Alzheimer’s Disease (AD) is a notorious death valley for drug discovery, with more than 100 candidate drugs having failed in clinical trials so far. The only approved drugs for this condition today just treat symptoms, and it affects millions of people. Many experts blame all these clinical disappointments on drug developers’ focus on the beta amyloid and tau proteins that build up in AD patients’ brains. Now scientists at Massachusetts General Hospital (MGH) have provided data supporting a new approach that takes aim at the brain-crippling neuroinflammation that occurs in response to those protein deposits. It’s a fresh perspective that might invigorate this potential multi-billion-dollar market.
Amyloid plaques and tau tangles are well known pathological signs of AD. “But if you just have plaques and tangles alone, you probably won’t develop Alzheimer’s disease for a long time, if at all,” says neuroscientist Rudolph E. Tanzi, PhD, director of MGH’s Genetics and Aging Research Unit, and senior author of the Neuron study. He and a growing number of scientists believe the synaptic dysfunction and cell death seen in AD is mainly caused by chronic neuroinflammation, the hallmark of dysregulated microglia cells in the brain.
“We are increasingly realizing that to help Alzheimer’s patients, it is most critical to stop the massive brain nerve cell death that is caused by neuroinflammation,” says Tanzi in a press release. Tanzi is also professor of neurology at Harvard Medical School.
In 2008 Tanzi’s lab discovered the first gene associated with neuroinflammation in AD, known as CD33. That gene produces receptors on microglia cells, which normally act as one of the brain’s housekeepers, clearing away neurological debris, including plaques and tangles. Other investigators identified another gene, TREM2, which has the opposite effect of CD33. TREM2 shuts down the microglia’s capacity to promote neuroinflammation. CD33 is thus the “on” switch for neuroinflammation, while TREM2 acts like an “off” switch.
“The Holy Grail in this field has been to discover how to turn off neuroinflammation in microglia,” says Tanzi. In this study, Tanzi, neuroscientist Ana Griciuc, PhD, an assistant professor of Neurology at MGH and Harvard Medical School (HMS), and their colleagues set out to discover how CD33 and TREM2 interact, and what role “crosstalk” plays in neuroinflammation and the origin of AD. To find the answer to that they silenced these genes individually and simultaneously in mouse models of AD.
The team found that mice whose CD33 genes where turned off had reduced amyloid plaque levels in their brains and performed better than other AD mice on tests of learning and memory. But mice with both CD33 and TREM2 silenced did not show these features, neither did mice with just TREM2 silenced. “That tells us that TREM2 is working downstream of CD33 to control neuroinflammation,” says Tanzi. That theory was bolstered by results from microglia RNA sequencing, which indicated that both CD33 and TREM2 regulate neuroinflammation by increasing or decreasing activity of an immune cell called IL-1 beta and the cell receptor IL-1RN.
Tanzi is also scientific advisor for and an equity stakeholder in AZTherapies, a Boston-based company that is testing a drug designed to reduce neuroinflammation called ALZT-OP1 in a phase III clinical trial. INmune BioIs another start-up pursuing this newer approach.