Tau-positive nuclear indentations in P301S tauopathy mice

Marta Fernández-Nogales, María Santos-Galindo, Jesús Merchán-Rubira, Jeroen J M Hoozemans, Alberto Rábano, Isidro Ferrer, Jesús Avila, Félix Hernández, José J Lucas

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term "tau nuclear rods (TNRs)." Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyze transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an efficient way to monitor pathology-associated nuclear indentations.

Original languageEnglish
Pages (from-to)314-322
Number of pages9
JournalBrain Pathology
Volume27
Issue number3
DOIs
Publication statusPublished - May 2017

Cite this

Fernández-Nogales, M., Santos-Galindo, M., Merchán-Rubira, J., Hoozemans, J. J. M., Rábano, A., Ferrer, I., ... Lucas, J. J. (2017). Tau-positive nuclear indentations in P301S tauopathy mice. Brain Pathology, 27(3), 314-322. https://doi.org/10.1111/bpa.12407
Fernández-Nogales, Marta ; Santos-Galindo, María ; Merchán-Rubira, Jesús ; Hoozemans, Jeroen J M ; Rábano, Alberto ; Ferrer, Isidro ; Avila, Jesús ; Hernández, Félix ; Lucas, José J. / Tau-positive nuclear indentations in P301S tauopathy mice. In: Brain Pathology. 2017 ; Vol. 27, No. 3. pp. 314-322.
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title = "Tau-positive nuclear indentations in P301S tauopathy mice",
abstract = "Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term {"}tau nuclear rods (TNRs).{"} Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyze transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an efficient way to monitor pathology-associated nuclear indentations.",
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author = "Marta Fern{\'a}ndez-Nogales and Mar{\'i}a Santos-Galindo and Jes{\'u}s Merch{\'a}n-Rubira and Hoozemans, {Jeroen J M} and Alberto R{\'a}bano and Isidro Ferrer and Jes{\'u}s Avila and F{\'e}lix Hern{\'a}ndez and Lucas, {Jos{\'e} J}",
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Fernández-Nogales, M, Santos-Galindo, M, Merchán-Rubira, J, Hoozemans, JJM, Rábano, A, Ferrer, I, Avila, J, Hernández, F & Lucas, JJ 2017, 'Tau-positive nuclear indentations in P301S tauopathy mice' Brain Pathology, vol. 27, no. 3, pp. 314-322. https://doi.org/10.1111/bpa.12407

Tau-positive nuclear indentations in P301S tauopathy mice. / Fernández-Nogales, Marta; Santos-Galindo, María; Merchán-Rubira, Jesús; Hoozemans, Jeroen J M; Rábano, Alberto; Ferrer, Isidro; Avila, Jesús; Hernández, Félix; Lucas, José J.

In: Brain Pathology, Vol. 27, No. 3, 05.2017, p. 314-322.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Tau-positive nuclear indentations in P301S tauopathy mice

AU - Fernández-Nogales, Marta

AU - Santos-Galindo, María

AU - Merchán-Rubira, Jesús

AU - Hoozemans, Jeroen J M

AU - Rábano, Alberto

AU - Ferrer, Isidro

AU - Avila, Jesús

AU - Hernández, Félix

AU - Lucas, José J

N1 - © 2016 International Society of Neuropathology.

PY - 2017/5

Y1 - 2017/5

N2 - Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term "tau nuclear rods (TNRs)." Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyze transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an efficient way to monitor pathology-associated nuclear indentations.

AB - Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term "tau nuclear rods (TNRs)." Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyze transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an efficient way to monitor pathology-associated nuclear indentations.

KW - Animals

KW - Cell Nucleus

KW - Cerebral Cortex

KW - Corpus Striatum

KW - Disease Models, Animal

KW - Frontotemporal Lobar Degeneration

KW - Hippocampus

KW - Humans

KW - Immunohistochemistry

KW - Mice, Transgenic

KW - Microscopy, Confocal

KW - Microscopy, Immunoelectron

KW - Mutation

KW - Neurons

KW - Tauopathies

KW - tau Proteins

KW - Journal Article

U2 - 10.1111/bpa.12407

DO - 10.1111/bpa.12407

M3 - Article

VL - 27

SP - 314

EP - 322

JO - Brain Pathology

JF - Brain Pathology

SN - 1015-6305

IS - 3

ER -

Fernández-Nogales M, Santos-Galindo M, Merchán-Rubira J, Hoozemans JJM, Rábano A, Ferrer I et al. Tau-positive nuclear indentations in P301S tauopathy mice. Brain Pathology. 2017 May;27(3):314-322. https://doi.org/10.1111/bpa.12407