Sex Differences in a Novel Triple Knock‐in Mouse Model of Alzheimer's Disease
Authors: Daphney Cedrick M , Chitre Neha Milind , Milfort Melissa M , Murnane Kevin Sean 
Published: June 2021

Alzheimer's disease (AD) affects approximately two‐thirds more women than men and is responsible for major financial and health‐care burdens worldwide. In an effort to understand the mechanisms underlying the differences in male and female vulnerability to AD‐related neuroinflammation, we established a breeding colony from a founding stock of novel AD triple knock‐in mice (APPNL‐G‐F) from Riken Brain, generated a progeny from that colony and set about testing that progeny with the preliminary results from those studies described herein. The three aims we sought to investigate were: (1) to relate sex‐dependent deficits in behavior to systemic cytokine levels, brain chemistry, and neuroinflammation, (2) to utilize behavioral and autoradiographic techniques to assess sex and age‐dependent changes in the expression and function of the 2A type of serotonin (5‐HT2A) receptor and (3) to assess whether short‐term stimulation of 5‐HT2A receptors improves memory or non‐memory function in APPNL‐G‐F mice in a sex dependent manner. The objective for aim 1 was to determine the extent of sex‐related differences and the methodology involved was to employ a battery of cognitive and emotionality tasks to extensively characterize the behavior of these animals as well as probe for differences in the following: systemic inflammatory markers, neuroinflammation, brain monoamines, and brain cytokines and proteins. We observed significant sex‐related differences in several study parameters including emotionality, brain monoamine levels and systemic cytokines. The objective for aim 2 was to determine receptor localization and density in the PFC of young and old, male and female, as well as wild type (WT) and APPNL‐G‐F mice. The methodology for aim 2 involved the use of R(−)‐2,5‐dimethoxy‐4‐iodoamphetamine (R(−)‐DOI) to elicit the head twitch response (HTR) and autoradiography. While the autoradiography results are still pending the HTR results displayed a downward shift in the dose‐response curve between young and aged WT male mice as well as significant differences in efficacy across age, sex, and genotype. The objective for aim 3 was to determine if cognitive and affective behavior is positively affected by the repeated administration of R(−)‐DOI. The methodology for aim 3 was to expose the animals to baseline behavioral tests, repeatedly administer R(−)‐DOI at 1.0 mg/kg, 0.3 mg/kg, 3.0 mg/kg, and 10.0 mg/kg sequentially with a 3‐day wash‐out period in between each dose, and re‐test the animals in the same order as before. The results display a significant decrease in anxiety between pre and post tested male APPNL‐G‐F mice. In conclusion, the preliminary studies discussed here have unmasked several sex‐related differences across several measures with these novel APPNL‐G‐F mice. We propose to continue this work to relate the changes in behavior to changes in neurochemistry and neuroinflammation. The completion of these studies will provide new discoveries in AD research that may translate into disease modifying therapeutics.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.