Neurodegenerative diseases are a group of heterogeneous diseases with diverse symptoms that progressively impair CNS function. Alzheimer's disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and other untreatable neurodegenerative diseases share the histological presence of hyperphosphorylated tau intracellular inclusions known as neurofibrillary tangles. In the first chapter, we explored the use of kinase inhibitors in tau aggregation mouse models as a potential therapeutical approach. The diaminothiazole series of compounds we developed are potent inhibitors of tau kinases CDK5 and GSK3-beta. Lead compounds from the series have IC50 values in the nanomolar range, and lack toxicity in this therapeutic range. Neuronal protective effects and decreased phosphorylated tau (PHF-1) immunoreactivity were observed in two mouse models, 3xTg-AD and CK-p25. This treatment nearly eliminated sarkosyl-insoluble tau.

A prominent effect was seen on the phosphorylation at Ser404. The treatment also induced the recovery of memory in fear conditioning assays. In the second chapter, we studied the cellular and molecular characteristics of a FTD/PSP cellular model. Induced pluripotent stem cells (IPSCs) were obtained by four factor reprogramming of skin fibroblasts from a patient diagnosed with FTD/PSP who harbors an A152T polymorphism in tau known to increase the risk for disease development. Three IPSCs clones of this patient were differentiated to human neurons (hIN). Skin fibroblasts from a clinically healthy A152T carrier beyond the expected age of onset, and two control individuals were also reprogrammed to IPSCs and differentiated to neurons. These hINs matured in vitro for five weeks, and expressed neuronal markers such as betaIII-tubulin, MAP2, Synapsin I, tau and PSD 95.

hINs from A152T carriers lacked axonal polarity, evidenced by the somato-dendritic presence of axonal proteins such as Synapsin I, tau and the axonal neurofilament antigen SMI312. The severity of the axonopathy correlated with the clinical evaluation of the patients. We aimed to explore the transcriptome of the hINs matured in vitro. Transcriptomes were obtained from total RNA and polyA selected RNA on the SOLiD platform. Mapping sequences were then analyzed for coverage of consensus coding sequences (CCDS) to determine expression levels. Gene expression was contrasted to mouse brain expression and HEK293T cells transcriptomes. Differentially expressed (DE) genes were then determined by comparing transcriptomes on the series of hINs, establishing a subset of candidates linked to the pathology of FTD/PSP.