title: Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease.
abstract: Amylin is an important gut-brain axis hormone. Since amylin and amyloid-β peptide (Aβ) share similar β sheet secondary structure despite not having the same primary sequences, we hypothesized that the accumulation of Aβ in the brains of subjects with Alzheimer's disease (AD) might compete with amylin for binding to the amylin receptor (AmR). If true, adding exogenous amylin type peptides would compete with Aβ and reduce the AD pathological cascade, improving cognition. Here we report that a 10-week course of peripheral treatment with human amylin significantly reduced multiple different markers associated with AD pathology, including reducing levels of phospho-tau, insoluble tau, two inflammatory markers (Iba1 and CD68), as well as cerebral Aβ. Amylin treatment also led to improvements in learning and memory in two AD mouse models. Mechanistic studies showed that an amylin receptor antagonist successfully antagonized some protective effects of amylin in vivo, suggesting that the protective effects of amylin require interaction with its cognate receptor. Comparison of signaling cascades emanating from AmR suggest that amylin electively suppresses activation of the CDK5 pathway by Aβ. Treatment with amylin significantly reduced CDK5 signaling in a receptor dependent manner, dramatically decreasing the levels of p25, the active form of CDK5 with a corresponding reduction in tau phosphorylation. This is the first report documenting the ability of amylin treatment to reduce tauopathy and inflammation in animal models of AD. The data suggest that the clinical analog of amylin, pramlintide, might exhibit utility as a therapeutic agent for AD and other neurodegenerative diseases.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA. Electronic address: hhzhu@bu.edu.
authors.forename: Haihao
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA; Affiliated Rehabilitation Hospital of Fujian, TCM University, China.
authors.forename: Xiehua
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Erming
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA; Harvard Medical School, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Wallack
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Hana
authors.initials: H
authors.lastname: Na
authors.affiliation: Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, USA; Harvard Medical School, USA.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hooker
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Kowall
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Qiushan
authors.initials: Q
authors.lastname: Tao
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Thor D
authors.initials: TD
authors.lastname: Stein
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolozin
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA, USA; Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA. Electronic address: wqiu67@bu.edu.
authors.forename: Wei Qiao
authors.initials: WQ
authors.lastname: Qiu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000627:therapeutic use; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D058287:Receptors, Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D065852:Spatial Memory / Q000187:drug effects; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D058228:Islet Amyloid Polypeptide; D008024:Ligands; D008840:Microfilament Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D058287:Receptors, Islet Amyloid Polypeptide; D016875:tau Proteins
keywords: Alzheimer's disease; Amylin; Amylin receptor; Aβ; Learning and memory; Neuroinflammation; Therapeutic; p-Tau