Impairment of Fast Axonal Transport in Alzheimer's Disease
thesisposted on 2013-06-28, 00:00 authored by Yuka Atagi
Alzheimer’s Disease (AD) manifests as memory deficit in early stages, and progresses into a more severe stage where patients may lose the ability to communicate and control bodily functions. Despite extensive studies, the cause of AD remains unclear except for a small number of cases in which genetic mutations in Presenilin 1 (PS1), Presenilin 2 (PS2) and Amyloid Precursor Protein (APP) have been identified. The mechanism through which these mutations cause pathogenesis is yet to be elucidated, and there is currently no cure. Accumulations of filamentous tau and Aβ plaques represent pathological hallmarks of AD. Previous work from our laboratory and others identified fast axonal transport (FAT) as a critical neuronal process that is regulated by phosphorylation of the microtubule-based motor proteins kinesin and dynein. Impairment of FAT can result in dying back neuropathy of affected neurons in which synaptic dysfunction initially occurs followed by axonal retraction, with cell death as a final stage. The phenotype of dying back neuropathy is characteristic of many neurodegenerative diseases including AD. Dysregulation of phosphotransferases that are involved in FAT have been reported in both human patients and animal models of AD. In this study, we have demonstrated that soluble oligomeric form of Aβ42 impairs both directions of FAT in squid axoplasm through a mechanism involving abnormal phosphorylation of kinesin by endogenous serine/threonine kinase CK2. We have further investigated effects of kinase activation on the binding of motor proteins to microtubules and to cargo vesicles. Studies using mouse primary cortical neurons revealed that binding of both kinesin and dynein to microtubules are negatively affected by activation of CK2 while association of motor proteins and vesicles were not affected. Also, studies with animal models of AD confirmed and extended our observations of impaired FAT caused by kinase dysregulation. Put together, these data demonstrate that dysregulation of kinases plays a critical role in pathogenesis of AD by impairing both anterograde and retrograde FAT.