Alzheimer's Disease

Chemistry is the key to the brain

Dementia associated with AD is the most common neurological disorder, affecting nearly 47 million people worldwide in 2015. That number is expected to rise by 2030 to 75 million and double every ~20 years thereafter. Total costs for patient care worldwide are now estimated to be over 1 trillion dollars annually, representing over 1% of the global gross domestic product. This does not include the billions of dollars that have been invested in research. Though many drugs have shown promise in early clinical trials, there is currently no cure or effective treatment for AD. Most drugs have been based on the amyloid hypothesis, which posits that aggregates of Aβ are the primary toxic species that causes AD. Perhaps the most convincing evidence in support of the amyloid hypothesis is that certain genetic mutations facilitate amyloid formation and lead to early-onset AD. On the other hand, there are also many unexplained phenomena that contradict the amyloid hypothesis, including subjects with significant amyloid deposits that do not suffer any mental decline. Given the uncertainties of the amyloid hypothesis and lack of current treatments, alternative theories for the cause of AD are worth considering.

Our lab is focused on exploring how spontaneous protein modifications such as isomerization influence lysosomal function. Although there are many pathways for protein degradation, the lysosome is uniquely susceptible to failure when substrates cannot be degraded, as illustrated by the many aptly named lysosomal storage disorders. At the same time, lysosomal malfunction is implicated in many age-related disorders of the central nervous system including AD, amyotrophic lateral sclerosis, and macular degeneration. Long-lived proteins are strongly associated with many of these diseases and are prone to spontaneous modifications. By revealing how isomerization and epimerization relate to lysosomal failure, we hope to significantly advance our understanding of cellular aging and illuminate new possibilities for preventing and treating AD.