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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]

• Primary astrocytes are activated in response to Amyloid-β insult within 6 h. • The Aβ-treated astrocyte conditioned medium protects primary neurons from Aβ insult. • TIMP-1 is the major component of the Aβ-treated astrocyte conditioned medium. • TIMP-1 provides neuroprotection against Aβ insult by activating Akt pathway. • TIMP-1 ameliorates cognitive behaviours of an Aβ-infused rats by reducing Aβ load. Alzheimer's disease (AD) is characterized by two pathologic species, extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles. Astrocytes that maintain normal homeostasis in the brain undergo a set of molecular, cellular and functional changes called reactive astrogliosis in various neurological diseases including AD. It is hypothesized that reactive astrocytes initially tend to protect neurons by reducing Aβ load and by secreting a plethora of cytokines, however, their functions have only been poorly investigated. Our studies on the kinetics of activation of cortical astrocytes following Aβ-exposure revealed significant level of activation as early as in 6 h. The astrocyte conditioned medium (ACM) from 6 h Aβ-treated astrocytes (Aβ-ACM) provided significant neuroprotection of cultured cortical neurons against Aβ insults. Analysis of the secreted proteins in Aβ-ACM revealed a marked increase of Tissue inhibitor of Metalloproteinase-1 (TIMP-1) within 6 h. Interestingly, we found that neutralization of TIMP-1 with antibody or knockdown with siRNA in astrocytes abolished most of the neuroprotective ability of the 6 h Aβ-ACM on Aβ-treated cultured neurons. Furthermore addition of exogenous rat recombinant TIMP-1 protein protects primary neurons from Aβ mediated toxicity. In a well characterized Aβ-infused rodent model of AD, intra-cerebroventricular administration of TIMP-1 revealed a reduction in Aβ load and apoptosis in hippocampal and cortical regions. Finally, we found that TIMP-1 can ameliorate Aβ-induced cognitive dysfunctions through restoration of Akt and its downstream pathway and maintenance of synaptic integrity. Thus, our results not only provide a functional clarity for TIMP-1, secreted by activated astrocytes, but also support it as a major candidate in cytokine-mediated therapy of AD especially at the early phase of disease progression. [ABSTRACT FROM AUTHOR]