Driving Breakthrough Discoveries in Neurodegenerative Diseases

With its broad array of scientific talent, UT Southwestern's CAND is bringing exciting new advances to the study of Alzheimer’s disease and related disorders.

UT Southwestern’s Center for Alzheimer’s and Neurodegenerative Diseases (CAND) was launched in 2014 with a unique mission to develop mechanism-based approaches to diagnose and treat Alzheimer’s disease and related disorders.

Part of the Peter O’Donnell Jr. Brain Institute (OBI) at UT Southwestern Medical Center, CAND exemplifies OBI’s ideal of uniting scientists with diverse interests around the common goal of curing brain disorders. The center’s founding director is Marc Diamond, M.D., a Professor in the Department of Neurology, whose vision has been to recruit a diverse and collaborative group of scientists focused on fulfilling that primary mission.

“An important aspect of the center is how it integrates basic science with clinical knowledge,” Dr. Diamond says. “CAND scientists work closely with clinician-investigators at UT Southwestern and beyond to study human samples and to bring new approaches to the clinic for diagnosis and treatment.”

A new era of collaboration

The study of neurodegenerative diseases has evolved from describing manifestations of abnormal brain function and neuropathology to understanding molecular mechanisms. Today, it is well known that many seemingly disparate neurodegenerative disorders share a common etiology based in abnormal protein folding.

“The vast majority of these diseases currently have no effective treatments, although the last few years have seen amazing breakthroughs with new FDA-approved drugs,” Dr. Diamond says. “It is for this reason that we continue to foster new collaborative research across various disciplines – we are trying to add substantially to the limited treatments currently available.”

The center’s active group is made up of eight principal investigators and five affiliated faculty members who have far-reaching and diverse interests, ranging from machine learning, structural biology, and biochemistry to advanced imaging and interventions using high-intensity focused ultrasound.

Now approaching nearly a decade of operation, the CAND continues to be a destination for talented faculty with complementary skills. Barbara Stopschinski, M.D., joined the faculty in July 2023 as an instructor and fellow in behavioral neurology. Her lab studies the molecular and cellular mechanisms driving tau uptake and propagation, and the mechanisms connecting neuroinflammation and neurodegeneration in tauopathies.

In keeping with the OBI mission, her research is directly tied to her clinical practice, where she treats patients with cognitive impairment and dementia.

“Our approach is unique in that we truly operate as a multidisciplinary team,” Dr. Diamond says. “In traditional academic environments, collaborations are expected to evolve organically, but here we cultivate a much more intentional environment by organizing weekly meetings, faculty events, and even dinners to discuss our research.”

Investigating immune components

As discoveries in the field continue to accelerate, Dr. Diamond and his team recognize that understanding the interplay of non-neuronal systems in relation to the changes that occur within the brain is essential. Consequently, they’ve started to focus on the immune system and its components – disentangling the shared dysfunctions that occur across the spectrum of neurodegenerative disorders.

“A substantial portion of the center's prior work has been devoted to structural biology and biochemistry, with the aim of utilizing that knowledge to target proteins that assume a pathological conformation,” Dr. Diamond says.

Building upon this foundation, an expanding direction for future research is to investigate the impact of the immune system and its contribution to these misfolding processes. The researchers hypothesize that immune-mediated mechanisms may play a key role in the pathogenesis of many neurodegenerative diseases.

“A plethora of immune factors have been associated with increased risk of neurodegeneration in recent genome-wide association studies,” Dr. Diamond explains. “Teasing out which signals are helpful and which are detrimental when devising strategies for immune modulation against neurodegeneration is one of our next major challenges.”

Strategically, the Department of Immunology is situated only one floor away from CAND scientists – a deliberate decision to promote collaboration.

The Diamond Lab

In addition to leading the CAND, Dr. Diamond has made original discoveries linking common disorders such as Alzheimer’s disease to rare infectious prion disorders. He holds multiple patents and is very focused on how to translate basic discoveries into effective therapy.

The Diamond Lab studies neurodegeneration from the standpoint of prion biology and protein aggregation. His ideas and the tools that have been developed in his lab have helped transform the scientific community’s understanding of how neurogenerative diseases progress.

“All major neurodegenerative diseases are relentlessly progressive, and virtually all are linked to the accumulation of protein amyloids,” Dr. Diamond says. “My lab focuses primarily on the tau protein, whose aggregation underlies neurodegeneration.”

Like the prion protein, tau adopts many distinct pathological conformations that replicate within cells and underlie different tauopathies, Dr. Diamond explains. In recent years, he and his team have uncovered how abnormal assemblies of the tau protein move between cells and serve as templates for their own replication.

“Our findings explain the relentless progression through brain networks and the phenotypic diversity of the myriad disorders termed ‘tauopathies,’ which include Alzheimer's disease, the frontotemporal dementias, and chronic traumatic encephalopathy,” he says.

Focusing in on tau

In collaboration with Lukasz Joachimiak, Ph.D., an Associate Professor at CAND and a member of the OBI, Dr. Diamond is using cell models to study fundamental events in the pathogenesis of tauopathies.

“We are using detailed knowledge of tau's structure to engineer proteins that target its pathological conformations and then test predictions of efficacy in mouse models,” Dr. Joachimiak says. “This involves studying how different conformations of tau originate in Alzheimer’s disease versus other disorders.”

The co-investigators anticipate that a clearer understanding of tau conformations will have important implications for the development of better diagnostic and therapeutic strategies.

In 2018, Dr. Diamond and Dr. Joachimiak published two seminal papers proposing a new idea –that the tau protein exists in two separable states, shifting from an “inert” form to one that is “seed-competent.”

“We discovered that tau populates two distinct conformational ensembles,” Dr. Diamond says. “The inert form is present in control brains, whereas the seed-competent form is present in disease states.”

The researchers traced this conformational change to a key component of the tau protein, proposing that a type of “hairpin” structure hides an amyloidogenic sequence in the inert monomer, whereas in the seed-competent monomer the tau “unfolds” locally to expose the amyloidogenic sequence so the protein can subsequently aggregate.

Most recently, the duo followed up these findings with a report describing how the tau monomer converting from the “inert” form to “seed-competent” form represents the first detectable step in the initiation of tauopathy. They are now using computational approaches coupled with experimental molecular genetics to decipher how tau folds to form pathological aggregates and what cellular factors might trigger this process.

“We are beginning to understand how a single tau monomer changes shape to form a pathological monomer and then a pathological aggregate,” Dr. Joachimiak explains. “A better knowledge of this process may contribute to the design of interventions that target disease-specific tau conformations.”

Future Directions

A next direction for the research is the development of tauopathy-specific therapies, Dr. Diamond says, adding, “We plan to leverage our insights to develop novel diagnostic and therapeutic interventions for Alzheimer's disease and possibly other tauopathies.”

Dr. Diamond acknowledges that while more studies are needed, clinical translation of their findings is imminent, largely due to support received from the OBI.

“Future investigations will be needed to fully elucidate the mechanistic origins of tauopathy – nevertheless, we’re thrilled about the progress made so far,” Dr. Diamond says. “With the backing of the O’Donnell Brain Institute, we’re confident our translational efforts will be a success.”

According to Dr. Diamond, OBI investigators experience unique scientific direction and growth through participation in recruitment, mentorship, and planning committees. In addition, he explains that partnerships within the Institute foster scholarly excellence and enhance connections among faculty working on brain science-related research.

“It is a great honor to work and collaborate with so many brilliant minds,” he says. “We are all excited about the generational impact the Institute is making in training future cohorts of researchers and clinicians.”