β-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or β-amyloid deposits

doi:10.1073/pnas.0602896103

β-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or β-amyloid deposits

*A. I. Virtanen Institute and
^¶Department of Chemistry, University of Kuopio, and
^‡‡Department of Oncology, Kuopio University Hospital, P.O. Box 1627, FI-70211, Kuopio, Finland;
^†Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4-Krc, Czech Republic;
^‡Department of Psychiatry, Charles University, Ke Karlovu 11, 121 28 Prague 2, Czech Republic;
^§Cerebricon, Ltd., Microkatu 1, FI-70210, Kuopio, Finland;
^‖Department of Medicine, University of California, Los Angeles, and the Veterans Administration Greater Los Angeles Healthcare System, Sepulveda, CA 91343; and
**Department of Neurology, University of California, Los Angeles, and the Geriatric Research Education and Clinical Core, North Hills, CA 91343

Contributed by Jan Bures, April 9, 2006

Abstract

β-Amyloid (Aβ) polypeptide plays a critical role in the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of Aβ deposits and neurofibrillary tangles, and loss of neurons. Increased genetic production or direct intracerebral administration of Aβ in animal models results in Aβ deposition, gliosis, and impaired cognitive functions. Whether aging renders the brain prone to Aβ and whether inflammation is required for Aβ-induced learning deficits is unclear. We show that intraventricular infusion of Aβ_1–42 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 Aβ deposition and are not associated with gliosis. In rats, Aβ infusion induced learning deficits that were detectable 6 months after the infusion. Approximately 20% of the Aβ immunoreactivity in rats was associated with astrocytes. NMR spectrum analysis of the animals cerebrospinal fluid revealed a strong reduction trend in several metabolites in Aβ-infused rats, including lactate and myo-inositol, supporting the idea of dysfunctional astrocytes. Even a subtle increase in brain Aβ_1–42 concentration may disrupt normal metabolism of astrocytes, resulting in altered neuronal functions and age-related development of learning deficits independent of Aβ deposition and inflammation.

Footnotes

^††To whom correspondence may be addressed. E-mail: bures{at}biomed.cas.cz or jari.koistinaho{at}uku.fi
Author contributions: T.M., J.P., R.L., M.K., J.B., and J.K. designed research; T.M., M.O., L.T., N.J., G.G., J.P., A.N., R.P., T.A., T.-K.M., K.K., S.L., and N.V. performed research; T.M., L.T., N.J., K.K., N.V., J.Y., R.L., M.E.H.-W., and S.A.F. contributed new reagents/analytic tools; T.M., M.O., L.T., J.P., T.-K.M., R.L., M.K., N.J., G.G., and J.B. analyzed data; and T.M., L.T., J.P., M.K., J.B., and J.K. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

Aβ,

β-amyloid;

AD,

Alzheimer's disease;

CSF,

cerebrospinal fluid;

HDL,

high-density lipoprotein;

MWM,

Morris Water Maze;

TG,

transgenic