The Role of Immunoproteasome Function in Alzheimer's Disease and Aging

ABSTRACT In Alzheimer's disease (AD), decreased activity of the constitutive form of proteasomes has been reported in the regions affected by amyloid plaque load and tau accumulation. In contrast to neurons, glial cells, besides expressing constitutive proteasomes, they express at basal levels specialized type of proteasomes called the immunoproteasomes that exhibit a higher rate of protein degradation compared to constitutive proteasomes. Upon inflammatory stimuli, such as pro-inflammatory cytokines IFN-? or under oxidative stress, the expression of the immunoproteasome subunits is increased, whereby three catalytic constitutive proteasome subunits (?5, ?1, and ?2) are exchanged for immunoproteasome subunits ?5i, ?1i, and ?2i and their proteolytic activities produce a distinct set of peptides for MHC Class I receptors and T-cell activation. Because immunoproteasomes are induced during neuroinflammation (the immune response) and oxidative stress (the non-immune response) in glial cells, their pathophysiological significance in AD is debated. It remains unclear whether immunoproteasomes, as part of cytokine inflammatory responses, contribute to the etiology of the AD progression. Or whether the biogenesis of immunoproteasomes that exhibit enhanced activity compared to constitutive proteasomes is part of a compensatory mechanism in activated glial cells to overcome inflammatory signals and protein accumulation during oxidative stress. The goal of the project is to elucidate the functional diversity of immunoproteasome across the tauopathy and AD knock-in mouse models by generating crosses with double deficient immunoproteasome model (L7M1) - (Aim 1). Moreover, utilizing single-nucleus RNA-sequencing and mass spectrometry-based quantitative proteomics, we aim to identify changes at the transcriptome and the proteome levels impacted by deficient immunoproteasomes in mice - (Aim 2). Elucidating the mechanisms of the neuro-glial feedback loop and the role of glial cells in the propagation of tau across neurons is the topic of Aim 3. Understanding the true nature of immunoproteasomes in AD is vital because its proteolytic activity and its biogenesis can be exploited pharmacologically as a novel therapeutic target against AD.