Muscle Weakness, Hyperactivity, and Impairment in Fear Conditioning in Tau-deficient Mice

Tau, one of the major neuronal microtubule-associated proteins (MAPs), is important for neuronal cell morphogenesis and axonal maintenance. Tau is also known to be a component of the paired helical filaments (PHFs) in Alzheimer's disease patients. Recently, mutations in the tau gene were found in a hereditary neurodegenerative disease called frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) which exhibits various neurological and neuropathological characteristics including PHF-like intracellular tau deposit formation. Currently, the phenotype of the disease is thought to be due to: (1) the toxicity of mutant tau molecules and and/or; (2) the loss of function of normal tau molecules in patients' brains. To test the latter hypothesis, we performed behavioral and neurological tests on tau-deficient mice. Tau-deficient mice showed muscle weakness in the wire-hanging test, hyperactivity in a novel environment, and impairment in the contextual fear conditioning. They also had a tendency to fall more easily in the rod-walking test. These phenotypes parallel some signs and symptoms of FTDP-17 patients. Our results show that the loss of tau protein may itself lead to some of the neurological characteristics observed in FTDP-17 patients.