The Center for Alzheimer’s and Neurodegenerative Diseases (CAND) was created in 2014 to develop mechanism-based approaches to diagnose and treat Alzheimer’s disease and related disorders. The CAND philosophy has been to recruit a diverse and collaborative group of scientists, all focused on the primary mission. This includes 9 primary and 5 affiliated faculty members whose interests include machine learning, molecular dynamic modeling, structural biology and biophysics, biochemistry, cell biology, mouse models, gene therapy, neuropathology, and advanced imaging and intervention using high intensity focused ultrasound.

Because of the broad array of scientific talent, we focus on interdisciplinary collaboration among the investigators to bring exciting new approaches to the study of neurodegenerative disease. CAND scientists also work closely with clinician-investigators at UT Southwestern and beyond to study human samples, and to bring new methods to the clinic for more accurate diagnosis. Marc Diamond, M.D. founded and directs the CAND. He trained as a neurologist, and spent over 15 years caring for patients with neurodegenerative diseases. He has devoted his research career to the basic mechanisms of neurodegenerative diseases, especially tauopathies. These disorders are caused by accumulation in ordered assemblies (also termed amyloids) of the microtubule associated protein tau. Additional self-assembling proteins are responsible for other diseases such as Parkinson’s and amyotrophic lateral sclerosis, and are also the focus of intense study in the CAND.

Many proteins associated with adult-onset neurodegenerative diseases have similar properties of self-assembly into amyloid fibrils that are typically rich in cross-beta sheets, and highly ordered. The Diamond lab was the first to recognize that tau aggregates are uniquely able to self-replicate in cultured cells, just as other groups recognized that inoculation triggers pathology in mouse brain. The Diamond lab was the first to determine that tau assemblies formed in vitro would propagate a defined conformation indefinitely in cells. His group further reported that tau assemblies of distinct conformation transmitted defined patterns of neuropathology from one animal to another after brain inoculation. This was based on faithful replication of unique assembly structures, termed “strains.”

These properties of tau have drawn comparisons to the prion protein, a bona fide infectious agent that accounts for a range of human disorders, including variant Creutzfeldt-Jakob Disease—the human manifestation of bovine spongiform encephalopathy, also called Mad Cow Disease. The recognition that common disorders such as Alzheimer’s and Parkinson’s disease share essential features of aggregate replication and propagation has transformed the study of neurodegenerative disease. This idea guided establishment of the CAND, its research focus, and recruitment of talented faculty with complementary skills.

Distinct, self-propagating conformations of the tau protein, termed strains, produce unique morphologies in cultured cells and propagate indefinitely. Different strains trigger distinct, transmissible patterns of neurodegeneration in susceptible mouse models.

To study human disease requires work across a biological scale from proteins to patients, and this is especially true for amyloid disorders. We must understand how proteins initially assume alternative conformations, how this leads to self-replicating pathological assemblies, the biological mechanisms that enable this process, and its manifestations in humans. This will form the basis of mechanism-based diagnosis and therapy.

With this in mind, the CAND represents an exciting ecosystem of dedicated scientists, each with unique talents to bring to this problem. The multidisciplinary nature of our approach has already manifested in multiple collaborative high-impact publications, and NIH and foundation-funded grants.

 CAND members, 2022

In keeping with their investigations across academic disciplines, researchers in the CAND hold faculty positions in multiple departments, including Neurology and Neurotherapeutics, Pathology, Pediatrics, Radiology, Neuroscience, the Cecil H. and Ida Green Center for Systems Biology, Biochemistry, Biophysics, and Molecular Biology.

The CAND is part of the Peter O’Donnell Jr. Brain Institute at UT Southwestern Medical Center, and supports the Texas Alzheimer’s Research and Care Consortium.