To view an abstract, select an author from the vertical list on the left.
2012 Grants - Frykman
Synaptic Production of Beta-Amyloid Peptide and Targeted Inhibition Thereof
Susanne Frykman, Ph.D.
2012 New Investigator Research Grant
One of the hallmarks of Alzheimer's disease is the loss of synapses in the brain. Synapses are tiny channels through which brain cells send and receive chemical messages; synaptic damage is closely associated with cognitive decline in dementia. Though the exact mechanisms underlying synaptic loss are unknown, current research suggests that the protein fragment beta-amyloid may play an important role. Beta-amyloid is clipped from its parent molecule, amyloid precursor protein (APP), by the action of other proteins called beta-secretase and gamma-secretase. Once produced, beta-amyloid tends to accumulate into toxic clumps in the Alzheimer's brain. Recently developed therapies for reducing beta-amyloid levels have targeted the activities of beta- and gamma-secretase. Yet such treatments have often caused negative side effects because they inhibit both the harmful and helpful functions of secretase proteins.
Susanne Frykman, Ph.D., and colleagues have been working on an anti-amyloid therapy that targets only the amyloid-producing activities of gamma-secretase. In preliminary research, they found that small amounts of gamma-secretase and APP exist in "synaptic vesicles"—the cellular components that release neurotransmitters (chemical messengers) to the synapse. This finding suggests that beta-amyloid is produced within the synaptic vesicles and then released (along with the neurotransmitters) into the synapse, where it can cause damage. It also suggests that the primary function of gamma secretase in synaptic vesicles is to generate beta-amyloid. Thus by targeting this form of gamma-secretase, one might produce a safer and more precise therapy for fighting amyloid-induced synaptic degeneration.
For their proposed grant, Dr. Frykman and colleagues hope to develop such a therapy. Using rat brains, they will test the ability of certain toxins to inhibit beta-amyloid production in synaptic vesicles. The team also hopes to identify other mechanisms that may be responsible for synaptic damage in Alzheimer's disease. Results from this work could shed new light on how cell-to-cell communication deteriorates in the Alzheimer's brain, and how such deterioration can be moderated.