ICAM-1 protects neurons against Amyloid-ß and improves cognitive behaviors in 5xFAD mice by inhibiting NF-κB.

Alzheimer's disease (AD) is mainly characterized by amyloid beta (Aß) 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 Aß1-42 treated cultured astrocytes (Aß1-42-ACM). Aß1-42-ACM was found to be neuroprotective, however, Aß1-42-ACM deprived of ICAM-1 was unable to protect neurons against Aß1-42 mediated toxicity. Moreover, exogenous ICAM-1 renders protection to neurons from Aß1-42 induced death. It blocks Aß1-42-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 Aß-infused rat model of AD and in 5xFAD mouse, intra-peritoneal administration of ICAM-1 revealed a reduction in Aß load in hippocampal and cortical regions. Moreover, ICAM-1 treatment led to an increment in the expression of the Aß-degrading enzyme, neprilysin in 5xFAD mice. Finally, we found that ICAM-1 can ameliorate cognitive deficits in Aß-infused rat and 5xFAD mouse. Interestingly, ICAM-1 could block the NF-κB upregulation by Aß 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.

Rheb-mTOR activation rescues Aß-induced cognitive impairment and memory function by restoring miR-146 activity in glial cells.

Deposition of amyloid beta plaques in adult rat or human brain is associated with increased production of proinflammatory cytokines by associated glial cells that are responsible for degeneration of the diseased tissue. The expression of these cytokines is usually under check and is controlled at the post-transcriptional level via several microRNAs. Computational analysis of gene expression profiles of cortical regions of Alzheimer's disease patients' brain suggests ineffective target cytokine mRNA suppression by existing micro-ribonucleoproteins (miRNPs) in diseased brain. Exploring the mechanism of amyloid beta-induced cytokine expression, we have identified how the inactivation of the repressive miR-146 miRNPs causes increased production of cytokines in amyloid beta-exposed glial cells. In exploration of the cause of miRNP inactivation, we have noted amyloid beta oligomer-induced sequestration of the mTORC1 complex to early endosomes that results in decreased Ago2 phosphorylation, limited Ago2-miRNA uncoupling, and retarded Ago2-cytokine mRNA interaction in rat astrocytes. Interestingly, constitutive activation of mTORC1 by Rheb activator restricts proinflammatory cytokine production by reactivating miR-146 miRNPs in amyloid beta-exposed glial cells to rescue the disease phenotype in the in vivo rat model of Alzheimer's disease.

P38K and JNK pathways are induced by amyloid-ß in astrocyte: Implication of MAPK pathways in astrogliosis in Alzheimer's disease.

Astrocyte activation is one of the crucial hallmarks of Alzheimer's disease (AD) along with amyloid-ß (Aß) plaques, neurofibrillary tangles and neuron death. Glial scar and factors secreted from activated astrocytes have important contribution on neuronal health in AD. In this study, we investigated the mechanisms of astrocyte activation both in in vitro and in vivo models of AD. In this regard, mitogen activated protein kinase (MAPK) signalling cascades that control several fundamental and stress related cellular events, has been implicated in astrocyte activation in various neurological diseases. We checked activation of different MAPKs by western blot and immunocytochemistry and found that both JNK and p38K, but not ERK pathways are activated in Aß-treated astrocytes in culture and in Aß-infused rat brain cortex. Next, to investigate the downstream consequences of these two MAPKs (JNK and p38K) in Aß-induced astrocyte activation, we individually blocked these pathways by specific inhibitors in presence and absence of Aß and checked Aß-induced cellular proliferation, morphological changes and glial fibrillary acidic protein (GFAP) upregulation. We found that activation of both JNK and p38K signalling cascades are involved in astrocyte proliferation evoked by Aß, whereas only p38K pathway is implicated in morphological changes and GFAP upregulation in astrocytes exposed to Aß. To further validate the implication of p38K pathway in Aß-induced astrocyte activation, we also observed that transcription factor ATF2, a downstream phosphorylation substrate of p38, is phosphorylated upon Aß treatment. Taken together, our study indicates that p38K and JNK pathways mediate astrocyte activation and both the pathways are involved in cellular proliferation but only p38K pathway contributes in morphological changes triggered by Aß.