The goal of our proposal is to determine the role of the master regulatory cytokine, Interleukin 10 (IL10), in regulating proteostasis in mouse models of Alzheimer’s disease (AD) in an Apolipoprotein E (ApoE) isoform dependent manner. Our proposal addresses two key questions that are relevant to understanding of AD pathogenesis: (1) how does immune pathways interact with and modulate the function of AD risk genes, such as APOE and (2) can we harness this knowledge to disrupt the IL-10/APOE axis and achieve therapeutic benefits in AD-relevant mouse models? Our preliminary data has shown that the anti-inflammatory cytokine Interleukin (IL)-10, has unexpected negative effect on Aβ and tau proteostasis in transgenic mouse models of AD. This demonstrates a complex interplay between innate immunity and proteostasis in AD type neurodegenerative diseases, an interaction we call immunoproteostasis. The mechanism(s) underlying such immunoproteostasis leading to neurodegenerative pathology in AD remain unknown; studying the mechanisms underlying immunoproteostasis can enable us to design immunobiotherapies targeting such signaling pathways. We have observed that overexpression of IL-10 in APP transgenic mice worsens Aβ plaque pathology and cognitive functions via an ApoE-dependent mechanism. Mechanistically, we could attribute the negative effects of IL-10 on Aβ proteostasis to synergistic effects of decreased Aβ phagocytosis by microglia, increased endogenous ApoE expression and enhanced accumulation of ApoE in insoluble amyloid plaques. In our study, the increased level of insoluble ApoE was plaque-associated, consistent with mouse ApoE functioning as a pathological chaperone for Aβ aggregates. Blocking IL-10 signaling using the soluble decoy receptor against IL-10 abrogated this effect and reduced brain amyloid plaque burden. We observed similar ApoE dependent effects on tau proteostasis following IL-10 overexpression in two independent mouse models of tauopathy. Essentially, IL-10 accelerated tauopathy and reduced time to survival in JNPL3 mice; it also promoted forebrain neurodegeneration and tauopathy in the rTg4510 mice. While this was an unexpected phenotype, we provide preliminary data that ApoE specifically interacts with fibrillar tau in a cell free system, which could partially explain the proteostasis, though other mechanisms, such as autophagy inhibition also need to be considered. Guided by these robust preliminary data, we will undertake the following specific aims: Aim 1. Assess whether APOE genotype affects IL10-induced proteostasis in APP mice and evaluate whether interaction of human APOE isoforms with Aβ aggregates alters microglial clearance of insoluble Aβ. We will test the effects of IL- 10 immunoproteostasis on amyloid plaque deposition in an APP transgenic mouse expressing human APOE protein (2 or 3 or 4) and provide mechanistic insights into APOE-dependent microglial uptake and clearance of aggregated Aβ. We expect that promoting ...