Sárkány B, Dávid C, Hortobágyi T, Gombás P, Somogyi P, Acsády L, Viney TJ.
Early and selective localization of tau filaments to glutamatergic subcellular domains within the human anterodorsal thalamus.
Acta Neuropathol. 2024 Jun 11;147(1):98.
PubMed.
I am curious what the Alzforum community thinks about tau pathology in the thalamus? Braak and Braak showed that the anterodorsal thalamic nucleus (ADn) is affected at very early stages (Braak and Braak, 1991) and is the most severely involved nucleus in the thalamus (Braak and Braak, 1991). This may explain why the ADn shows severe neurodegeneration in Alzheimer's disease (Xuereb et al., 1991). A more recent review also highlights the considerably dense and selective tau pathology in the ADn (Rüb et al., 2016).
The ADn is now well-known for its high density of head direction cells—neurons that are important for spatial orientation. But back in the early 1990s, the significance of ADn tau pathology was not realized, as ADn head direction cells were not reported until 1995 (Taube, 1995). We now know that disorientation is a very early sign of dementia, and disruption of ADn head direction cells might explain this symptom (e.g., Forno et al., 2021; Coughlan et al., 2018; Hort et al., 2007; Allison et al., 2016; Colman et al., 2023).
We were able to detect AT8 immunoreactivity in the ADn even at "pre-Braak" stage 0. In fact, AT8 is such a reliable marker that we routinely use it to help find the ADn in brain sections of almost every human thalamus. We are quite confident that we can use AT8 in just a few sections of rostral thalamus to predict the cortical Braak stage (see first three figures). We are also curious about how ADn tau pathology relates to other subcortical brain regions such as the mammillary bodies, locus coeruleus, and dorsal raphe nuclei. The supplementary material of the paper includes a few examples of such pathology in relation to the ADn, from the same cases.
Furthermore, we also used double immunolabelling with immunogold and diaminobenzidine to localize, at the electron microscopic level, paired helical filaments of tau to specific subcellular domains, including to large vGLUT2+ terminals from the lateral mammillary body. This goes toward helping us understand how tau can spread across synapses.
We hope that the Alzforum community finds these results informative, and welcome replies to this comment.
References:
Allison SL, Fagan AM, Morris JC, Head D.
Spatial Navigation in Preclinical Alzheimer's Disease.
J Alzheimers Dis. 2016 Feb 9;52(1):77-90.
PubMed.
Braak H, Braak E.
Neuropathological stageing of Alzheimer-related changes.
Acta Neuropathol. 1991;82(4):239-59.
PubMed.
Braak H, Braak E.
Alzheimer's disease affects limbic nuclei of the thalamus.
Acta Neuropathol. 1991;81(3):261-8.
PubMed.
Colman L, Boyer E, Gérard T, Bierbrauer A, Kunz L, Sleegers K, Axmacher N, Lefèvre P, Hanseeuw BJ.
Path integration deficits related to Alzheimer’s disease pathology in clinically normal older adults.
Alzheimer's & Dementia, 2023, 19: e078924
Forno G, Lladó A, Hornberger M.
Going round in circles-The Papez circuit in Alzheimer's disease.
Eur J Neurosci. 2021 Nov;54(10):7668-7687. Epub 2021 Nov 2
PubMed.
Hort J, Laczó J, Vyhnálek M, Bojar M, Bures J, Vlcek K.
Spatial navigation deficit in amnestic mild cognitive impairment.
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4042-7.
PubMed.
Rüb U, Stratmann K, Heinsen H, Del Turco D, Ghebremedhin E, Seidel K, den Dunnen W, Korf HW.
Hierarchical Distribution of the Tau Cytoskeletal Pathology in the Thalamus of Alzheimer's Disease Patients.
J Alzheimers Dis. 2016;49(4):905-15.
PubMed.
Taube JS.
Head direction cells recorded in the anterior thalamic nuclei of freely moving rats.
J Neurosci. 1995 Jan;15(1 Pt 1):70-86.
PubMed.
Xuereb JH, Perry RH, Candy JM, Perry EK, Marshall E, Bonham JR.
Nerve cell loss in the thalamus in Alzheimer's disease and Parkinson's disease.
Brain. 1991 Jun;114 ( Pt 3):1363-79.
PubMed.
Comments
Oxford
I am curious what the Alzforum community thinks about tau pathology in the thalamus? Braak and Braak showed that the anterodorsal thalamic nucleus (ADn) is affected at very early stages (Braak and Braak, 1991) and is the most severely involved nucleus in the thalamus (Braak and Braak, 1991). This may explain why the ADn shows severe neurodegeneration in Alzheimer's disease (Xuereb et al., 1991). A more recent review also highlights the considerably dense and selective tau pathology in the ADn (Rüb et al., 2016).
The ADn is now well-known for its high density of head direction cells—neurons that are important for spatial orientation. But back in the early 1990s, the significance of ADn tau pathology was not realized, as ADn head direction cells were not reported until 1995 (Taube, 1995). We now know that disorientation is a very early sign of dementia, and disruption of ADn head direction cells might explain this symptom (e.g., Forno et al., 2021; Coughlan et al., 2018; Hort et al., 2007; Allison et al., 2016; Colman et al., 2023).
We were able to detect AT8 immunoreactivity in the ADn even at "pre-Braak" stage 0. In fact, AT8 is such a reliable marker that we routinely use it to help find the ADn in brain sections of almost every human thalamus. We are quite confident that we can use AT8 in just a few sections of rostral thalamus to predict the cortical Braak stage (see first three figures). We are also curious about how ADn tau pathology relates to other subcortical brain regions such as the mammillary bodies, locus coeruleus, and dorsal raphe nuclei. The supplementary material of the paper includes a few examples of such pathology in relation to the ADn, from the same cases.
Furthermore, we also used double immunolabelling with immunogold and diaminobenzidine to localize, at the electron microscopic level, paired helical filaments of tau to specific subcellular domains, including to large vGLUT2+ terminals from the lateral mammillary body. This goes toward helping us understand how tau can spread across synapses.
We hope that the Alzforum community finds these results informative, and welcome replies to this comment.
References:
Allison SL, Fagan AM, Morris JC, Head D. Spatial Navigation in Preclinical Alzheimer's Disease. J Alzheimers Dis. 2016 Feb 9;52(1):77-90. PubMed.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. PubMed.
Braak H, Braak E. Alzheimer's disease affects limbic nuclei of the thalamus. Acta Neuropathol. 1991;81(3):261-8. PubMed.
Colman L, Boyer E, Gérard T, Bierbrauer A, Kunz L, Sleegers K, Axmacher N, Lefèvre P, Hanseeuw BJ. Path integration deficits related to Alzheimer’s disease pathology in clinically normal older adults. Alzheimer's & Dementia, 2023, 19: e078924
Coughlan G, Laczó J, Hort J, Minihane AM, Hornberger M. Spatial navigation deficits - overlooked cognitive marker for preclinical Alzheimer disease?. Nat Rev Neurol. 2018 Aug;14(8):496-506. PubMed.
Forno G, Lladó A, Hornberger M. Going round in circles-The Papez circuit in Alzheimer's disease. Eur J Neurosci. 2021 Nov;54(10):7668-7687. Epub 2021 Nov 2 PubMed.
Hort J, Laczó J, Vyhnálek M, Bojar M, Bures J, Vlcek K. Spatial navigation deficit in amnestic mild cognitive impairment. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4042-7. PubMed.
Rüb U, Stratmann K, Heinsen H, Del Turco D, Ghebremedhin E, Seidel K, den Dunnen W, Korf HW. Hierarchical Distribution of the Tau Cytoskeletal Pathology in the Thalamus of Alzheimer's Disease Patients. J Alzheimers Dis. 2016;49(4):905-15. PubMed.
Taube JS. Head direction cells recorded in the anterior thalamic nuclei of freely moving rats. J Neurosci. 1995 Jan;15(1 Pt 1):70-86. PubMed.
Xuereb JH, Perry RH, Candy JM, Perry EK, Marshall E, Bonham JR. Nerve cell loss in the thalamus in Alzheimer's disease and Parkinson's disease. Brain. 1991 Jun;114 ( Pt 3):1363-79. PubMed.
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