Reversing Alzheimer's Disease Pathology in Zebrafish by Photobiomodulation Treatment

Abstract

Zebrafish (Danio rerio) are one of the widely used research models due to their characteristics such as being transparent during development, sharing 70% of genes with humans, and having conserved features of vertebrate aging including deterioration of mitochondrial and cognitive functions. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s Disease (HD), are associated with aging and characterized by amyloid plaques and tau tangles leading to progressive neuronal loss and cognitive deficits. While affecting approximately 15% of the world population, neurodegenerative diseases are currently not curable which is why this study was conducted with the following two aims: (1) generate a pharmacological zebrafish model of AD by adding small amounts (100 nM) of okadaic acid (OKA) directly to fish tanks for 9 days and (2) reverse the AD pathology and impaired cognitive function by applying a sequential photobiomodulation (PBM) therapy. When examined after OKA treatment, zebrafish brains displayed histological hallmarks of AD including amyloid plaques, neurofibrillary tangles, vacuoles, and accumulation of GSK3β-pSer9. Furthermore, behavioral studies using a T-maze revealed that OKA-treated zebrafish spend significantly less time in the reward arm compared to untreated controls (15.2% vs. 50%). In contrast, a sequential PBM therapy at two different doses (i.e., 3 J/cm2 and 4.5 J/cm2) significantly reduced formation of amyloid plaques, neurofibrillary tangles, and vacuoles, as well as accumulation of GSK3β-pSer9 in brains of OKA-treated zebrafish while also improving their cognitive function as evidenced by being able to recall the reward arm and spending more time there (55 and 57%, respectively) similar to controls. Together these findings suggest that (1) a fast and cost-effective zebrafish model of AD can be established by OKA treatment and (2) PBM therapy is a promising approach to reverse AD pathology.