Regenerating islet-derived 1 alpha (REG-1 alpha) protein increases tau phosphorylation in cell and animal models of tauopathies

REG-1 alpha, a secreted protein containing a C-type lectin domain, is expressed in various organs and plays different roles in digestive system cells in physiological and pathological conditions. Like other members of the Reg family, REG-1 alpha is expressed also in the brain where it has different functions. For instance, we previously reported that REG-1 alpha regulates neurite outgrowth and is overexpressed during the very early stages of Alzheimer's disease (AD). However, REG-1 alpha function in neural cells during neural degeneration remains unknown. First, REG-1 alpha and phosphorylated tau expression were assessed in tissue sections from the hippocampus, representing neurofibrillary tangles (NFTs), from patients with AD, and from basal ganglia, representing sub-cortical NFTs, from patients with progressive supranuclear palsy (PSP). We found an association between REG-1 alpha expression, tau hyperphosphorylation and NFTs in human brain samples from patients with these neuro-degenerative diseases. Then, the effects of REG-1 alpha overexpression on tau phosphorylation and axonal morphology were investigated i) in primary cultures of rat neurons that express human tau P301L and ii) in a transgenic zebrafish model of tauopathy that expresses human tau P301L. In the tau P301L cell model, REG-1 alpha overexpression increased tau phosphorylation at the S202/T205 and 5396 residues (early and late stages of abnormal phosphorylation, respectively) through the AKT/GSK3-beta pathway. This effect was associated with axonal defects both in tau P301L-expressing rat neurons and zebrafish embryos. Our findings suggest a functional role for REG-1 alpha during tauopathy development and progression and, specifically, its involvement in the modification of tau phosphorylation temporal sequence.