The world already is very familiar with both Alzheimer’s disease (AD), primarily a disease that occurs in the elderly, and Down syndrome (DS), a genetic condition present at birth. What many don’t realize is that these two conditions also overlap. By age 40, nearly all people born with Down syndrome have begun accruing the plaque and tangle hallmarks of Alzheimer’s. By age 60, most exhibit signs of dementia.
Why does this happen? The culprit is genetic. Humans have 23 chromosomes; Down syndrome, also known as “Trisomy 21,” is caused by the overproduction of chromosome 21 during the development of the egg, sperm or embryo. Instead of the usual two copies (one from mom, the other from dad), children with Down syndrome are born with three copies of chromosome 21 in every cell. This additional chromosome is responsible for the overproduction of various proteins—including those that cause the plaques and tangles behind Alzheimer’s.
The AD-DS connection
Focusing on this intriguing AD-DS connection, Cure Alzheimer’s Fund’s Rudy Tanzi, Ph.D., was one of three researchers in 1986 to discover the first-known Alzheimer’s gene, known as Alzheimer’s Precursor Protein (APP), located on chromosome 21. This discovery helped usher in a new era of Alzheimer’s genetic research. Since then, researchers have continued studying the AD-DS connection for further clues about the precise mechanisms of both conditions.
Since 2013, Cure Alzheimer’s Fund has been supporting research by the distinguished neuroscientist and Down syndrome expert William Mobley, M.D., Ph.D., whose lab is based at the University of California, San Diego. Mobley is part of a team working to exploit a hypothesis that inhibiting a protein called monoacylglycerol lipase (MAGL)—which gets overproduced in people with Down syndrome—will, in turn, reduce the production of Abeta and, subsequently, Alzheimer’s neuropathology.
Mobley, who recently joined the Scientific Advisory Board of Cure Alzheimer’s Fund (CAF), is working with fellow researcher Alexander Kleschevnikov, Ph.D., to develop therapeutic techniques for inhibiting MAGL; this work is being done in collaboration with Abide Therapeutics. Based in San Diego, Abide specializes in developing drugs connected to a class of enzymes called serine hydrolases, which play an important role in regulating central nervous system signaling as well as digestion, metabolism, inflammation, blood clotting and the life cycle of pathogens.
“We are extremely grateful to the Cure Alzheimer’s Fund for supporting this project,” said Mobley after the CAF grant last year, “which has the potential to benefit persons with Down syndrome and, if successful, will have a direct application to patients with Alzheimer’s disease.”
One step closer
“This is a terrific example of a ‘cross-platform’ project that we’re especially proud to support,” said Tim Armour, president and CEO of Cure Alzheimer’s Fund. “The results of Dr. Mobley’s work will undoubtedly help improve our understanding of both Alzheimer’s and Down syndrome.”