Protective role of Akt1 in amyloid beta peptide induced degeneration in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders in elderly, characterized by loss of higher cognitive functions. The major hallmarks of AD seen in late stages are gross neurodegeneration, presence of extracellular amyloid plaques and intracellular neurofibrillary tangles. But in the recent years, there has been paradigm shift in AD research. It is now clear that synapse is the main target of attack in AD, with spine and synapse loss thought to be an early event in AD pathologies. Research in our lab has shown that oxidative stress could potentially play a critical role in mediating synaptic dysfunction through redox modifications of key proteins at the synapse leading to signaling changes. Studies in our laboratory have showed a critical role of Protein Kinase B (PKB, also called Akt1); a protein implicated in cell survival pathways, in activity-dependent translation. Moreover, we have also observed a synapse-specific deregulation of Akt1 signaling very early in our AD mouse model, indicative of its role in the pathogenesis of AD. Hence, deregulation of Akt1 signaling and consequent disrupted activity-dependent synaptic protein translation might culminate into compromised synaptic function and plasticity, activation of molecular cell death pathway and or reduction of cell survival signaling. Deregulation of Akt1 signaling in AD mouse model indicates that it might play a crucial role in synaptic dysfunction/ spine loss observed in AD. Hence, the objective of this study is to assess if Akt1 overexpression can be used as a protective measure to rescue synaptic function in AD. To this end, a lentiviral construct expressing myristoylated Akt1 (MyrAkt1) fluorescently tagged with pmCherry marker is produced with a titer value of 2.2×106 TU/ml. And its effect on spine pathology will be monitored upon over-expressing it in primary cortical culture derived from APP/PS1 transgenic mice.