The neuroprotective role of somatostatin against beta amyloid induced toxicity in in vitro models of Alzheimer’s disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease affecting more than 60 million people worldwide. This debilitating disease harbors toxic environment to the brain causing neuronal cell death and causes general impairment of the cognitive function. In our laboratory, we have been studying the effect of somatostatin (SST) in serving neuroprotective role against various disease models including hyperinflammation, Huntington’s disease and AD. In the present study, we aim to study the mechanisms involved in SST mediated neuroprotection against beta amyloid induced toxicity in blood brain barrier and in neurons. In AD, the impaired clearance of β-amyloid peptide (Aβ) due to disrupted tight junction and transporter proteins is the prominent cause of disease progression. We demonstrate that SST prevents Aβ induced blood brain barrier permeability by regulating low density lipoprotein receptor-related protein and receptor for advanced glycation end products expression and improving the disrupted tight junction proteins. Furthermore, SST abrogates Aβ induced c-JUN NH2-terminal kinase phosphorylation and expression of matrix metalloproteinase. Next, as the neurites are often the initial point of damage upon accumulation of Aβ, we examined the role of SST in all-trans retinoic acid (RA) induced progression of neurite outgrowth in SH-SY5Y cells. We also determined the morphological changes in prominent intracellular markers of neurite growth including microtubule-associated protein 2, Tuj1 and Tau. Here, we present evidence that SST is a molecular determinant in regulating the transition of SH-SY5Y cells from non-neuronal entity to neuronal phenotype in response to RA. Lastly, to elucidate the mechanism involved in SST mediated protection against Aβ-induced toxicity in neurons, phosphorylation level of collapsing response mediator 2 (CRMP2), a well-established regulator of neurite homeostasis hyperphosphorylated in AD was monitored. We demonstrate that SST effectively inhibits the hyperphosphorylation of CRMP2 as Ser522, which plays a critical role in priming the phosphorylation of subsequent sites. Furthermore, we identified the underlying mechanism involved in the regulation of CRMP2 phosphorylation by monitoring the SST mediated regulation of calcium influx. Taken together, results presented here suggest that SST might serve as a therapeutic intervention in AD via targeting multiple pathways responsible for neurotoxicity, impaired BBB function and disease progression.Pharmaceutical Sciences, Faculty ofGraduat