Synaptic Dynamics Inc., a spinoff from the University of Connecticut incubator, is screening variants of a common synthetic molecule to clear plaques that build up in the brains of Alzheimer’s patients. The company has shown that PADK, a molecule in the public domain since the 1970s, can increase — by three- to nine- fold — the expression of enzymes which work to dissolve plaques, making it a promising new idea for treatment.
Neurons have two systems for removing cell waste: the proeasome system, a mechanism that tags old cell junk and chops it up like a garbage disposal, and the lysosome system, which lassos waste and dissolves it with enzymes. These two systems function as tiny garbage men, taking out the trash of old proteins and broken down cells, and putting it into a recycling stream. Synaptic’s compound stimulates more enzymes to work in the lysosome; in effect, more hands go to work for one of the garbage trucks.
Alzheimer’s disease has for decades been dominated by the “amyloid-beta cascade hypothesis,” the theory amyloid-beta proteins build up in the brain to block and starve neurons of nutrients, but no one is sure that these deposits actually cause the disease. Of late, drug developers have focused either on the processing systems thought to enable the plaques to accumulate — so called secretases that process them — or on mopping up and disposal of those peptides with antibodies that target them directly.
Since the first monoclonal antibody was introduced to the U.S. market in 1986, more than 25 antibodies have gained regulatory approval and more than 100 are in development. Alzheimer’s does not yet have an approved antibody, but it could within a decade. Industry giant Genentech has an antibody that targets beta-secretace 1 (BACE1). Roche’s Ganetnerumab, Pfizer’s Bapineuzumab and Eli Lilly’s Solanezumab each are antibodies shown to target and reduce deposits.
Yet one emerging theory suggests it is smaller species of amyloid-beta, not larger ones, that cause the disease. The smaller species, supporters of this theory say, start the disease by sticking to cell receptors and short-circuiting cell signaling. Since plaque size is not always related to severity of the disease, this “would help to explain questions we’ve had for decades,” said Ben Bahr, a co-founder of Synaptic.
William L. Klein, a neurobiologist at Northwestern University, found these smaller species were binding to insulin receptors and to a spot near a receptor in the hippocampus called NMDA which makes new long-term memories. The NMDA receptor works like a tiny gate that opens and closes to let molecules into its cell to reinforce cell communication. The small molecules were binding to a spot near the receptor and keeping its tiny gates propped open, overusing the cell signals needed to form memory.
If the disease starts with cells that are overworking, it helps to explain why one drug works. The Federal Drug Administration in 2003 approved an NMDA inhibitor called Memantine for Alzheimer’s treatment, one of the few drugs with moderate therapeutic effects, but scientists were without good explanation for why it worked. “Why should a blocker of NMDA receptors be useful to people with memory problems?” Klein asked. “NMDA receptors after all are essential for memories to form.”
While antibodies are now in the works to the small species, Synaptic comes at the problem from a new stance, promoting the body’s internal systems to pick up its own mess — in effect, giving its garbage men a raise. The closest analog in medicine may be the adjuvant, a type of drug that stimulates the immune system to perform better. PADK hikes up enzymes and a trafficking protein which helps to transport the garbage in the cell. Bahr is studying its ability to dissolve the smaller species and screening variants of the compound for a proprietary lead, its best form, to take to trial.
