application): Alzheimer's disease (AD) is a common neurodegenerative disorder affecting more than three million people in the United States. AD etiology is only partially understood. Recently, the applicants and others studying frontotemporal dementia (FTD), found causative mutations in the gene encoding tau. Tau is the main protein of neurofibrillary tangles (NFT's) that are found in both AD and FTD. Other variants of tau pathology are also found in FTD (e.g., glial fibrillary tangles). The FTD mutations show that genetic alterations in tau cause both neurodegeneration and tau pathology, that in some cases closely parallels the changes observed in AD. Different tau mutations cause FTD by different mechanisms; in some cases, the biochemical properties of tau are altered while in others, splicing of exon 10 (E10) is altered. Mutations affecting splicing act by altering at least four different regulatory mechanisms: 1) the strength of the 5'splice site of E10, 2) an exon splicing enhancer regulatory element in E10, 3) an exon splicing silencer in E10, and 4) an inhibitory sequence directly adjacent to the 3' end of E10. FTD mutations either increase or decrease E10 incorporation into tau mRNA. In some families that show linkage to chromosome 17, no mutations in the open reading frame of tau or in sequences directly flanking exons have been found. Also, for progressive supranuclear palsy (PSP), association studies demonstrate that tau genetic variability is a risk factor for PSP, yet no mutations/risk factors are present in the open reading frame of tau. Thus, additional regulatory mutations in intronic sequences not directly adjacent to exons remain to be found. The different mechanisms affected by the different mutations are responsible for the diverse phenotype observed in different FTD kindreds. The following will be performed: 1) additional FTD families will be screened for tau mutations, 2) sporadic FTD subjects will be screened for mutations, 3) the functional consequences of each mutation on RNA splicing and tau protein faction will be determined, 4) a P1 artificial chromosome (PAC) clone containing the complete tau gene will be characterized for use in generating transgenic animals, 5) tau mutations will be introduced into the PAC, 6) the normal and mutant PACs will be used to generate transgenic animals. This work will determine how tau mutations function in vivo and generate transgenic animals with tau pathology.
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