TIMP-1: A key cytokine released from activated astrocytes protects neurons and ameliorates cognitive behaviours in a rodent model of Alzheimer's disease

Abstract

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.

Keywords: Akt; Alzheimer’s disease; Amyloid-β; Cognitive dysfunctions; Cytokines; Neuroprotection; Reactive astrogliosis; Rodent model; TIMP-1.