Telmisartan Alleviates Alzheimer’s Disease-Related Neuropathologies and Cognitive Impairments

Article type: Research Article

Authors: Fu, Xin-Xin^{a; b; 1} | Wei, Bin^{a; 1} | Cao, Hai-Ming^{a; 1} | Duan, Rui^{a; b} | Deng, Yang^{a; b} | Lian, Hui-Wen^a | Zhang, Ying-Dong^{a; b; *} | Jiang, Teng^{a; *}

Affiliations: [a] Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China | [b] Department of Neurology, Nanjing First Hospital, China Pharmaceutical University, Nanjing, Jiangsu Province, PR China

Correspondence: [*] Correspondence to: Prof. Teng Jiang, MD, PhD, and Prof. Ying-Dong Zhang, MD, PhD, Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No.68 Changle Road, Nanjing, Jiangsu Province, 210006, PR China. E-mail: jiang_teng@njmu.edu.cn (Teng Jiang) and zhangyingdong@njmu.edu.cn (Ying-Dong Zhang); ORCID: 0000-0003-4170-1156; 0000-0001-7803-5367

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

Abstract: Background:Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder. There are few effective medications for halting the progression of AD. Telmisartan (TEL) is a widely used anti-hypertensive drug approved by FDA. Aside from treating hypertension, TEL has been revealed to provide protection against AD. However, the underlying mechanisms remain unclear. Objective:To investigate the mechanisms underlying the beneficial effects of TEL against AD. Methods:Eight-month-old APP/PS1 mice were administered with 5 mg/kg TEL once per day for 4 successive months. Nesting test, Y-maze test, and Morris water maze test were employed to assess the cognitive and executive functions. Neuronal and synaptic markers, amyloid-β (Aβ) pathology, neuroinflammation, and oxidative stress in the brains were measured. Specifically, components involved in Aβ production and degradation pathway were analyzed to explore the mechanisms underlying the therapeutic effect of TEL against Aβ pathology. The primary microglia were used to uncover the mechanisms underlying the anti-inflammatory effects of TEL in AD. Additionally, the preventive effect of TEL against AD were investigated using 4-month-old APP/PS1 mice. Results:TEL treatment ameliorated cognitive and executive impairments, neuronal and synaptic injury, Aβ pathology, neuroinflammation, and oxidative stress in APP/PS1 mice. The favorable effects of TEL on Aβ pathology were achieved by inhibiting enzymatic Aβ production and facilitating enzymatic and autophagic Aβ degradation. Meanwhile, the anti-inflammatory effects of TEL were accomplished via microglial PPARγ/NLRP3 pathway. The administration of TEL prior to symptom onset prevented AD-related cognitive decline and neuropathologies. Conclusion:TEL represents a promising agent for AD prevention and treatment.

Keywords: Alzheimer’s disease, amyloid-β pathology, autophagy, cognitive and executive impairments, neuroinflammation, neuronal and synaptic injury, NLRP3, oxidative stress, PPARγ , telmisartan

DOI: 10.3233/JAD-230133

Journal: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 919-933, 2023