Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder that leads to cognitive dysfunction, memory impairment and emotional disturbance in elderly persons. Activated microglia and reactive astrocytes are commonly found in and around the senile plaques that are the central pathological hallmark of AD. Beta-amyloid peptide (Abeta) accumulates in these plaques. Astrocytes respond to neuronal activity through the release of gliotransmitters such as glutamate, d-serine and adenosine 5′-triphosphate (ATP). How gliotransmitters regulate neuronal activity, however, is not well defined and even controversial. Also, astrocyte secreted several proteins to the synapse, which modulate synaptic function including synaptogenesis and neurogenesis directly or indirectly to the neurons. In the present study, we examined the effect of one of gliotransmiitters, ATP on neurons damaged by Abeta42 peptides in both primary astrocytes and U373 astrocyte cell line. We found that exogenous ATP protects against Abeta42-mediated reduction in synaptic molecules, such as NMDA receptor 2A, PSD-9ATP5 and synaptophysin, through purinergic receptor P2X in primary hippocampal neurons. ATP also prevented Abeta42-induced spine reduction and impaired long-term potentiation in the hippocampal neurons. Our findings suggest that Abeta-induced gliotransmitter ATP plays a protective role against Abeta42-mediated synaptic plasticity disruption. As an astrocyte-secreted protein, thrombospondin-1 (TSP-1) was examined in vitro and in AD animal model (5XFAD mice). The release of TSP-1 from astrocytes was decreased by Abeta42 in vitro, and the reduced level of TSP-1 was observed in brains of AD animal models. Synaptic pathology caused by Abeta42 such as decreased dendritic density, impaired synaptic activity, and reduced long-term potentiation (LTP) were prevented by co-incubation with TSP-1 and Abeta. TSP-1 is a potential therapeutic component against the damaging effects caused by Abeta42 in AD pathogenesis.