TAU ISOFORMS IN HUMAN BRAIN DISEASE AND TRANSGENIC MICE

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DESCRIPTION: (Verbatim from the Applicant's Abstract) There is a growing body of evidence that mutations in the human gene encoding the microtubule-associated protein tau result in neuronal death and dementia. Tau is present in the central nervous system in 6 isoforms, which are products of alternative splicing of the tau mRNA. Although some mutations occur in the coding sequence of tau, several mutations appear to act by changing the pattern of splicing of the tau mRNA, resulting in changes in the ratio of the tau isoforms expressed in the brain. These changes appear to be sufficient to cause a late-onset neuronal death, especially in neurons of the frontal and temporal cortex. Tau accumulation in neurons and glia also occurs in diseases in which no tau mutations have yet been found, such as Alzheimer's disease, Pick's disease and Progressive Supranuclear Palsy. In the latter two conditions, accumulation of specific tau isoforms occurs in neurons and glia. Little is currently known about the normal pattern of tau isoform expression in specific neuronal populations of the human or animal brain, and even less information is available on tau isoform expression in glia. Such knowledge is essential to our understanding of the importance of tau for neuronal survival, and to develop testable hypotheses regarding the role of tau isoform pattern changes in neuronal dysfunction and death. The work proposed in this application will involve the production of monoclonal antibodies that will allow examination of the expression of specific tau isoforms in neurons and glia of the normal human brain, in cases of dementia with tau accumulation in neurons and/or glia, and in the brains of mice transgenic for human tau.