The excitatory amino acid transporter EAAT-2 is physiologically expressed in astrocytes. This study demonstrates that distinct subclasses of neurons exhibited EAAT-2 immunoreactivity in cases with Alzheimer's disease (AD). EAAT-2 was identified in the following types of neurons: Cortical pyramidal cells, fascia dentata granule cells, neurons of the basal nucleus of Meynert, the substantia nigra, the paraventricular nucleus of the hypothalamus, oral and central raphe nuclei, locus coeruleus, parabrachial nucleus, and neurons of the reticular formation of the brain stem. All EAAT-2-positive neurons displayed cytoskeletal abnormalities with abnormal tau-protein and often showed condensed and shrunken nuclei. None of the control cases without AD-related pathology showed EAAT-2-immunoreactive neurons. These results indicate that AD-related neurodegeneration is associated with the expression of the glutamate transporter EAAT-2 in altered neurons. Since an aberrant expression of EAAT-1 in neurons has recently been described, the finding of a neuronal expression of EAAT-2 strongly supports the hypothesis that abnormalities in glutamate transport play an important role in the pathogenesis of AD.