Redirected CaMKII for restoring deficits in Alzheimer's disease models

PROJECT SUMMARY/ABSTRACT Alzheimer's disease is a progressive, degenerative brain disease. The major symptoms are impairments in memory and cognitive functions. These changes accompany a significant loss of dendritic spines and, eventually, neurons themselves. A defining pathological feature of Alzheimer's disease is the presence of amyloid plaques

and neurofibrillary tangles in the brain. There has been remarkable progress in understanding the pathophysiological processes leading to this cellular pathology. Despite this progress, little is known about molecular interventions to restore dendritic and memory deficits in Alzheimer's disease models. Converging lines

of evidence have documented a significant alteration in the subcellular distribution of calcium/calmodulin- dependent protein kinase II alpha (CaMKIIa), which is a critical memory molecule, in many Alzheimer's disease models. Evidence also indicates a close link between CaMKIIa dysregulation and tau pathology (phosphorylation

and inclusion) in various Alzheimer's disease models, highlighting CaMKIIa as a significant target molecule to be intervened to restore the deficits seen in Alzheimer's disease. As such, approaches capable of redirecting this dysregulation of CaMKIIa may offer unique avenues for the treatment of Alzheimer's disease. In this

application, we propose to explore this possibility. Our recent work reported a novel intrabody that specifically targets N-methyl-D-aspartate receptors (NMDARs) located at the core of dendritic spines. We found that adeno- associated virus (AAV)-mediated delivery of CaMKIIa conjugated with the anti-NMDAR intrabody results in

postsynapse-targeted local enrichment of exogenous CaMKIIa in the mouse hippocampus and a significant increase in contextual fear memory of mice. Therefore, based on the complex formation and dynamics of CaMKIIa, we propose to evaluate our molecular intervention in reversing the CaMKIIa dysregulation, tau

phosphorylation, dendritic spinopathy, and memory deficits in in vitro and in vivo models of Alzheimer's disease. Knowledge of the functional roles of CaMKIIa dysregulation in Alzheimer's disease and subsequent tau abnormality will clarify the pathways of Alzheimer's disease pathogenesis and has the potential to accelerate

progress toward Alzheimer's disease treatments by challenging the key memory pathway with a new but validated molecular approach based on a solid foundation of knowledge in synapse biology.