Urolithin A Inhibits Anterior Basolateral Amygdala to Ventral Hippocampal CA1 Circuit to Ameliorate Amyloid-β-Impaired Social Ability

Article type: Research Article

Authors: Xiong, Rui^{a; b; 1} | Li, Binrui^{b; 1} | Yu, Haitao^{a; d; 1} | Fan, Tianceng^b | Yu, Huiling^b | Yang, Ying^{a; b} | Wang, Jian-Zhi^{a; b} | Pi, Guilin^{a; c; *} | Yang, Xifei^{a; *}

Affiliations: [a] Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China | [b] Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [c] Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [d] Department of Fundamental Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China

Correspondence: [*] Correspondence to: Guilin Pi, Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Tel.: +86 027 85726359; E-mail: [email protected] and Xifei Yang, Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen 518073, China. Tel.: +86 755 25601914; E-mail: [email protected].

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

Abstract: Background:Anxiety and social withdrawal are highly prevalent among patients with Alzheimer’s disease (AD). However, the neural circuit mechanisms underlying these symptoms remain elusive, and there is a need for effective prevention strategies. Objective:This study aims to elucidate the neural circuitry mechanisms underlying social anxiety in AD. Methods:We utilized 5xFAD mice and conducted a series of experiments including optogenetic manipulation, Tandem Mass Tag-labeled proteome analysis, behavioral assessments, and immunofluorescence staining. Results:In 5xFAD mice, we observed significant amyloid-β (Aβ) accumulation in the anterior part of basolateral amygdala (aBLA). Behaviorally, 6-month-old 5xFAD mice displayed excessive social avoidance during social interaction. Concurrently, the pathway from aBLA to ventral hippocampal CA1 (vCA1) was significantly activated and exhibited a disorganized firing patterns during social interaction. By optogenetically inhibiting the aBLA-vCA1 pathway, we effectively improved the social ability of 5xFAD mice. In the presence of Aβ accumulation, we identified distinct changes in the protein network within the aBLA. Following one month of administration of Urolithin A (UA), we observed significant restoration of the abnormal protein network within the aBLA. UA treatment also attenuated the disorganized firings of the aBLA-vCA1 pathway, leading to an improvement in social ability. Conclusions:The aBLA-vCA1 circuit is a vulnerable pathway in response to Aβ accumulation during the progression of AD and plays a crucial role in Aβ-induced social anxiety. Targeting the aBLA-vCA1 circuit and UA administration are both effective strategies for improving the Aβ-impaired social ability.

Keywords: Alzheimer’s disease, amyloid-β, anxiety, aBLA-vCA1 circuit, urolithin A

DOI: 10.3233/JAD-240298

Journal: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1303-1316, 2024