Neuroimmunology Core

Columbia University Health Sciences, New York NY

Investigators

Linked publications & trials

Abstract

As outlined in the overview of this P30 application, contributing to the understanding of immune responses in Alzheimer’s Disease and Alzheimer’s Disease-related traits is a major theme of this proposal, especially as it relates to understanding Alzheimer’s Disease in at risk populations and informs participation in and the design of clinical trials. The Neuroimmunology Core (NI) – which is the only core of this type in the Alzheimer’s Disease Research Center network – has played an important role in driving innovation in sample, data and biomarker resource-building for the Columbia Alzheimer’s Disease Research Center team in its last cycle. It addresses a key need in the Alzheimer’s Disease community to develop the sample collections, assays, and reference data necessary to advance our understanding of the stages of Alzheimer’s Disease as well as our development of immunomodulatory strategies for Alzheimer’s Disease and biomarkers that can serve as covariates or outcome measures. The biggest challenge in developing resources to address the role of immune responses in Alzheimer’s Disease involves connecting measures of immune responses in blood and cerebrospinal fluid earlier in the disease trajectory to those that we are increasingly understanding in the brain obtained at autopsy. Bridging the ante-mortem to post-mortem divide is an urgent goal for the Alzheimer’s Disease community so that we can develop the tools to both monitor the disease as an individual ages and intervene to modulate different immune responses at different times along the trajectory of the disease. To support discovery research and biomarker development, we will therefore continue to cryopreserve and bank peripheral blood mononuclear cells from Alzheimer’s Disease Research Center participants. Further, single nucleus RNA sequencing (snucRNASeq) studies led by NI Core Director De Jager have uncovered two aspects of aging-related brain changes relevant to this application: (1) that there are at least two trajectories of brain aging, one of which leads to Alzheimer’s Disease, providing structure to the heterogeneity observed in aging individuals and (2) that cellular communities defined by glial cell subtypes are driving the trajectory that leads to Alzheimer’s Disease. These two empirically defined trajectories (based on snucRNASeq data) assume that each brain is somewhere along one of the two trajectories. These graphs are based on >1.5 million transcriptomes from 436 brains. Each of these trajectories is driven by distinct cellular communities driven by the frequency of the certain microglial and astrocyte subtypes. The Neuroimmunology Core proposal for this cycle leverages these new insights into the biology of Alzheimer’s disease in two different ways: (1) we continue to develop new cerebrospinal fluid biomarkers that are proxies for markers of certain microglial subtypes which are associated with the neuropathologies of Alzheimer’s Disease (amyloid and/or Tau proteinopathy) and (2) we develop new image segmentation pipelines that annotate microglial state in brain tissue.