Question
Question Posted 02/12/25:
As is well known, changes in the ratio of 3R TAU protein to 4R TAU protein in the brain of patients can lead to different neurodegenerative diseases. An important pathological feature of Alzheimer's disease is also changes in tau protein. So I want to know if there is also an imbalance between 3R TAU protein and 4R TAU protein in the brain of late-onset Alzheimer's patients? If so, what is its proportion?
As is well known, changes in the ratio of 3R TAU protein to 4R TAU protein in the brain of patients can lead to different neurodegenerative diseases. An important pathological feature of Alzheimer's disease is also changes in tau protein. So I want to know if there is also an imbalance between 3R TAU protein and 4R TAU protein in the brain of late-onset Alzheimer's patients? If so, what is its proportion?
Response posted 02/14/25 by Haley Bernhardt:
Based on my understanding, the simplest answer to this question is that, overall, there is NO (large) imbalance between 3R TAU protein and 4R TAU protein in brains affected by late-onset Alzheimer disease (AD); immunoblot analyses, including those with 3R and 4R specific antibodies, show roughly equal amounts of 3R and 4R in both soluble and insoluble fractions of postmortem brain homogenates. In contrast, the insoluble fractions of brain homogenates representing Pick disease show mostly 3R TAU, and those representing progressive supranuclear palsy or corticobasal degeneration show mostly 4R TAU.
However, if one investigates this question with more nuanced techniques (like immunofluorescent histology) applied to different brain areas and to specimens representing different stages of AD pathology (presymptomatic or early symptomatic versus advanced symptomatic) the story becomes more complex. Individual neurons – and their tangles, which may persist even after the neurons have died – may show different amounts of 3R or 4R tau signal over the course of disease, perhaps due to differential expression, differential modification, or differential degradation of 4R vs 3R tau. Neurons in different brain areas (e.g., hippocampus versus neocortex versus midbrain) may show somewhat differing patterns, as well.
I hope this response is at least somewhat helpful. For additional exploration, two published articles that begin to address this issue are listed below:
Espinoza M, de Silva R, Dickson DW, Davies P. Differential Incorporation of Tau Isoforms in Alzheimer’s Disease. Journal of Alzheimer’s Disease. 2008;14(1):1-16. doi:10.3233/JAD-2008-14101
Uchihara, T., Hara, M., Nakamura, A. et al. Tangle evolution linked to differential 3- and 4-repeat tau isoform deposition: a double immunofluorolabeling study using two monoclonal antibodies. Histochem Cell Biol 137, 261–267 (2012). https://doi.org/10.1007/s00418-011-0891-2
Regards,
Richard J. Perrin, MD, PhD
ADNI Neuropathology Core Leader
However, if one investigates this question with more nuanced techniques (like immunofluorescent histology) applied to different brain areas and to specimens representing different stages of AD pathology (presymptomatic or early symptomatic versus advanced symptomatic) the story becomes more complex. Individual neurons – and their tangles, which may persist even after the neurons have died – may show different amounts of 3R or 4R tau signal over the course of disease, perhaps due to differential expression, differential modification, or differential degradation of 4R vs 3R tau. Neurons in different brain areas (e.g., hippocampus versus neocortex versus midbrain) may show somewhat differing patterns, as well.
I hope this response is at least somewhat helpful. For additional exploration, two published articles that begin to address this issue are listed below:
Espinoza M, de Silva R, Dickson DW, Davies P. Differential Incorporation of Tau Isoforms in Alzheimer’s Disease. Journal of Alzheimer’s Disease. 2008;14(1):1-16. doi:10.3233/JAD-2008-14101
Uchihara, T., Hara, M., Nakamura, A. et al. Tangle evolution linked to differential 3- and 4-repeat tau isoform deposition: a double immunofluorolabeling study using two monoclonal antibodies. Histochem Cell Biol 137, 261–267 (2012). https://doi.org/10.1007/s00418-011-0891-2
Regards,
Richard J. Perrin, MD, PhD
ADNI Neuropathology Core Leader
