Cell-Cycle Reentry and Cell Death in Transgenic Mice Expressing Nonmutant Human Tau Isoforms

TLDR

Tau gene mutations are linked to neurofibrillary tangle formation in tauopathies, yet Alzheimer's disease shows NFTs without tau mutations, and the mechanism of tau‑mediated neuronal death remains unclear. In aged htau mice, neurodegeneration occurs with NFTs and extensive cell death, but tau filaments do not directly predict cell death; instead, abnormal, incomplete cell‑cycle reentry with DNA synthesis links nonmutant tau pathology to neuronal loss.

Abstract

Mutations in the microtubule-associated protein tau gene have been linked to neurofibrillary tangle (NFT) formation in several neurodegenerative diseases known as tauopathies; however, no tau mutations occur in Alzheimer's disease, although this disease is also characterized by NFT formation and cell death. Importantly, the mechanism of tau-mediated neuronal death remains elusive. Aged mice expressing nonmutant human tau in the absence of mouse tau (htau mice) developed NFTs and extensive cell death. The mechanism of neuron death was investigated in htau mice, and surprisingly, the presence of tau filaments did not correlate directly with death within individual cells, suggesting that cell death can occur independently of NFT formation. Our observations show that the mechanism of neurodegeneration involved reexpression of cell-cycle proteins and DNA synthesis, indicating that nonmutant tau pathology and neurodegeneration may be linked via abnormal, incomplete cell-cycle reentry.