Abstract
Human tauopathies, such as Alzheimer’s disease (AD), have been widely studied in transgenic mice overexpressing human tau in the brain. The longest brain isoforms of Tau in mice and humans show 89% amino acid identity; however, the expression of the isoforms of this protein in the adult brain of the two species differs. Tau 3R isoforms are not present in adult mice. In contrast, the adult human brain contains Tau 3R and also Tau 4R isoforms. In addition, the N-terminal sequence of Tau protein in mice and humans differs, a Tau peptide (residues 17–28) being present in the latter but absent in the former. Here we review the main published data on this N-terminal sequence that suggests that human and mouse Tau proteins interact with different endogenous proteins and also show distinct secretion patterns.
Highlights
The microtubule-associated protein Tau is mainly expressed in neurons (Weingarten et al, 1975; Drubin and Kirschner, 1986)
Alzheimer’s disease (AD) is characterized by the accumulation of extracellular plaques of β-amyloid peptide and intracellular neurofibrillary tangles (NFTs) formed by aggregated and hyperphosphorylated Tau protein
The amyloid cascade theory proposes that β-amyloid drives Tau phosphorylation and Tau forms filaments and these filaments accumulate in NFTs (Selkoe and Hardy, 2016)
Summary
The microtubule-associated protein Tau is mainly expressed in neurons (Weingarten et al, 1975; Drubin and Kirschner, 1986). AD is characterized by the accumulation of extracellular plaques of β-amyloid peptide and intracellular neurofibrillary tangles (NFTs) formed by aggregated and hyperphosphorylated Tau protein. The hypothesis suggests that β-amyloid accumulation precedes altered Tau metabolism. The hyperphosphorylation of Tau protein prevents its binding to microtubules, resulting in its accumulation in the cytosol and consequent formation of intracellular NFTs. Aggregated Tau present in tauopathies does not seem to be the main toxic species. Altered mouse models have been widely used to study Tau metabolism (see https://www.alzforum.org/researchmodels) and have greatly contributed to our understanding of disease-related mechanisms. They are valuable for the evaluation of novel therapeutic approaches. We focus on recent data suggesting that the N-terminal end of Tau protein explains why none of the murine models fully reproduces the complete spectrum of AD or related tauopathies
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