Paired helical filaments (PHFs) make up the neurofibrillary tangles (NFTs) of Alzheimer's disease (AD), which are well correlated spatiotemporally with cell loss and dementia. The mechanisms by which they form from normal tau protein thus may be important pathogenic factors in AD. Tau in PHFs is hyperphosphorylated, glycated and binds AL+3, all of which increase its resistance to proteolysis and induce aggregation and/or cytotoxicity. PHF-tau hyperphosphorylation in AD brain appears to be at least partly due to a serine/threonine phosphatase deficiency. Tau overexpression in transgenic mice can also cause its hyperphosphorylation in otherwise normal neurons, while human tau overexpressed more powerfully in lamprey neurons (ABCs) via plasmid injection in situ exhibits similar changes, but in addition, aggregates in condensed masses that resemble NFTs; this is then followed by neurodegeneration. The goal of this project is to use the technical advantages of ABCs to test directly the relationships between (1) levels of human tau expression and accumulation, (2) the activity of serine/threonine phosphatases, (3) tau phosphorylation, glycation, and Al+3 binding, (4) rates of tau proteolysis, and (5) the development of neurofibrillary pathology in identified vertebrate neurons in situ. The pathological effects of human tau overexpression on ABCs will be characterized electrophysiologically and also immunocytochemically at the light and electron microscopic levels and correlated to the rate of expression and accumulation of tau and control proteins. Artificially glycated tau as well as de- phosphorylated, Al+3 treated, and normal PHF-tau isolated from AD brain will each be microinjected into ABCs in situ and their intracellular residence times compared to those of normal tau. Any pathological effects of microinjected tau will also be characterized. Finally, the effects of blocking phosphatase activities on the proteolysis of microinjected PHF-tau and/or AD type cytopathological changes in ABCs overexpressing tau will be examined with specific phosphatase inhibitors. The results of this study should indicate whether and how specific manipulations of tau metabolism are related to the development of neurofibrillary changes resembling those seen in AD in single, identified vertebrate central neurons in vivo. Consequently, the proposed studies may lead to fundamental new insights into the mechanisms connecting tau metabolism with PHF and NFT formation and (possibly) the cytopathology of AD that are presently unavailable from studies in cell culture or murine transgenic systems.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013919-04
Application #
2837324
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1996-08-15
Project End
2000-11-30
Budget Start
1999-01-15
Budget End
1999-11-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Massachusetts Lowell
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
956072490
City
Lowell
State
MA
Country
United States
Zip Code
01854