The Quest to Understand Alzheimer's Causes
With 26.6 million known cases of Alzheimer’s worldwide in 2006, and projections that show this number quadrupling by 2050, scientists are in a race to understand Alzheimer’s disease. Scientific inquiry has recently homed in on two types of protein deposits in the brain: amyloid aggregates and neurofibrillary tangles. Intrigued by the fact that large, rod-shaped clusters of the protein actin and its regulatory component, cofillin, are especially abundant near these two types of deposits, Scripps Research professor Gary Bokoch turned his focus to understanding how the rods form.
“Actin/cofillin rods are abundant in brains of neurodegenerative disease patients, particularly Alzheimer’s patients, and have long been suspected of playing a role in the progression of the underlying disease,” explains Bokoch. “However, until our study, no one really knew how these rods were formed.”
Bokoch’s study focused on the process by which these rods form when energy production is disturbed. Although the brain represents just two percent of the body’s mass, it uses 20 percent of the body’s energy – which makes neurons highly susceptible to fluctuations in energy production.
“The polymerization and de-polymerization of actin, which is necessary for cell movement among other things, takes a great deal of energy,” explains Bokoch. “That energy depletion initiates rod formation to help conserve [energy].” The problem, however, is that these rods can remain in the cell for long periods of time, causing serious damage. For example, studies in mice have shown that these rods can block the transport and cause the accumulation of precursor proteins associated with Alzheimer’s in neurons. In the neurons of sea slugs, rod formation reduces synaptic strength and neurotransmission.
Looking closely at the process, Bokoch’s team found that when stress or cell damage depletes neurons of an important source of energy, the cofilin-activating enzyme chronophin is released from its “chaperone” and triggers the rod-forming mechanism. Further investigation proved that chronophin is a critical prerequisite to a process of rod formation, indicating that it could be targeted in future therapies.
The evidence from Bokoch’s study, combined with previous studies that have shown that inhibition of chronophin’s molecular chaperone (heat shock protein-90) can provide a level of neuroprotection in disease models, suggests that the chronophin mechanism will be an important focus of further scientific investigation.
As scientists at Scripps Research race to understand the workings of devastating neurodegenerative diseases, your support provides them with the resources and the technology that are critical to closing in on discovery.