Accumulation of proteinaceous aggregates is one of the defining hallmarks of neurodegenerative diseases. How these proteins cause disease and how they are subsequently cleared has remained an enigma. Tau, a microtubule binding protein, is one such aggregated protein found in multiple neurodegenerative syndromes including Frontotemporal dementia (FTD), Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), and Corticobasalganglionic Degeneration (CBD). Understanding tau mediated neurodegeneration may lead to important therapeutic strategies for these disorders. Our goal is to study how decreasing tau levels and decreasing 4R:3R tau ratios affects the behavioral and pathological abnormalities in mouse models of dementia. Previous studies demonstrate that tau knockout animals are protected from amyloid beta induced behavioral abnormalities in mice. Our goal is to test whether decreasing mouse tau in older animals will also provide protection. Some mutations in tau that cause FTD lead to changes in alternative splicing and increased levels of 4R:3R tau. An N279K FTD mouse model replicates the splicing defect and behavioral pathological changes. Our goal is to test whether reversing the splicing defect in an adult N279K can reverse the behavioral and pathologic changes. In order to decrease tau mRNA and protein levels, we will infuse antisense oligonucleotides into the cerebral spinal fluid that bathes the brain and spinal cord. These oligos activate RNAse H and degrade tau mRNA. To decrease 4R:3R tau ratios, we will use a similar antisense oligo strategy, but with antisense oligos designed to promote exclusion of exon 10 (and thus decrease 4R:3R ratio) rather than decreasing tau mRNA. We show preliminary evidence for a set of oligos that decrease tau mRNA in vitro and for another group of oligos that decrease 4R:3R ratios in vitro. After establishing the efficacy of these oligos following intraventricular infusion, we will treat J20 APP mice with oligos that decrease mouse tau mRNA and protein and treat N279K tau mice with oligos that decrease 4R:3R ratios by changing tau splicing. We anticipate that these oligos will prevent the behavioral and pathological changes seen in these models. These data would form the basis for a similar treatment strategy in patients.