ABSTRACT Today 5.8 million people in the United States live with Alzheimer’s disease (AD), including 1 in 10 of those 65 and over, estimates the Alzheimer’s Association. It is the fifth leading cause of death in that age group. Despite growing investment by the NIH ($2.4 billion in 2019) and pharma, Alzheimer’s research has failed to deliver a cure, let alone a disease-slowing treatment. Dogmatic belief in the amyloid hypothesis, for example, has stifled emergence of new ideas. We advance a new approach: preventing CRMP2 phosphorylation. Collapsin response mediator protein 2 (CRMP2), a microtubule associated protein, was identified as a physiological substrate for glycogen synthase kinase 3β (GSK3β) and cyclin dependent kinase 5 (Cdk5), two protein kinases reported to have with greater activity in AD. Indeed, phosphorylation of CRMP2, at the residues targeted by GSK3b and Cdk5, is relatively high in cortex isolated from human AD brains, as well as in the brains of animal models of AD, while phospho-CRMP2 is found in neurofibrillary tangles along with amyloid beta (Ab) protein. In mouse models of AD, increased phosphorylation occurs prior to pathology, suggesting that hyperphosphorylation of CRMP2 is an early event in the development of AD. Studies have documented the presence of increased phosphorylation of CRMP2 in transgenic mouse models of AD and in postmortem human AD brains, but the functional consequences of CRMP2 hyperphosphorylation to the development of AD have not been fully addressed. To date, only one study has examined the role of CRMP2 phosphorylation in AD pathogenesis. By examining the effects of a core toxic fragment of Aβ proteins on behavioral and electrophysiological features in CRMP2 phosphorylation-deficient knock-in (crmp2ki/ki) mice, in which residue 52 SeràAla, this study revealed that Ab25– 35 oligomer–induced impairments of memory and synaptic plasticity in wildtype (wt) mice but not in crmp2ki/ki mice. Here, we test the hypothesis that preventing CRMP2 phosphorylation (at S522) will block impairment of memory and synaptic plasticity in a mouse AD model. The J20 mouse model of AD will be bred with the crmp2ki/ki mouse to interrogate the importance of CRMP2 phosphorylation in the pathogenesis of AD. In the double transgenic J20–crmp2ki/ki compared to J20–crmp2wt mice we will evaluate cognition using the novel object recognition and Morris water maze tests. We will utilize immunohistochemistry and biochemistry to evaluate the status of CRMP2 phosphorylation, Aβ burden, and synaptic dysfunction. We will also assess neuronal apoptosis using the TUNEL assay. Using electrophysiology, we will assess long-term potentiation (LTP) in hippocampal slices. Comparing to J20 mice with intact CRMP2 phosphorylation, we expect that J20–crmp2ki/ki mice will have reduced CRMP2 phosphorylation, improved memory, decreased Aβ burden and synaptic dysfunction, decreased cell death, and no impairment in LTP. This information will provide the pre...