Abstracts

Rationale: Early-onset Alzheimer’s disease (AD) is associated with variants in presenilin 2 (PSEN2) and seizures are common in AD patients. It is unclear whether chronic seizures impact neuroplasticity-related protein expression and/or neuroinflammation subsequent to loss of PSEN2 function, which may underlie cognitive deficits. PSEN2 is an underexplored molecular contributor to neuroinflammation; neuroinflammation may itself impact neuroplasticity through suppression of brain-derived neurotrophic factor (BDNF) expression. BDNF regulates the expression of Arc, a regulator of AMPA receptor localization essential to neuroplasticity. We thus sought to define the extent to which chronic seizures impact neuroinflammatory and neuroplasticity-related protein expression with loss of normal PSEN2 function. Methods: Male and female PSEN2 KO and age- and sex-matched wild-type (WT) C57Bl/6J mice were sham or corneal kindled at 6-months-old. Fully- and sham-kindled mice were challenged 3-6 weeks after acquisition in the Barnes maze (BM) test of spatial learning and memory (the impact of chronic seizures and PSEN2 loss on behaviors will be presented in a 2019 AES abstract by Knox et al.). Two hours after completion of the BM task, animals were euthanized and brain tissues collected for immunohistochemical quantification of the expression of the neuroplasticity-associated proteins, BDNF and Arc, in sham- and fully-kindled PSEN2 KO and WT mice (n = 8-11/group). The extent of reactive astrogliosis and microgliosis, markers of neuroinflammation, was also quantified with expression of GFAP and Iba-1, respectively. Results: Kindled female, but not male, PSEN2 KO mice demonstrated significant deficits in the BM task suggestive of spatial working memory deficits, thus we sought to define the extent to which molecular markers of synaptic plasticity (BDNF and Arc) and neuroinflammation were additively impacted by chronic seizures. The extent of reactive astrogliosis within dorsal hippocampus (CA1, CA3, and dentate gyrus) of female WT and PSEN2 KO kindled and sham-kindled mice was assessed following performance on the BM task. The extent of astrogliosis of corneal-kindled PSEN2 KO female mice was markedly greater than that of corneal kindled PSEN2 KO female mice within CA1 (corneal kindled WT: 9516+/-4825 um^2; corneal kindled KO: 18575+/-5654 um^2). The impact of chronic corneal kindled seizures and loss of normal PSEN2 function on microgliosis (Iba-1), as well as the expression of the synaptic plasticity-associated proteins, BDNF and Arc, will be further discussed. Conclusions: Loss of normal PSEN2 function influences formation of an epileptic network in an age-dependent manner (Beckman et al. AES Meeting 2018), and chronic seizures may exclusively worsen hippocampal memory of female PSEN2 KO mice (Knox et al. AES Meeting 2019). This present study thus sought to address how chronic seizures influence molecular indices of neuroinflammation and neuroplasticity in the context of loss of normal PSEN2 function, which may underlie cognitive deficits of both epilepsy and AD. Funding: This work was supported by the University of Washington Royalty Research Fund (MBH).