Nasal Delivery of D-Penicillamine Hydrogel Upregulates a Disintegrin and Metalloprotease 10 Expression via Melatonin Receptor 1 in Alzheimer's Disease Models.

Abstract

Alzheimer's disease (AD) is a type of neurodegenerative disease that is associated with the accumulation of amyloid plaques. Increasing non-amyloidogenic processing and/or manipulating amyloid precursor protein signaling could reduce AD amyloid pathology and cognitive impairment. D-penicillamine (D-Pen) is a water-soluble metal chelator and can reduce the aggregation of amyloid-β (Aβ) with metals in vitro. However, the potential mechanism of D-Pen for treating neurodegenerative disorders remains unexplored. In here, a novel type of chitosan-based hydrogel to carry D-Pen was designed and the D-Pen-CS/β-glycerophosphate hydrogel were characterized by scanning electron microscopy and HPLC. Behavior tests investigated the learning and memory levels of APP/PS1 mice treated through the D-Pen hydrogel nasal delivery. In vivo and in vitro findings showed that nasal delivery of D-Pen-CS/β-GP hydrogel had properly chelated metal ions that reduced Aβ deposition. Furthermore, D-Pen mainly regulated A disintegrin and metalloprotease 10 (ADAM10) expression via melatonin receptor 1 (MTNR1α) and the downstream PKA/ERK/CREB pathway. The present data demonstrated D-Pen significantly improved the cognitive ability of APP/PS1 mice and reduced Aβ generation through activating ADAM10 and accelerating non-amyloidogenic processing. Hence, these findings indicate the potential of D-Pen as a promising agent for treating AD.

• Authors: Manli Zhong, Hejia Kou, Pu Zhao, Wei Zheng, He Xu, Xiaoyu Zhang, Wang Lan, Chuang Guo, Tao Wang, Feng Guo, Zhanyou Wang, Huiling Gao
• Journal: Frontiers in aging neuroscience (Front Aging Neurosci) Vol. 13 Pg. 660249 ( 2021) ISSN: 1663-4365 [Print] Switzerland
• PMID: 33935689 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Zhong, Kou, Zhao, Zheng, Xu, Zhang, Lan, Guo, Wang, Guo, Wang and Gao.