Melatonin production by the pineal gland occurs only at night and is an important component of the synchronization system, regulating circadian and seasonal rhythms. Melatonin effects are not restricted to chronobiotic actions, as it also exhibits immunomodulatory, antioxidative and cytoprotective properties. Two specific G protein-coupled membrane receptors, MT₁ and MT₂, mediate most of melatonin effects. Impairment in melatonin synthesis and altered expression of its membrane receptors have been described in Alzheimer’s disease (AD), a neurological disorder characterized by the presence of aggregates of amyloid-beta peptide (Abeta), which exert neurotoxic effects and induce neuroinflammatory responses. Because we have recently demonstrated that melatonin synthesis is impaired during inflammatory responses, here we investigated whether Abeta impairs the melatonergic system, directly affecting pineal physiology and/or melatonin signaling through its membrane receptors. Abeta (0.03µM-1µM, 24h-72h) reduced norepinephrine-induced melatonin synthesis by cultured rat pineal glands (50-75%) through activation of NF-kB pathway. In addition, Abeta up-regulated the expression of several inflammatory genes in the pineal gland, as interleukins and cytokines, and increased TNF (tumor necrosis factor) release in the culture medium (control: 20.65 ± 5.56pg/mL x Abeta: 74.45 ± 19.27pg/mL). Melatonin receptors function was also affected by Abeta incubation (1µM, 24h), as HEK293 cells stable expressing MT₁ melatonin showed 50% reduction in the number of melatonin binding sites. Moreover, melatonin-induced activation of ERK1/2 signaling pathway (100nM, 2-20min) in both MT₁- and MT₂-expressing HEK293 cells showed 40% reduction by Abeta. This phenomenon was not observed when ERK phosphorylation was triggered by activation of beta-adrenoceptor. In conclusion, our results suggest that Abeta disrupts the melatonergic system by inhibiting pineal-derived melatonin synthesis and impairing melatonin receptor function. This might represent an early Abeta-triggered event, which could favor the development of AD pathology. Financial support: FAPESP, CAPES and CNPq.