Single Nucleus RNA Sequencing Analysis of ACE1 R1284Q Knockin Mice

The gene for angiotensin converting enzyme (ACE1) recently was shown to be a genetic risk factor for Alzheimer’s disease (AD). Our collaborators, Dr. Rudolph Tanzi and his group, discovered mutations in the ACE1 gene that are associated with AD in families. One of these mutations was introduced into mice by genetic “knockin” (KI) technology. We analyzed the effects of the ACE1 KI mutation on the brain and its functions, and the memory performance of mice. We discovered that the ACE1 KI mutation caused the hippocampus, a part of the brain important for memory, to degenerate in an age- and sex-associated manner, in that females were affected more severely than males, like in human AD. Moreover, the ACE1 KI showed impaired memory performance and electrical activity in the brain. Brain inflammation also was increased in the ACE1 KI mice. Drugs that block the ACE1 pathway were able to prevent the degeneration of the hippocampus in ACE1 KI mice. Finally, when crossed to mice that develop the AD hallmark amyloid plaque pathology, hippocampus degeneration was accelerated in ACE1 KI mice. Our results strongly suggest that the ACE1 pathway in the brain plays an important role in AD. However, very little is known about the ACE1 pathway in the central nervous system. In this project, we will use a technique called single nucleus RNA sequencing, an unbiased systems biology approach, to determine the genes that are turned on or turned off in different cell types of the hippocampus during early, middle and late stages of degeneration in ACE1 KI mice compared with wild-type mice. These data will allow us to define the ACE1 pathway in the brain that is important for the degeneration of the hippocampus caused by the ACE1 KI mutation, information we anticipate will be valuable for the design of therapies to block brain degeneration in AD.