P4‐098: An Exploration of the Gender Differences in Early Behavior and Pathology Relating to Heat Shock Protein and Amyloid Beta Protein Expression in the 5xFAD Mouse Model of Alzheimer’s Disease

Abstract

AD patients and, by impairing vessel-mediated clearance of amyloidbeta, may accelerate disease development. We have shown that neutrophils plug blood flow in a small fraction of brain capillaries and that blocking this adhesion substantially increases brain blood flow in mouse models of AD. Therapies that interfered with this capillary plugging could complement those aimed at reducing amyloid. Background: Alzheimer's disease (AD) is an intricate protein misfolding neurodegenerative disorder, largely characterized by the misfolding and seeding of amyloid beta (Ab) and tau proteins. There are a myriad of risk factors associated with developing AD, with age being the number one factor. Although this is true, gender is also a risk factor of concern with the proportion of women-to-men diagnosed with AD skewed, with women being diagnosed significantly more than men. Heat shock protein 70 (HSP70) has the ability to bind to misfolded proteins and either tag them for the ubiquitin/lysosomal pathway or refold them into the correct structural configuration. Myocardial research has indicated gender bias in HSP70 expression, with men showing higher HSP70 expression. It is hypothesized that an interaction between 17-beta estradiol (E2), estrogen receptor-a (ER-a) and HSP90 is causing a decrease in HSP70 translation. The premise behind this study was to examine this relationship, in addition to behavior, at early time-points of disease progression in a neurodegenerative transgenic mouse model of AD. Methods: Male and female 5xFAD transgenic mice at the ages of 1, 2 and 4 months of age underwent a series of behavioral assays to assess motoric and cognitive abilities, including open field, novel object recognition, and passive avoidance. At the end of the study, immunohistology and Western blot analysis were conducted to determine protein expression of HSP70, 90, ER-a, and Ab. An ELISA was conducted to analyze plasma estrogen levels (E2). Results: Preliminary results indicate that there is a gender-specific difference in performance in the passive avoidance task, AD females have a significantly shorter latency compared to their AD male littermates. Preliminary results also indicate differences in various protein expression levels in Western blot analysis. Conclusions: A gender difference exists in 5xFAD mice, but more research is warranted to further analyze this difference.