Neurodegenerative processes in Alzheimer disease (AD) are thought to be driven in part by the deposition of amyloid f3 (Af8), a 39-to 43-amino acid peptide product resulting from an alternative cleavage of amyloid precursor protein. Recent descriptions ofin vitro neurotoxic effects ofA18 support this hypothesis and suggest toxicity might be mediated by A,B-induced neuronal calcium disregulation. In addition, it has been reported that "aging" A18 results in increased toxic potency due to peptide aggregation and formation of a (8-sheet secondary structure. In addition, Aj8 might also promote neuropathology indirectly by activating immune/inflammatory pathways in affected areas of the brain (e.g., cortex and hippocampus). Here we report that A13 can modulate cytokine secretion ] from human astrocytoma cells (U-373 MG). Freshly prepared and aged Af8 modestly stimulated IL-6 and IL-8 secretion from U-373 MG cells. However, in the presence of interleukin-1g3 (IL-1p8), aged, but not fresh, Ai3 markedly potentiated (3-to 8-fold) cytokine release. In contrast, aged A(3 did not potentiate substance P (NK-1)-or histamine (H1)-stimulated cytokine production. Further studies showed that IL-1p8-induced cytokine release was potentiated by A13-(25-35), while A(8-(1-16) was inactive. Calcium disregulation may be responsible for the effects of A(3 on cytokine production, since the calcium ionophore A23187 similarly potentiated IL-1p8-induced cytokine secretion and EGTA treatment blocked either A(8 or A23187 activity. Thus, chronic neurodegeneration in AD-affected brain regions may be mediated in part by the ability of A(3 to exacerbate inflammatory pathways in a conformation-dependent manner.Alzheimer disease (AD) is a progressive dementia affecting 1-6% of the elderly (>65 years old) and is the fourth leading cause of death in developed countries (1). As a neurodegenerative disorder, AD is pathologically characterized by cortical atrophy, neuronal loss, and the presence of neurofibrillary tangles and senile amyloid plaques. Amyloid plaques are anatomically defined as (i) "diffuse" or "preamyloid" plaques that consist of amorphous, noncongophillic amyloid 13 (AP3) deposits containing few, if any, reactive astrocytes and microglia (diffuse plaques are not associated with neuronal pathology); and (ii) "senile" or "neuritic" plaques consisting of fibrillar, congophillic AP3 deposits containing reactive astrocytes and microglia and surrounded by neuritic degeneration. These characteristic lesions are localized to regions of the brain important for cognition, learning, and memory-e.g., cerebral cortex and hippocampus (1). The neuropathology of AD, driving the progressive loss of cognitive function and memory, may result from the deposition of A,B, a 39-to 43-amino acid peptide product of an alternative cleavage of amyloid precursor protein (APP) (2,3