Early-onset Alzheimer's Disease Mouse Models Exhibit Differential Adenosine Receptor Expression in Response to Chronic Kindled Seizures
Abstract number :
1.055
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2023
Submission ID :
339
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Aaron del Pozo, PhD – University of Washington,
Seongheon (Leo) Rho, BS – Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy – University of Washington; Kevin Knox, BS – Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy – University of Washington; Leanne Lehmann, BS – Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy – University of Washington; Stephanie Davidson, BS – Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy – University of Washington; Melissa Barker-Haliski, PhD – Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy – University of Washington
Rationale:
People with early-onset Alzheimer’s disease (AD) with amyloid precursor protein (APP) duplications or presenilin (PSEN) variants are at elevated seizure risk. Yet the heterogeneity in seizure-related impact between AD-related risk genes is not routinely assessed. Despite both mouse lines harboring AD-associated risk factors, we have previously reported that young APP/PS1 mice are more sensitive to corneal kindling and subsequent mortality than PSEN2 variant mice. Further, we observed notable genotype-related differences in seizure-induced serotonin synthesis and metabolism (Del Pozo et al, 2023), revealing understudied heterogeneity in seizure-related behavioral and neuropathological impacts. The toll-like-receptor 4 (TLR4) pathway plays a key role regulating neuroinflammation in AD and epilepsy. Moreover, adenosine receptors contribute to microglia activation and functioning and likely also regulate glutamate and GABA uptake by astrocytes. Hence, we hypothesized that differences in kindling acquisition and seizure-induced premature mortality in APP/PS1 mice were due to a discordant change in adenosine receptor expression and/or TLR4 signaling.
Methods:
Male and female APP/PS1 and PSEN2-N141I and their respective wild-type (WT) counterparts underwent sham or corneal kindling beginning at two months-old. Mice were electrically kindled twice-daily for two to three weeks. After kindling, brains were hemisected along the sagittal plane. TLR4 and adenosine 1A (A1A) and 2A (A2A) receptor expression was quantified by western blot of the microdissected hippocampus (HPC) and cortex (CTX). Neurons (NeuN), microglia (Iba1), and astrocytes (GFAP) were quantified by immunohistochemistry in hemibrain HPC and CTX. Protein changes were compared to sham-kindled non-transgenic (Tg-) mice within genotypes.
Results:
NeuN expression in CTX and HPC in both genotypes was markedly reduced by kindling versus sham: Tg- mice [HPC: -40% (APP/PS1); -45% (PSEN2) p< 0.01
Basic Mechanisms