Neurons were the cell type of focus for Alzheimer’s research for decades; after all, they die off in large numbers over the course of the disease and are considered the primary cells for memory and other cognitive brain activity. However, when large-scale genetic sequencing of Alzheimer’s patients became possible, the field discovered that the genetics of neurons are not primary for most cases of Alzheimer’s. Of the common protein-encoding genes with variants that affect risk of Alzheimer’s disease, more than half are primarily expressed not in neurons, but in microglia, astrocytes and peripheral myeloid cells.
These cells are the primary immune cells of the central nervous system. The proteins they express participate in innate immune pathways rather than in amyloid or tau pathways. They survey the brain, respond rapidly to pathological conditions, and maintain homeostasis in the healthy brain by isolating and cleaning up debris, from invading pathogens to cellular byproducts to amyloid beta plaques. However, their behavior can become mistargeted, degrading healthy synapses and neurons, eventually causing most of the neurodegeneration and cognitive loss seen in AD. Better understanding of both healthy and pathogenic neuroinflammation is thus integral to redressing the damage that translates into AD symptoms.
The researchers in the Neuroimmune Consortium are building the first comprehensive map of immune and neural cell state changes in Alzheimer’s disease to uncover how the different microglial states relate to other neural cells in vulnerable brain regions. Since gene expression differs for microglia in various states of activation, the group hypothesizes that imaging and fluid biomarkers tied to the proteins expressed in these states could indicate when someone is in an early stage of the disease, potentially in time to intervene. To achieve this map, the members of the consortium are developing new markers for specific microglial functional states; better knowledge of the biological function of the AD risk gene variants; computational tools to integrate genomic, biological, and proteomics data; and new imaging tools able to show the location and progression of neuroinflammation in a living brain. These tools will be shared across the Alzheimer’s disease field to accelerate research beyond this consortium.
NEUROIMMUNE CONSORTIUM: FUNDED RESEARCHERS
Mathew Blurton-Jones, Ph.D., University of California, Irvine
Sandeep Robert Datta, M.D., Ph.D., Harvard Medical School
Christopher K. Glass, M.D., Ph.D., University of California, San Diego
Jacob Hooker, Ph.D., Massachusetts General Hospital
Shane Liddelow, Ph.D., New York University Langone Medical Center
*Beth Stevens, Ph.D., Boston Children’s Hospital