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␤-Amyloid (A␤) 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␤ deposits and neurofibrillary tangles, and loss of neurons. Increased genetic production or direct intracerebral administration of A␤ in animal models results in A␤ deposition, gliosis, and impaired cognitive functions. Whether aging renders the brain prone to A␤ and whether inflammation is required for A␤-induced learning deficits is unclear. We show that intraventricular infusion of A␤ 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␤ deposition and are not associated with gliosis. In rats, A␤ infusion induced learning deficits that were detectable 6 months after the infusion. Approximately 20% of the A␤ immunoreactivity in rats was associated with astrocytes. NMR spectrum analysis of the animals cerebrospinal fluid revealed a strong reduction trend in several metabolites in A␤-infused rats, including lactate and myo-inositol, supporting the idea of dysfunctional astrocytes. Even a subtle increase in brain A␤ 1-42 concentration may disrupt normal metabolism of astrocytes, resulting in altered neuronal functions and age-related development of learning deficits independent of A␤ deposition and inflammation.aging ͉ cerebrospinal fluid ͉ learning ͉ oxidative stress ͉ Alzheimer's disease A lzheimer's disease (AD) is the most common cause of progressive impairment of cognitive functions in humans during aging (1). Diagnosis is confirmed by the presence of neurofibrillary tangles (formed via hyperphosphorylation of tau) and ␤-amyloid (A␤)-containing plaques (2). A␤, a 39-to 43-aalong polypeptide derived from the A␤ precursor protein (APP), is neurotoxic and plays a critical role in the pathogenesis of AD (1, 2). Mutations in APP or presenilin genes that lead to the elevation of fibrillogenic form of A␤ are responsible for only a small portion of AD cases (1,3,4). In addition, triplication of APP gene-containing chromosome 21 in Down's syndrome results in AD, and the transgenic (TG) mouse models (5) overexpressing human mutant APP or presenilin genes severalfold, show progressive accumulation of A␤ deposits, gliosis, and cognitive decline (2). The relationship between A␤ deposition and cognitive decline is unclear because the severity of dementia does not correlate with A␤ plaques (6). In TG models, cognitive deficits can occur in the absence of A␤ deposits (7-10). Recent findings emphasize the role of soluble A␤ oligomers. A␤ oligomers are highly neurotoxic (11), and their amount in the brain correlates with the severity of AD and with spatial learning deficits in APP TG mice (12). However, it is not completely clear whether the neuropathology in these mice is solely a consequence of A␤ accumulation or whether increased concentrations of other cle...

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