Temporal Dynamics of Hippocampal Pathophysiology and Epileptiform Activity in an hAPP-J20 Mouse Model of Alzheimer's Disease
Abstract number :
2.461
Submission category :
1. Basic Mechanisms / 1C. Electrophysiology/High frequency oscillations
Year :
2023
Submission ID :
1348
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Keng Ying Liao, MS – Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
Yue Loong Hsin, MD – Department of Neurology, Chung Shan Medical University Hospital, Taichung, Taiwan; Xu Han, MS – Department of Bioengineering, University of California, Los Angeles, CA, USA; Wen Ying Chen, PhD – Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan; Wentai Liu, PhD – Department of Bioengineering, University of California, Los Angeles, CA, USA
Rationale: Alzheimer's disease (AD) and epilepsy often co-occur, with epilepsy manifesting at various AD stages. In vivo studies using mouse models with mutations in human amyloid precursor protein (hAPP) and presenilins have demonstrated the epileptogenic properties of amyloid-beta peptide (Aβ). The study aims to correlate the temporal evolution in the hippocampal pathophysiology of epilepsy with the staging of Aβ deposition.
Methods: The hAPP-J20 transgenic mouse model, born to develop Aβ depositions while also known for manifesting seizures, was employed. Signals of the hippocampal CA1 area of transgenic (Tg) and non-transgenic (NTg) mice sampled at 2K Hz were recorded using a wireless system. We investigated the dynamic alterations in hippocampal pyramidal and parvalbumin (PV) interneuron populations, neuropeptide Y (NPY) expression, and electrophysiology signals related to epilepsy from 9 to 28 weeks of age.
Results: A total of 32 Tg mice and 35 age-matched NTg mice were used for our study. Based on the emergence of Aβ plaques after 18 weeks (Fig. 1B), we conducted a comparative analysis between two stages: pre-plaque (from week 10 to 18) and post-plaque (from week 19 to 27). Tg mice exhibited a significantly higher incidence of death mostly due to convulsive seizures, particularly in the pre-plague stage (Fig. 1D). Histochemically, the expression of NPY mirrored this pattern, with elevated levels during the pre-plaque stage followed by a subsequent decline (Fig. 1C). Tg mice also showed a higher count of excitatory pyramidal cells and a decreased count of inhibitory interneurons, resulting in a statistically significant rise in the excitatory-to-inhibitory neuron ratio during the post-plaque stage (Fig. 2A-C). We also investigated various forms of electrophysiologic activity associated with epileptogenesis, including visible interictal epileptiform discharges (IEDs) and high-frequency oscillations categorized into low-frequency (80-200 Hz) ripples and high-frequency (250-600 Hz) fast ripples. Our study revealed a persistent elevation of IEDs in Tg mice across Aβ stages (Fig. 2D). Ripples remained relatively steady but showed a significant increase in the Tg group after week 19, possibly due to the increase of fast ripples. Fast ripples were more frequent in Tg mice, with a significant increase in the later post-plaque stage (Fig. 2E, 2F).
Conclusions: Our study found evidence linking hippocampal Aβ deposition with epileptiform activities. The remodeling of hippocampal circuits was associated with life-threatening convulsions before plague deposition. Temporal variations in the numbers of pyramidal and PV interneuron numbers may play a role in the dynamics of high-frequency oscillation, which are recognized as a biomarker of epileptogenesis emerging along Aβ deposition.
Funding: This research was funded by the "Taiwan Brain Technology Development and International Raising Program (108-2321-B-040-001-MY2)" and the "General Research Project (110-2314-B-040-021-)" under the auspices of the "National Science and Technology Council". It was also partially supported by a Faculty Endowment Fund by Dr. P. Soon-Shiung and Bioengineering Fellowship at UCLA.
Basic Mechanisms