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

beta-Amyloid (A beta) polypeptide plays a critical role in the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of A beta deposits and neurofibrillary tangles, and loss of neurons. Increased genetic production or direct intracerebral administration of A beta in animal models results in A beta deposition, gliosis, and impaired cognitive functions. Whether aging renders the brain prone to A beta and whether inflammation is required for A beta-induced learning deficits is unclear. We show that intraventricular infusion of A beta(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 A beta deposition and are not associated with gliosis. In rats, A beta infusion induced learning deficits that were detectable 6 months after the infusion. Approximately 20% of the A beta immunoreactivity in rats was associated with astrocytes. NMR spectrum analysis of the animals cerebrospinal fluid revealed a strong reduction trend in several metabolites in All-infused rats, including lactate and myo-inositol, supporting the idea of dysfunctional astrocytes. Even a subtle increase in brain A beta(1-42) concentration may disrupt normal metabolism of astrocytes, resulting in altered neuronal functions and age-related development of learning deficits independent of A beta deposition and inflammation.