New findings about a key enzyme in the development of Alzheimer’s could point to new way of targeting an important protein for therapies.
Few disorders are as insidious as Alzheimer’s disease, the most common form of dementia. Characterized by the formation of tangles and plaques made of abnormal proteins, Alzheimer’s slowly eats away at the brain, destroying memories, thoughts, the ability to recognize loved ones and even oneself. The lack of a cure, treatment, or even an adequate understanding of the underlying biological causes of the disease is excruciating for the tens of millions of patients worldwide, their loved ones and caregivers.
Which makes research from the lab of Gopal Thinakaran, PhD, Professor of Neurobiology, so critical. In a study published December in Cell Reports, he and his team described how BACE1, a key enzyme in the development of Alzheimer’s, utilizes a unique, previously unknown transportation system in the brain. Their finding could one day point to new ways of targeting an important Alzheimer’s-associated protein for future therapies.
“It’s estimated that Alzheimer’s disease currently affects over 5 million Americans,” Thinakaran said. “In addition to the heavy toll it takes on the family members and caregivers, is an ever-increasing burden for the health care system and the national economy. Better understanding of the disease and new therapies are desperately needed.”One of the famous hallmarks of Alzheimer’s disease is the formation of clumps of misfolded proteins known as amyloid plaques. These are formed from fragments of protein known as beta-amyloid, which is toxic to neurons. High levels of beta-amyloid can begin to damage the brain a decade or longer before memory and cognitive problems become evident in Alzheimer’s patients.
Responsible for a key step in the formation of beta amyloid in neurons is the enzyme Beta-secretase 1 (BACE1). This enzyme is known to travel along nerve projections and accumulate in the junctions between neurons, where it initiates the production of beta-amyloid. But how this transport occurs was unknown.
Led by post-doctoral fellow Virginie Buggia-Prévot, PhD, and neuroscience graduate student Celia Fernandez, Thinakaran and his team devised a way to track BACE1 movement. They labelled BACE1 with a jellyfish-derived yellow fluorescence protein, allowing them to visualize and record in real-time the dynamic movement of BACE1 through neurons with a microscope. They also developed a technique that allowed them to track the fate of BACE1 from the cell surface through a red fluorescence label.
Through a series of remarkable videos, the team found that BACE1 was transported in a manner never before seen. The enzyme traveled back and forth from the cell body of the neuron down the axon, a long projection that sends electrical signals to other neurons. But BACE1 moved in only one direction—toward the cell body—along dendrites, the multi-branched neuronal projections, which receive electrical impulses from other neurons.
Video of the BACE1 enzyme in Alzheimer’s disease as it moves along neurons in a unique way
“The BACE1 enzyme is conveyed through the neuronal processes using a unidirectional transport, not previously seen for any protein,” Thinakaran said. “And this maneuvering seems to contribute to the development of Alzheimer’s disease. BACE1 is a prime therapeutic target.”
Searching for the underlying mechanism of this unique transportation system, Thinakaran and his team looked to endosomes, small bubbles produced inside neurons that deliver material from one part of the cell to another. The researchers found that BACE1 resides and travels in these endosomes, and that a group of proteins known as EHD, regulates this movement. When EHD was blocked, BACE1 transport was reduced. Importantly, this reduced the levels of beta-amyloid as well.
Thinkaran and his team are now testing whether this new transport mechanism plays a role in the formation and accumulation of beta-amyloid plaques. Ultimately, the team hopes to develop a comprehensive understanding of this transport system, what role it plays in Alzheimer’s disease, and how it might someday be controlled.
“Understanding the details regarding the cellular and molecular mechanisms involved in beta-amyloid production is a topic of central importance in Alzheimer’s disease research,” Thinakaran said.
Buggia-Prévot V., Fernandez C.G., Udayar V., Vetrivel K.S., Elie A., Roseman J., Sasse V.A., Lefkow M., Meckler X. & Bhattacharyya S. & A Function for EHD Family Proteins in Unidirectional Retrograde Dendritic Transport of BACE1 and Alzheimer’s Disease Aβ Production., Cell reports, PMID: 24373286