title: The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice.
abstract: APP/PS1 double transgenic mice expressing human mutant amyloid precursor protein (APP) and presenilin-1 (PS1) demonstrate robust brain amyloid beta (Aβ) peptide containing plaque deposition, increased markers of oxidative stress, behavioral dysfunction, and proinflammatory gliosis. On the other hand, lack of growth hormone, prolactin, and thyroid-stimulating hormone due to a recessive mutation in the Prop 1 gene (Prop1df) in Ames dwarf mice results in a phenotype characterized by potentiated antioxidant mechanisms, improved learning and memory, and significantly increased longevity in homozygous mice. Based on this, we hypothesized that a similar hormone deficiency might attenuate disease changes in the brains of APP/PS1 mice. To test this idea, APP/PS1 mice were crossed to the Ames dwarf mouse line. APP/PS1, wild-type, df/+, df/df, df/+/APP/PS1, and df/df/APP/PS1 mice were compared at 6 months of age through behavioral testing and assessing amyloid burden, reactive gliosis, and brain cytokine levels. df/df mice demonstrated lower brain growth hormone and insulin-like growth factor 1 concentrations. This correlated with decreased astrogliosis and microgliosis in the df/df/APP/PS1 mice and, surprisingly, reduced Aβ plaque deposition and Aβ 1-40 and Aβ 1-42 concentrations. The df/df/APP/PS1 mice also demonstrated significantly elevated brain levels of multiple cytokines in spite of the attenuated gliosis. These data indicate that the df/df/APP/PS1 line is a unique resource in which to study aging and resistance to disease and suggest that the affected pituitary hormones may have a role in regulating disease progression.
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Puig
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Kulas
authors.affiliation: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA; Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Whitney
authors.initials: W
authors.lastname: Franklin
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Sharlene G
authors.initials: SG
authors.lastname: Rakoczy
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Taglialatela
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Brown-Borg
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA. Electronic address: colin.combs@med.und.edu.
authors.forename: Colin K
authors.initials: CK
authors.lastname: Combs
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression; D005911:Gliosis; D013006:Growth Hormone / Q000172:deficiency*; D018398:Homeodomain Proteins / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D058225:Plaque, Amyloid / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism*; D011388:Prolactin / Q000172:deficiency*; D013972:Thyrotropin / Q000172:deficiency*
chemical_list: D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D018398:Homeodomain Proteins; D053764:Presenilin-1; C102134:Prophet of Pit-1 protein; D007334:Insulin-Like Growth Factor I; D011388:Prolactin; D013972:Thyrotropin; D013006:Growth Hormone
keywords: Aging; Alzheimer; Amyloid; Cytokine; Dwarf; Growth hormone; IGF-1; Neuroinflammation