How Immune Cells Impair Neuronal Health and Function in Alzheimer’s Disease
This project will investigate whether brain macrophages mediate synapse loss via SPP1 in Alzheimer's disease. Aim 1 will determine whether SPP1 contributes to synapse loss in AD-like brains. We will test if SPP1 is required for synapse loss using in vivo mouse models of Abeta-induced synapse loss, and examine which immune cells in the brain express SPP1. Aim 2 will investigate whether SPP1 and complement work together to drive synapse loss. We will test if SPP1 and C1q, the initiating protein of the classical complement cascade, are in the same pathway to mediate microglia-synapse engulfment. Aim 3: We will examine whether SPP1 is unregulated in macrophage subsets in AD brain tissues.
A major challenge in AD is to identify microglia that have gone rogue and are eliminating synapses versus other microglial cells clustering around toxic aggregates and working to retain homeostasis. This proposal will help gain insight into a specific molecular machinery involved in aberrant synaptic elimination in AD brain. Specifically, it will enable us to understand whether SPP1 is specifically upregulated by a unique subset of macrophages engulfing synapses.SPP1 could serve as a therapeutic target to functionally dampen the synapse-eliminating activity by macrophages in the AD brain. Furthermore, it will reveal how immune cells communicate with each other to maintain synaptic health and function, and how this immune cell-cell communication goes awry in AD.