title: beta-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or beta-amyloid deposits.
abstract: beta-Amyloid (Abeta) polypeptide plays a critical role in the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of Abeta deposits and neurofibrillary tangles, and loss of neurons. Increased genetic production or direct intracerebral administration of Abeta in animal models results in Abeta deposition, gliosis, and impaired cognitive functions. Whether aging renders the brain prone to Abeta and whether inflammation is required for Abeta-induced learning deficits is unclear. We show that intraventricular infusion of Abeta1-42 results in learning deficits in 9-month-old but not 2.5-month-old mice. Deficits that become detectable 12 weeks after the infusion are associated with a slight reduction in Cu,Zn superoxide dismutase activity but do not correlate with Abeta deposition and are not associated with gliosis. In rats, Abeta infusion induced learning deficits that were detectable 6 months after the infusion. Approximately 20% of the Abeta immunoreactivity in rats was associated with astrocytes. NMR spectrum analysis of the animals cerebrospinal fluid revealed a strong reduction trend in several metabolites in Abeta-infused rats, including lactate and myo-inositol, supporting the idea of dysfunctional astrocytes. Even a subtle increase in brain Abeta1-42 concentration may disrupt normal metabolism of astrocytes, resulting in altered neuronal functions and age-related development of learning deficits independent of Abeta deposition and inflammation.
authors.affiliation: A. I. Virtanen Institute and Department of Chemistry, University of Kuopio, Kuopio, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Malm
authors.forename: Michael
authors.initials: M
authors.lastname: Ort
authors.forename: Leena
authors.initials: L
authors.lastname: Tähtivaara
authors.forename: Niko
authors.initials: N
authors.lastname: Jukarainen
authors.forename: Gundars
authors.initials: G
authors.lastname: Goldsteins
authors.forename: Jukka
authors.initials: J
authors.lastname: Puoliväli
authors.forename: Antti
authors.initials: A
authors.lastname: Nurmi
authors.forename: Raimo
authors.initials: R
authors.lastname: Pussinen
authors.forename: Toni
authors.initials: T
authors.lastname: Ahtoniemi
authors.forename: Taina-Kaisa
authors.initials: TK
authors.lastname: Miettinen
authors.forename: Katja
authors.initials: K
authors.lastname: Kanninen
authors.forename: Suvi
authors.initials: S
authors.lastname: Leskinen
authors.forename: Nina
authors.initials: N
authors.lastname: Vartiainen
authors.forename: Juha
authors.initials: J
authors.lastname: Yrjänheikki
authors.forename: Reino
authors.initials: R
authors.lastname: Laatikainen
authors.forename: Marni E
authors.initials: ME
authors.lastname: Harris-White
authors.forename: Milla
authors.initials: M
authors.lastname: Koistinaho
authors.forename: Sally A
authors.initials: SA
authors.lastname: Frautschy
authors.forename: Jan
authors.initials: J
authors.lastname: Bures
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
mesh_terms: D000375:Aging / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D007249:Inflammation / Q000378:metabolism; D007262:Infusions, Intravenous; D007859:Learning Disabilities / Q000139:chemically induced* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)