beta-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or beta-amyloid deposits.
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.
Malm
Tarja
T
A. I. Virtanen Institute and Department of Chemistry, University of Kuopio, Kuopio, Finland.
Ort
Michael
M
Tähtivaara
Leena
L
Jukarainen
Niko
N
Goldsteins
Gundars
G
Puoliväli
Jukka
J
Nurmi
Antti
A
Pussinen
Raimo
R
Ahtoniemi
Toni
T
Miettinen
Taina-Kaisa
TK
Kanninen
Katja
K
Leskinen
Suvi
S
Vartiainen
Nina
N
Yrjänheikki
Juha
J
Laatikainen
Reino
R
Harris-White
Marni E
ME
Koistinaho
Milla
M
Frautschy
Sally A
SA
Bures
Jan
J
Koistinaho
Jari
J
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
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)