's take on "Move Along" Alicia Witt channeled Britney Spears for "Lucky" Hallmark stars group number to "I Gotta Feeling" And a group finale to "Beautiful Day" "We are beyond grateful to the Nashville community, performers, generous sponsors and attendees near and far who joined us at the sixth annual Dance Party to End ALZ," said co-hosts Ashley Williams and Nikki DeLoach. "Everyone coming together for this cause means the world to us and our families. Together, we raised awareness and funds to support the Alzheimer's Association's research grant program, which is helping us get one step closer to ending Alzheimer's and all other dementia." Event committee included: Ashley Williams, actor and director Nikki DeLoach, actor, producer and writer Annie Howell, chief communications officer, Hallmark Media Blake McDaniel, music touring agent, CAA Andrew Walker, actor, producer, co-founder of Little West Jay Williams, CEO & apiarist of Williams Honey Farm Generous sponsors included: Hallmark Media Kimberly Williams-Paisley & Brad Paisley Boot Barn Sidekick Therapy Partners The Buffaloe Family DeBartolo Family Foundation Denise Cummins Rosenthal Family Foundation Andrew & Cassandra Walker Nikki DeLoach & Ryan Goodell The Graham Family Charitable Trust Brandon and Karen Jondle family and Tom and Beth Jost family Michael and Sarah Lorance family In Loving Memory of Micheal MacDowell, beloved Husband, father and friend Harley Neuman & Daniel Lam "Paisley Park Girls" in honor of Beth Machado Michael Yu & Erin Zervos Yu R3 Stem Cell/R3 Anti Aging Romance University Southbound Tequila Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center Williams Honey Farm The Ken and Beth Dunn Family Foundation CAA Empathy Studios Paul Greene & Kate Austin McKellar/Sveslosky & Hart Lillie Pawluk Sandy & Doug Paisley Jennifer Wayne Celebrities in attendance included: Benjamin Ayres Brooke D'Orsay Cindy Busby Danica McKeller Erich Hover Erin Cahill Jen Lilley Jesse Hutch Kimberly Williams-Paisley Kristoffer Polaha Melissa Joan Hart Riley Weston Sarah Drew Trevor Donovan Funds raised through the Dance Party to End ALZ will directly support the Alzheimer's Association's research grant program. To date, Dance Party to End ALZ has raised more than $2.1M to fund diverse and exciting Alzheimer's research — from studying the impacts of genetics and sleep on the brain, to developing a smartwatch-based intervention for dementia risk reduction. For more information and to donate, visit alz.org/DanceParty. About the Alzheimer's Association® The Alzheimer's Association leads the way to end Alzheimer's and all other dementia — by accelerating global research, driving risk reduction and early detection, and maximizing quality care and support. Our vision is a world without Alzheimer's and all other dementia®. For more information, visit alz.org or call the 24/7 Helpline at 800.272.3900. SOURCE Alzheimer's Association

A gene encoding a protein linked to tau production -- tripartite motif protein 11 (TRIM11) -- was found to suppress deterioration in small animal models of neurodegenerative diseases similar to Alzheimer's disease (AD), while improving cognitive and motor abilities, according to new research. A gene encoding a protein linked to tau production -- tripartite motif protein 11 (TRIM11) -- was found to suppress deterioration in small animal models of neurodegenerative diseases similar to Alzheimer's disease (AD), while improving cognitive and motor abilities, according to new research from the Perelman School of Medicine at the University of Pennsylvania. Additionally, TRIM11 was identified as playing a key role in removing the protein tangles that cause neurodegenerative diseases, like AD. The findings are published today in Science. AD is the most common cause of dementia in older adults, with an estimated 6 million Americans currently living with the disease. It is a progressive brain disorder that slowly destroys memory and thinking skills. Foundational research at Penn Medicine led by Virginia M.Y. Lee, PhD, the John H. Ware III Professor in Alzheimer's Research in Pathology and Laboratory Medicine, and the late John Q. Trojanowski, MD, PhD, a former professor of Geriatric Medicine and Gerontology in Pathology and Laboratory Medicine, reveals that one of the underlying causes of neurodegenerative diseases is neurofibrillary tangles (NFTs) of tau proteins, which cause the death of neurons, leading to the symptoms of AD, like loss of memory. In addition to AD, aggregation of tau proteins into NFTs is associated with over 20 other dementias and movement disorders including progressive supranuclear palsy, Pick's disease, and chronic traumatic encephalopathy, collectively known as tauopathies. Nevertheless, how and why tau proteins clump together and form the fibrillar aggregates that make up NFTs in patients with these diseases remains unclear. This major gap in knowledge has made the development of effective therapies challenging for researchers. "Most organisms have protein quality control systems that remove defective proteins, and prevent the mis-folding and accumulation of tangles -- like the ones we see with tau proteins in the brain of those with taupathies -- but until now we didn't know how this works in humans, or why it malfunctions in some individuals and not others," said senior author, Xiaolu Yang, PhD, a professor of Cancer Biology at Penn. "For the first time, we have identified the gene that oversees tau function, and have a promising target for developing treatments to prevent and slow the progression of Alzheimer's disease and other related disorders." Yang and his team, including first author Zi-Yang Zhang, PhD, a postdoctoral researcher in Yang's lab, previously found that TRIM proteins play an important role in protein quality control in animal cells. After examining over 70 human TRIMs, they found that TRIM11 has a major role in suppressing tau aggregation. TRIM11 possesses three main functions related to the quality control of tau proteins. First, it binds to tau proteins, especially the mutant variants that cause disease, and helps eliminate them. Second, it acts as a "chaperone" for tau, preventing the proteins from mis-folding. Finally, TRIM11 dissolves pre-existing tau aggregates. Using postmortem brain tissues of 23 individuals with AD and 14 health controls from the Center for Neurodegenerative Disease Research tissue bank -- created and maintained by Lee and Trojanowski -- researchers validated these findings, and found that levels of TRIM11 protein are substantially reduced in the brains of individuals with AD, compared to healthy control individuals. To determine the potential utility of TRIM11 as a therapeutic agent, researchers used adeno-associated viral vector (AAV), a tool commonly used in gene therapy, to deliver the TRIM11 gene into the brain of multiple mouse models. Researchers found that mice with tau pathologies receiving the TRIM11 gene exhibited a marked decrease in the development and accumulation of NFTs, and had much improved cognitive and motor abilities. "Not only do these findings tell us that TRIM11 could play an important role in protecting people from Alzheimer's and similar diseases, but we also see that we might be able to develop future therapies that replenish TRIM11 in individuals with lower levels," said Yang. "We are eager to work with our colleagues to explore the possibility of developing gene therapies that halt the progression of neurodegenerative disease." This study was supported by the National Institutes of Health (R01CA243520, UL1TR000003) and funding received by Penn under a sponsored research agreement with Wealth Strategy Holding Limited. Note:Yang is an inventor on patents and patent applications owned by the University of Pennsylvania related to TRIM proteins, and is a co-founder and equity holder of Evergreen Therapeutics LLC, which received investments from Wealth Strategy Holding Limited. Penn and Yang have either received, or may receive in the future, financial consideration related to the licensing of certain Penn intellectual property to Evergreen Therapeutics LLC.