Amyloid beta pathology starts to build up in the brain years before tau tangles appear in Alzheimer’s disease (AD) patients. However, the onset of clinical symptoms corresponds best with the transition from amyloid buildup to tau spread, which leads to synapse loss and cell death. Remarkably, some people with high levels of amyloid and even tau pathology do not lose their cognitive abilities. These people are resilient to AD pathologies. While many studies have provided valuable insights into the genetic risk factors and biological mechanisms of AD, fewer have focused on identifying natural factors that promote brain resilience and protection against AD. Resilient individuals provide an outstanding opportunity to identify protective factors that could be translated into novel therapeutics for people who experience cognitive decline caused by AD.
Dr. Hide is an expert in big data—extremely large datasets analyzed computationally to reveal patterns, trends, and associations. His team uses this approach to identify genes and biological markers linked with disease that might be promising targets for drug development. He works closely with Dr. Rudy Tanzi and has played an important role in developing computational tools to manage and leverage genetic data from the Alzheimer’s Genome Project™ (AGP) and the massive gene expression datasets (transcriptomics) generated by CIRCUITS. His team integrated these (and other) datasets to create a catalog of molecular changes in Alzheimer’s. This database system, called Genedex, was designed to be accessible to other scientists for their own discovery research. In this proposal, the Hide team wants to further improve Genedex by adding newly available datasets from AD-relevant tissues from both AD and resilient cases. Their goal is to use Genedex to uncover signaling molecules associated with resilience to AD pathology in human brains. These candidates would then be tested in future experiments.
Dr. Hide proposed two aims. In the first aim, his team is expanding Genedex to include new single-cell transcriptomics (scRNAseq) datasets from more than 10 million individual cells from AD patients and control donors. In the second aim, they are integrating information on rare gene variants that may contribute to resilience. Dr. Tanzi and the AGP team have provided the Hide team with candidate genetic variants derived from whole-genome sequencing of brains sourced from the MGH biobank. By adding single-cell and new genetic data into Genedex, they can identify which signaling pathways change during AD and which cell types are affected. Understanding these pathways—particularly those that might support resilience—will help in the creation of new cell culture models using the relevant cell types to screen drugs that target these pathways. The Hide team has ongoing collaborations with Drs. Pfenning, Tanzi, and Kim, continuing partnerships formed during their CIRCUITS work.
In the first funding period, Dr. Hide’s team made substantial strides across their aims, which resulted in several publications. In comparing resilient and disease cases, the team successfully identified groups of genes involved in brain growth and communication that remain active in resilient individuals but are disrupted in severe AD. They also identified neuronal subpopulations associated with three outcomes: AD risk, resilience (maintaining cognition despite pathology, and resistance (never developing pathology). The collective results led Dr. Hide’s team to focus in on a key disease pathway, the p38 MAPK–MK2 axis. In 3D cell culture models of AD, treatment with Losmapimod, an inhibitor of p38 MAPK, reduced abnormal tau buildup, lowered amyloid levels, and protected brain cells from damage. Losmapimod has been tested as a potential therapeutic in several diseases, including major depressive disorder and chronic obstructive pulmonary disease (COPD), because it plays a role in several major inflammatory pathways.
