Assessing effects of manipulation of expression of kinesins in a mouse modelof Alzheimer's disease

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PROJECT SUMMARY The presence of distinct lesions caused by the formation of filamentous deposits of abnormal brain proteins in neurons is a hallmark of Alzheimer’s Disease (AD). These filamentous deposits contain tau, a prominent intracellular protein that normally stabilizes microtubules. Fibrillar amyloid beta plaques arising from the aggregation of amyloid precursor protein (APP) is another hallmark of AD. Several studies have shown that both tau and APP are key facilitators of fast axonal transport in neurons. Importantly, axonal transport is implicated in several neuropsychiatric disorders. Though a causal role of axonal transport in AD is not known, several studies have reported axonal transport deficits both in tau and APP mutant models of AD. Based on our studies on the effect of manipulation of kinesins that RNAi mediated loss of function resulting in loss of memory whereas overexpression mediated gain of function resulting in enhanced memory, we here propose to assess the effect of overexpression of kinesins in APP-NL-G-F knockin mouse model of AD. Specifically we will study the effect of overexpression in ameliorating plaque formation, microgliosis, synaptic proteins and memory deficit. Based on our studies demonstrating memory enhancement with Kinesin overexpression, we anticipate to observe improvements in cytopathology and memory deficit in APP NL-G-F knockin mice. Positive outcomes from these studies are expected to impact our understanding of pathobiology of AD and discovery of new therapeutic targets.