To make much-needed progress in treating brain disorders, we have to decipher the disease from the bottom up. From Alzheimer’s disease to CTE and beyond, cryo-EM gives us the power to do that.
The prime suspects for the devastation caused by Alzheimer’s disease were named more than 30 years ago: two proteins called amyloid-beta and tau, which form clumps and tangles in the brain. Yet all efforts to halt this disease with drugs that target these molecules have failed.
In search of a new way forward, Anthony Fitzpatrick, PhD, has been taking a closer look at these infamous proteins. He has used new imaging technologies to map — for the first time — the three-dimensional atomic model of tau tangles inside the brain, as published in 2017 in the journal Nature.
“By zooming in to that level of detail, we got a first-ever look at tau’s ‘building blocks’,” says Dr. Fitzpatrick, a structural biologist and principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute. “We could see — atom by atom — how tau tangles form, and infer how it grows over time to take hold in the brain.”
Tau is just the beginning for Dr. Fitzpatrick. He has begun to examine the amyloid-beta proteins that glob together in Alzheimer’s brains, and is exploring other brain diseases characterized by abnormal protein aggregation, from Parkinson’s and Huntington’s diseases to amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and frontotemporal dementia. He believes that creating 3D images of how protein fibrils grow in the brain could accelerate the development of new medicines.
“To understand why these protein fibrils are so nefarious, we need to understand their structure — what they’re made of and how they invade the brain,” says Dr. Fitzpatrick, who trained in both chemistry and physics. “And recently, a revolutionary imaging technology called cryo-electron microscopy, or cryo-EM, gave us the ability to do that.”
Cryo-EM, developed in part by last year’s Nobel Prize winner and fellow Columbia scientist Joachim Frank, PhD, allows scientists to view the individual atoms that make up microscopic biological structures.
“With cryo-EM, we first capture pictures of a protein from different perspectives, and then we painstakingly reconstruct that protein into a three-dimensional structure,” explains Dr. Fitzpatrick, who is also an Assistant Professor of Biochemistry and Molecular Biophysics at Columbia University Irving Medical Center. “It’s like putting together a microscopic, three-dimensional puzzle, without knowing in advance what the final structure should look like.”
Cryo-EM has proven indispensable for investigations into the extremely small. For example, in 2016, researchers used cryo-EM to decipher the structure of the Zika virus. In recognition of cryo-EM’s enormous potential across many fields of science, Dr. Frank won the 2017 Nobel Prize in Chemistry, along with co-inventors Drs. Jacques Dubochet and Richard Henderson.
Dr. Fitzpatrick’s work on tau tangles, conducted while a postdoctoral fellow at the University of Cambridge, will help scientists scrutinize the protein’s structure for weaknesses. It could also speed up the development of drugs that adhere to tau at specific locations and neutralize it.
Since arriving at Columbia’s Zuckerman Institute in January of 2018, Dr. Fitzpatrick has also begun to study chronic traumatic encephalopathy, or CTE. Like Alzheimer’s, this brain disorder is characterized by the abnormal accumulation of tau. Unlike Alzheimer’s, CTE is caused by repetitive head trauma. A July 2017 study of the brains of 111 ex-NFL players revealed that 99% showed signs of CTE; their brains were riddled with tau tangles.
“If we can understand how CTE progresses, we can take controls, say, to limit the number of hits that players take in a training session, or develop better diagnostic tools to catch the earliest signs of CTE before it expands out of control,” says Dr. Fitzpatrick.
People with CTE exhibit memory loss, anxiety and severe depression. They often experience Parkinson’s-like symptoms, as well as progressive dementia. The disease can present in a patient decades after their last head injury.
For Dr. Fitzpatrick, CTE hits particularly close to home. He played rugby for years while a university student. He wonders what an examination of his own brain — or the brains of his former teammates — would reveal.
No one has yet mapped the shape tau takes in the brains of people with CTE. Dr. Fitzpatrick believes that cryo-EM could crack this puzzle – as the technology stands poised to revolutionize the study of neurological disorders.
“To make much-needed progress in treating brain disorders, we have to decipher the disease from the bottom up,” says Dr. Fitzpatrick. “From Alzheimer’s disease to CTE and beyond, cryo-EM gives us the power to do that.”
At Columbia’s Zuckerman Institute, Anthony Fitzpatrick, PhD, traces the molecular building blocks of Alzheimer’s, CTE and other devastating diseases.
Meet the scientists leveraging technological advances to reveal aspects of the disease long hidden from view.
This video shows Paired Helical Filaments (PHF). Powered by Thermo Scientific Amira Software. Data courtesy of The Medical Research Council Laboratory of Molecular Biology and Fitzpatrick et al., 2017.