Autophagy-ERK1/2-Involved Disinhibition of Hippocampal Neurons Contributes to the Pre-Synaptic Toxicity Induced by Aβ₄₂ Exposure

Article type: Research Article

Authors: Yin, Yanling^{a; *} | Zhao, Yuanyuan^b | Han, Song^a | Zhang, Nan^c | Chen, Hanyu^d | Wang, Xiaomin^{a; *}

Affiliations: [a] Department of Neurobiology and Beijing Institute for Brain Disorders, School of Basic Medical Sciences, Capital Medical University, Beijing, PR China | [b] Core Facility Center, Capital Medical University, Beijing, PR China | [c] Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, PRChina | [d] Wyoming Seminary College Preparatory School, Kingston, PA, USA

Correspondence: [*] Correspondence to: Xiaomin Wang, MD, PhD, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, #10 You An Men Wai Xi Tou Tiao, Beijing 100069, P.R. China. Tel.: +8610 8391 1492; Fax: +8610 8391 1491; E-mail: xmwang@ccmu.edu.cn and Yanling Yin, MD, PhD, Department of Neurobiology, Beijing Institute for Brain Disorders, Capital Medical University, #10 You An Men Wai Xi Tou Tiao, Beijing 100069, P.R. China. Tel.: +8610 8391 1492; Fax: +8610 8391 1491; E-mail: yyling@ccmu.edu.cn.

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most frequent cause of progressive cognitive decline in the elderly population. To date, there is still no effective treatment for AD, requiring more underlying mechanisms. In the present study, we investigated the effects of Aβ42 on the inhibitory synaptic transmission in the cultured hippocampal neurons, and explored the possible mechanism. The frequency, but not amplitude, of miniature inhibitory post-synaptic currents was significantly suppressed by Aβ42, indicating that Aβ42 played its role in inhibitory transmitter release at the pre-synaptic sites. Aβ42 had no effect on miniature excitatory post-synaptic currents, suggesting GABAergic synapses are more susceptible to Aβ42 exposure. However, the number of GABAergic neurons or synapses was not influenced, suggesting the corresponding stage may be a preclinical one. The effect of Aβ42 can be mimicked by PD98059 (an inhibitor of ERK1/2) and blocked by curcumin (an activator of MEK), which reveals Aβ-involved influence is via the decreased phosphorylation of MAPK-ERK1/2. In addition, synaptophysin is confirmed to be a downstream protein of MAPK-ERK1/2 at the pre-synaptic site. At the same time, suppressed autophagy was observed after Aβ42 exposure, and the activation of autophagy increased pERK1/2 level and salvaged the disinhibition of hippocampal neurons. These data suggest that diminished GABAergic tone likely starts from the preclinical stage of AD, so some GABAergic stress test may be effective for identifying cognitively normal elder adults. Strategies against the dysfunction of autophagy should be adopted in the early stage of AD because of its initial effects.

Keywords: Alzheimer’s disease, autophagy, LC3, MAPK/ERK1/2, miniature inhibitory post-synaptic currents, synaptophysin

DOI: 10.3233/JAD-170246

Journal: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 851-869, 2017