Amyloid-β Protein Precursor Deficiency Changes Neuronal Electrical Activity and Levels of Mitochondrial Proteins in the Medial Prefrontal Cortex

Article type: Research Article

Authors: Huo, Qingwei^{a; b; 1} | Tabassum, Sidra^{a; 1} | Chen, Ming^c | Sun, Mengyao^d | Deng, Yueming^d | Zheng, Xingzhi^d | Li, Yi^d | Chen, Jian^d | Long, Cheng^{d; *} | Yang, Li^{a; *}

Affiliations: [a] Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China | [b] Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China | [c] Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China | [d] School of Life Sciences, South China Normal University, Guangzhou, China

Correspondence: [*] Correspondence to: Li Yang, Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Gua-ngzhou, 510006, China. E-mail: yang_li@gzhu.edu.cn; Cheng Long, School of Life Sciences, South China Normal University, Guangzhou, 510631, China. E-mail: longcheng@m.scnu.edu.cn.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Neuropathological features of Alzheimer’s disease are characterized by the deposition of amyloid-β (Aβ) plaques and impairments in synaptic activity and memory. However, we know little about the physiological role of amyloid-β protein precursor (AβPP) from which Aβ derives. Objective:Evaluate APP deficiency induced alterations in neuronal electrical activity and mitochondrial protein expression. Methods:Utilizing electrophysiological, biochemical, pharmacological, and behavioral tests, we revealed aberrant local field potential (LFP), extracellular neuronal firing and levels of mitochondrial proteins. Result:We show that APP knockout (APP-/-) leads to increased gamma oscillations in the medial prefrontal cortex (mPFC) at 1-2 months old, which can be restored by baclofen (Bac), a γ-aminobutyric acid type B receptor (GABABR) agonist. A higher dose and longer exposure time is required for Bac to suppress neuronal firing in APP-/- mice than in wild type animals, indicating enhanced GABABR mediated activity in the mPFC of APP-/- mice. In line with increased GABABR function, the glutamine synthetase inhibitor, L-methionine sulfonate, significantly increases GABABR levels in the mPFC of APP-/- mice and this is associated with a significantly lower incidence of death. The results suggest that APP-/- mice developed stronger GABABR mediated inhibition. Using HEK 293 as an expression system, we uncover that AβPP functions to suppress GABABR expression. Furthermore, APP-/- mice show abnormal expression of several mitochondrial proteins. Conclusion:APP deficiency leads to both abnormal network activity involving defected GABABR and mitochondrial dysfunction, suggesting critical role of AβPP in synaptic and network function.

Keywords: Amyloid-β precursor protein, GABA_BR, gamma oscillations, L-methionine sulfonate, medial prefrontal cortex, mitochondria, spikes

DOI: 10.3233/JAD-201557

Journal: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1469-1482, 2021