Effects of Amylin Against Amyloid-β-Induced Tauopathy and Synapse Loss in Primary Neurons

Article type: Research Article

Authors: Gan, Qini^{a; 1} | Yao, Hongbo^{a; e; 1} | Na, Hana^a | Ballance, Heather^a | Tao, Qiushan^a | Leung, Lorene^a | Tian, Hua^{a; e} | Zhu, Haihao^a | Wolozin, Benjamin^{a; b} | Qiu, Wei Qiao^{a; c; d; *}

Affiliations: [a] Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA | [b] Department of Neurology, Boston University School of Medicine, Boston, MA, USA | [c] Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA, USA | [d] Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA | [e] Department of Histology and Embriology, Qiqihaer Medical University, China

Correspondence: [*] Correspondence to: Wendy Wei Qiao Qiu, MD, PhD, Department of Psychiatry, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 72 East Concord Street, R-623, Boston, MA 02118, USA. Tel.: +1 617 638 4336; Fax: +1 617 638 5254; E-mail: [email protected].

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

Abstract:  Recent studies demonstrate that peripheral amylin treatment reduces pathology in mouse models of Alzheimer’s disease (AD). However, soluble and aggregated amylin are distinct species; while amylin is a physiological neuropeptide, amylin aggregation is a pathological factor for diabetes. We thus hypothesized that because of their similarity in secondary structures, amylin antagonizes amyloid-β peptide (Aβ)-induced AD pathology in neurons with a dose-dependent pattern. To test the hypothesis, we conducted both in vitro and in vivo experiments with different doses of amylin and with its analog, pramlintide. Here we report that a high concentration of either Aβ or amylin alone induced tau phosphorylation (pTau) in primary neurons. Interestingly, with a low concentration, amylin had direct effects to reverse the Aβ-induced pTau, as well as damaged neuronal synapses and neurite disorganization. However, when the concentration was high (10.24 μM), amylin lost the effects against the Aβ-induced cellular AD pathology and, together with Aβ, worsened tauopathy in neurons. In the 5XFAD AD mouse model, daily peripheral amylin treatment with a low dose (200 μg/kg) more effectively reduced amyloid burden, and increased synapse, but with a high dose (800 μg/kg), it more effectively reduced tauopathy. Correspondingly, amylin treatment improved learning and memory in these mice. It demonstrates that amylin has a dose-dependent U-shape effect against AD pathogenesis. Within a physiological range, amylin is a neuroprotective hormone against AD in neurons; but when both Aβ and amylin concentrations are elevated, imbalance of Aβ and amylin may contribute to brain AD pathogenesis.

Keywords: Alzheimer’s disease, amylin, amyloid-β peptide, pramlintide, synapse, tauopathy, U-shape

DOI: 10.3233/JAD-190161

Journal: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 1025-1040, 2019