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

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.

• Authors: Qini Gan, Hongbo Yao, Hana Na, Heather Ballance, Qiushan Tao, Lorene Leung, Hua Tian, Haihao Zhu, Benjamin Wolozin, Wei Qiao Qiu
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 70 Issue 4 Pg. 1025-1040 ( 2019) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 31306122 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Islet Amyloid Polypeptide
• Peptide Fragments
• amyloid beta-protein (1-42)

Topics

• Amino Acid Sequence
• Amyloid beta-Peptides (toxicity)
• Animals
• Animals, Newborn
• Cells, Cultured
• Dose-Response Relationship, Drug
• Female
• Humans
• Islet Amyloid Polypeptide (pharmacology, therapeutic use)
• Mice
• Mice, Transgenic
• Neurons (drug effects, pathology)
• Peptide Fragments (toxicity)
• Pregnancy
• Rats
• Rats, Wistar
• Synapses (drug effects, pathology)
• Tauopathies (chemically induced, drug therapy, pathology)