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[Display omitted] • Astrocytes display an increased secretion of sICAM-1 upon Aβ 1-42 treatment. • ICAM-1 protects neurons from Aβ induced neurotoxicity both in vitro and in vivo. • ICAM-1 reduces Aβ load and improves cognition in animal models of AD. • ICAM-1 blocks upregulation of NF-κB in neurons and provides neuroprotection. • NF-κB inhibitor PDTC improves cognitive functions in 5xFAD mice. Alzheimer's disease (AD) is mainly characterized by amyloid beta (Aβ) plaque deposition and neurofibrillary tangle formation due to tau hyperphosphorylation. It has been shown that astrocytes respond to these pathologies very early and exert either beneficial or deleterious effects towards neurons. Here, we identified soluble intercellular adhesion molecule-1 (ICAM-1) which is rapidly increased in astrocyte conditioned medium derived from Aβ 1-42 treated cultured astrocytes (Aβ 1-42 –ACM). Aβ 1-42 –ACM was found to be neuroprotective, however, Aβ 1-42 –ACM deprived of ICAM-1 was unable to protect neurons against Aβ 1-42 mediated toxicity. Moreover, exogenous ICAM-1 renders protection to neurons from Aβ 1-42 induced death. It blocks Aβ 1-42 –mediated PARP cleavage and increases the levels of anti-apoptotic proteins such as Bcl-2 and Bcl-xL, and decreases pro-apoptotic protein Bim. In an Aβ-infused rat model of AD and in 5xFAD mouse, intra-peritoneal administration of ICAM-1 revealed a reduction in Aβ load in hippocampal and cortical regions. Moreover, ICAM-1 treatment led to an increment in the expression of the Aβ-degrading enzyme, neprilysin in 5xFAD mice. Finally, we found that ICAM-1 can ameliorate cognitive deficits in Aβ-infused rat and 5xFAD mouse. Interestingly, ICAM-1 could block the NF-κB upregulation by Aβ and inhibition of NF-κB recovers cognitive impairments in 5xFAD mice. Thus, our study finds a neuroprotective role of ICAM-1 and suggests that it can be a major candidate in cytokine-mediated therapy of AD. [ABSTRACT FROM AUTHOR]