Phospho–Synapsin Regulation of Alzheimer Precursor Protein–JIP1–Kinesin Medicated Cargo Vesicle Traffic in Embryonic Lens Development and Alzheimer Transgenic Models.

Abstract

Abstract: : Purpose:In early stages of AD, synapses are disrupted by ß–amyloid stress. Previously, we demonstrated APP is a key element in fiber cell development, and early–onset cataract in Down syndrome. Others recently posited lens Aß levels as a correlate of AD. APP, JIP1b, and kinesins, link cargo vesicles to the cytoskeleton, and phosphorylation of Synpasins regulates vesicle release. Here we investigate expression and regulation of synaptic vesicle proteins in lens. Methods:Immunohistochemistry, western blot and RT–PCR were used to identify and quantify expression in fetal and adult lenses. Results:APP, JIP1b, and KLC1,2 KIF5AB, Synaptophysin I, Synaptotagmin I and all Synapsin genes are expressed beginning in earliest stages of embryonic lens development, consistent with a role for APP medicated cargo vesicle traffic in fiber cell formation. Neuron–specific Kinesin subunits are expressed in lens. In fetal lens, Synapsins IIa and IIIa, not Synapsin I are expressed. In adult lens, Synapsin I, but not IIIa are expressed, agreeing with Synapsin gene regulation in neuronal development. Discrete, differential distributions of Site–1 Phospho– and Dephospho–Synapsin in developing fibers is consistent with regulation of vesicle trafficking, and with EM demonstration of neuron–like microtubules and vesicles in lens (WK Lo; EER, 2003). Conclusions: A substantial complement of proteins involved in APP–mediated vesicle traffic and synaptic vesicle proteins are expressed in lens beginning early in fetal development. Phospho– and DePhospho Synapsin distribution in embryonic lens fibers is consistent with neuronal vesicle trafficking mechanisms in lens development. Aberrant ratios of APP, kinesin and other vesicle proteins linked with trafficking defects in Alzheimer mechanisms, occur in lenses in AD mice, and with aging. Here we identify more extensive parallels between lens and neuron differentiation and cell biology, which are also fundamentally involved in Alzheimer disease and highlight shared degenerative disease mechanisms in lens and brain.

Keywords: transgenics/knock–outs • cataract • synapse