Basic pathology of tauopathies

Tetsuaki Arai¹⁾²⁾

¹⁾Department of Neuropsychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba
²⁾Department of Dementia and Higher Brain Function, Dementia Research Project, Tokyo Metropolitan Institute of Medical Science

    Tau belongs to a family of microtubule-associated proteins that are involved in microtubule assembly and stabilization.  In the human brain, alternative splicing causes production of six tau isoforms, three with three microtubule-binding repeats in the carboxyl-terminal region (3Rtau) and the other three with four microtubule-binding repeats (4Rtau), containing the insertion of an exon 10-derived 31-amino acid fragment.  Tau aggregates as cytoplasmic inclusions in neurons and glial cells in a variety of neurodegenerative diseases, which are collectively referred as tauopathies.  The differences of isoform composition, phosphorylation state and proteolytic processing characterize the abnormal tau in each tauopathies.
Recent studies showed intraneuronal accumulation of phosphorylated tau as pretangles began in selected subcortical nuclei including locus coeruleus quite early, i.e., before puberty or in early young adulthood.  Thus, it precedes accumulation of amyloid beta protein and formation of senile plaques in the brain, and progresses from subcortical nuclei to cerebral cortex in Alzheimer's disease (AD).  Primary age-related tauopathy (PART), which was recently defined as pathology with neurofibrillary tangles that were indistinguishable from those of AD in the absence of senile plaques may ultimately lead to AD or to non-AD tauopathies like senile dementia of neurofibrillary tangles.
Recent research revealed that injection of tau fibrils into mouse brains was sufficient to induce pathology similar to that of human tauopathies, and that the pathologies spread as prion-like phenomena.  The propagation of abnormal tau may explain the disease progression of tauopathies.  Therapeutic strategies targeting the cell to cell propagation of abnormal tau using anti-tau antibodies may be useful as novel disease-modifying therapy of tauopathies.

Address correspondence to Dr. Tetsuaki Arai, Department of Neuropsychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba(1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575)