Involvement of CRMP2 Phosphorylation in Amyloid Beta-induced Tau Phosphorylation of Hippocampal Neurons in Alzheimer’s Disease Mouse Model

Alzheimer's disease (AD) is the most common form of dementia, characterized by amyloid-β (Aβ) deposition and the formation of neurofibrillary tangles composed of hyperphosphorylated tau. Collapsin response mediator protein 2 (CRMP2), a microtubule (MT)-binding protein, regulates MT dynamics and is phosphorylated at Ser522 by cyclin-dependent kinase 5. Previous studies have shown increased CRMP2 phosphorylation at Ser522 (CRMP2-pSer522) in early AD stages and AD mouse models, where it colocalizes with phosphorylated tau. However, the role of CRMP-pSer522 in AD pathology remains unclear. In this study, we generated double transgenic mice by crossing tau Tg (PS19) mice and CRMP2 S522A knock-in (CRMP2KI) mice, in which S522 of CRMP2 was replaced with alanine to create a phospho-defective model. No significant change in tau phosphorylation was observed in the hippocampus of tau Tg; CRMP2KI mice compared to tau Tg littermates. However, when Aβ25-35 oligomers were injected into the hippocampus, tau phosphorylation was significantly reduced in Aβ-injected tau Tg; CRMP2KI mice compared to Aβ-injected tau Tg controls. These findings suggest that CRMP2 phosphorylation at Ser522 promotes Aβ-induced tau phosphorylation in this mouse model of AD.