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.
