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.

Genetic studies implicate microglia, the primary immune cells of the brain, to modulate Alzheimer’s disease (AD). However, how microglia contribute to memory loss is unclear. We and others recently found that microglia eliminate synapses, the major communication bridges of neurons. This elimination involves an aberrant reactivation of a pruning pathway in microglia called complement. Emerging data further suggest that microglia are heterogeneous and have diverse functions crucial to brain health. These data altogether raise the critical need to specifically target the cells that are aberrantly eliminating synapses versus those that are working to retain brain homeostasis. However, which microglia are aberrantly mediating synapse loss is unknown. Recent single-cell profiling studies have shown that certain ‘activated’ microglia surround amyloid plaques in AD brains and express a unique set of genes, hence coined as ‘disease-associated macrophages’ (DAMs). What DAMs do and whether DAMs are beneficial or detrimental are not known. Our pilot data suggest that DAM-like cells are expressed early in AD models when synapses are vulnerable to loss. Here, we propose a new role for DAMs: that DAMs facilitate synapse loss in AD via upregulation of SPP1 (Osteopontin). We will test if SPP1 mediates synapse loss using in vivo mouse and in vitro models and human AD brains, and if this is complement-dependent. Our proposal has the potential to reveal a new therapeutic target to save synapses.

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.