title: Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease.
abstract: Amylin, a pancreatic peptide, and amyloid-beta peptides (Aβ), a major component of Alzheimer's disease (AD) brain, share similar β-sheet secondary structures, but it is not known whether pancreatic amylin affects amyloid pathogenesis in the AD brain. Using AD mouse models, we investigated the effects of amylin and its clinical analog, pramlintide, on AD pathogenesis. Surprisingly, chronic intraperitoneal (i.p.) injection of AD animals with either amylin or pramlintide reduces the amyloid burden as well as lowers the concentrations of Aβ in the brain. These treatments significantly improve their learning and memory assessed by two behavioral tests, Y maze and Morris water maze. Both amylin and pramlintide treatments increase the concentrations of Aβ1-42 in cerebral spinal fluid (CSF). A single i.p. injection of either peptide also induces a surge of Aβ in the serum, the magnitude of which is proportionate to the amount of Aβ in brain tissue. One intracerebroventricular injection of amylin induces a more significant surge in serum Aβ than one i.p. injection of the peptide. In 330 human plasma samples, a positive association between amylin and Aβ1-42 as well as Aβ1-40 is found only in patients with AD or amnestic mild cognitive impairment. As amylin readily crosses the blood-brain barrier, our study demonstrates that peripheral amylin's action on the central nervous system results in translocation of Aβ from the brain into the CSF and blood that could be an explanation for a positive relationship between amylin and Aβ in blood. As naturally occurring amylin may play a role in regulating Aβ in brain, amylin class peptides may provide a new avenue for both treatment and diagnosis of AD.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University Medical Campus, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University Medical Campus, Boston, MA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University Medical Campus, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wallack
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University Medical Campus, Boston, MA, USA.
authors.forename: H
authors.identifier: 0000000249521734
authors.initials: H
authors.lastname: Li
authors.affiliation: 1] Department of Neurology, Boston University Medical Campus, Boston, MA, USA [2] Alzheimer's Disease Center, Boston University Medical Campus, Boston, MA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Carreras
authors.affiliation: 1] Department of Neurology, Boston University Medical Campus, Boston, MA, USA [2] Alzheimer's Disease Center, Boston University Medical Campus, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dedeoglu
authors.affiliation: Memorial Sloan-Kettering Institute, New York, NY, USA.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Hur
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: 1] Alzheimer's Disease Center, Boston University Medical Campus, Boston, MA, USA [2] ENRM VA Medical Center, Bedford, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Fine
authors.affiliation: Department of Public Health and Family Medicine, Tufts University, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mwamburi
authors.affiliation: 1] Department of Neurology, Boston University Medical Campus, Boston, MA, USA [2] Alzheimer's Disease Center, Boston University Medical Campus, Boston, MA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.affiliation: 1] Department of Neurology, Boston University Medical Campus, Boston, MA, USA [2] Alzheimer's Disease Center, Boston University Medical Campus, Boston, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Kowall
authors.affiliation: 1] Department of Neurology, Boston University Medical Campus, Boston, MA, USA [2] Alzheimer's Disease Center, Boston University Medical Campus, Boston, MA, USA [3] Department of Neural Surgery, Boston University Medical Campus, Boston, MA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Stern
authors.affiliation: 1] Department of Pharmacology and Experimental Therapeutics, Boston University Medical Campus, Boston, MA, USA [2] Alzheimer's Disease Center, Boston University Medical Campus, Boston, MA, USA [3] Department of Psychiatry, Boston University Medical Campus, Boston, MA, USA.
authors.forename: W Q
authors.initials: WQ
authors.lastname: Qiu
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D065091:Amylin Receptor Agonists / Q000627:therapeutic use*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D001523:Mental Disorders / Q000188:drug therapy* / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D011569:Psychiatric Status Rating Scales
chemical_list: D065091:Amylin Receptor Agonists; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D058228:Islet Amyloid Polypeptide; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse