Immunoproteostasis refers to the relationship between the immune system, proteinopathies present in many neurodegenerative disorders, and brain cell dysfunction. The relevance of immunoproteostasis to Alzheimer’s disease (AD) is supported by genetic, pathological, and modeling studies. In AD, as in cancer, multiple lines of evidence now support the benefits of immune activating therapies, but for AD this concept is not settled science. More generally, manipulation of the immune activation states regardless of “direction”, has potential for harm as well as benefit. The overarching goal of these studies is to determine whether we can identify immune manipulations in preclinical models of amyloid pathology that potentially fall within a “Goldilocks zone”- where disease modification, with minimal or no damage, is achieved. We propose three aims that will test our global hypothesis that it is possible to identify immune modulatory therapies that fall within a Goldilocks zone. In aim 1, we will systematically evaluate liabilities and benefits of immune manipulations that have been shown to modulate immunoproteostasis in amyloid depositing mice. In aim 2, we will survey a broader set of immune manipulations targeting putative microglial immune checkpoints to evaluate whether a manipulation of any of these checkpoints falls within the Goldilocks zone. In aim 3, we will evaluate whether targeting of immune modulating factors to the plaque microenvironment can maintain or increase beneficial impact on AD relevant pathologies while reducing potential liabilities. Several overarching principles provide a framework for these studies. First, as the balance of positive and negative effects of any immune manipulation may limit therapeutic benefit, we will use transcriptomic and proteomic analyses, assessments of pathology, and assays of synaptic number and function to assess disease modifying potential and liabilities more broadly and systematically. Second, we will focus on non-cell autonomous manipulations of immune signaling pathways, as such studies are more likely to identify translatable interventions. Third, we will evaluate whether we can increase efficacy and limit liabilities by more precisely targeting the immune manipulations to the plaque microenvironment. The studies are highly translational, as they can validate novel approaches to immune modulatory therapies for AD. Finally, these studies have relevance beyond the AD field, as they broadly explore immune checkpoints in the brain and thus the data generated may inform studies relating to immuno-oncology of the brain and other neuroimmune disorders.

There remains a critical need to both explore novel therapeutic approaches and timing of the intervention that could clinically impact Alzheimer’s disease (AD). Immune alterations are linked to AD risk and pathology. Here, we propose to evaluate multiple immune manipulations that could inform on novel approaches to harness the immune system for benefit in AD.