Early and Selective Localization of Tau Filaments to Glutamatergic Subcellular Domains within the Human Anterodorsal Thalamus

Neurology Medical Laboratory Science Medicine Cell Biology Biochemistry Life Sciences
Tau protein anterodorsal thalamus Alzheimer's disease VGluT2 neurodegenerative diseases paired helical filaments

Background

The main purpose of this study is to investigate the distribution and diffusion patterns of tau protein in the early stages of Alzheimer’s disease, with a particular focus on the vulnerability of calretinin-positive neurons in the anterodorsal thalamic nucleus of the human subcortical region and the accumulation of tau pathology protein (ptau). While many studies have concentrated on the cortical regions of Alzheimer’s disease, some subcortical regions such as the thalamus, locus coeruleus, and dorsal raphe nucleus also exhibit selective vulnerability to tau pathology. The ultimate goal of this study is to determine how tau pathology spreads within these regions at different stages of the disease and the role of cell subtype specificity and presynaptic terminals in the propagation of pathology.

Source

This study, titled “Early and Selective Localization of Tau Filaments to Glutamatergic Subcellular Domains within the Human Anterodorsal Thalamus,” was published in Acta Neuropathologica (2024, Vol. 147: 98-126). The main authors include Barbara Sárkány, Csaba Dávid, Tibor Hortobágyi, Péter Gombás, Peter Somogyi, László Acsády, and Tim J. Viney. The paper is a collaborative effort between the University of Oxford and several research institutions in Hungary. It was received on January 12, 2024, revised on May 21, 2024, and accepted for publication on June 1, 2024.

Research Process

Samples and Methods

The study collected 26 human brain samples from different brain banks, including the Human Brain Research Laboratory (Hungary), MRC London Neurodegenerative Diseases Brain Bank (King’s College London, UK), Queen Square Brain Bank for Neurological Disorders (University College London, UK), and Oxford Brain Bank (Oxford, UK). These samples were classified using standardized Braak staging, ranging from Braak stage 0 (no tau pathology) to Braak stage VI (late-stage Alzheimer’s pathology).

Study Details

  1. Tissue Processing:

    • Brain tissues were processed using various fixation methods such as perfusion-fixed, flash-frozen, and formalin-fixed paraffin-embedded techniques.
    • Immunohistochemistry experiments were conducted using anti-TAU protein antibodies (e.g., AT8, PHF1, and CP13).
    • The distribution of ptau in cells and cellular components was analyzed through optical and electron microscopy.

  2. Image Analysis and Quantification:

    • Images were analyzed using QuPath and Python software, with a pixel classifier used to quantify ptau coverage and the number of immunoreactive cells.
    • The proportion of presynaptic and postsynaptic elements containing ptau at different Braak stages was statistically analyzed.

Research Results

  1. Early Sensitivity of the Anterodorsal Thalamic Nucleus (ADN) to Tau Pathology:

    • In Braak stage 0, ptau was found in calretinin-positive neurons in the ADN region of control samples (64.3%).
    • In early-stage Alzheimer’s (Braak stages III-IV), the ADN region showed moderate levels of ptau accumulation (8.54% coverage, density of 11.65), which increased significantly in late stages (Braak stages V-VI) with ptau coverage reaching 36.31% and ptau+ neuron density reaching 118.89 cells/mm². This indicates a continuous and significant accumulation of tau pathology in the ADN region during Alzheimer’s Disease progression.

  2. Impact of Tau on Axon Terminals in the Anterodorsal Thalamus:

    • The distribution of tau, both at presynaptic terminals (particularly large presynaptic axon terminals positive for vesicular glutamate transporter 2 (VGluT2)) and postsynaptic terminals, was primarily concentrated in the ADN region.
    • Electron microscopy data showed that in mid and late-stage samples, 5-20% of presynaptic terminals were ptau-positive (mainly VGluT2+ axon terminals), while postsynaptic ptau positivity was 21.6% and 51.5%, respectively.

  3. Preliminary Exploration of Tau Diffusion Pathways:

    • The accumulation of ptau in VGluT2-positive axon terminals suggests possible synaptic transmission routes, particularly potential trans-synaptic pathways from the mammillary body to the ADN and from the ADN to the Retrosplenial cortex (RS).

  4. Selective Vulnerability of Cell Types:

    • Calretinin-positive neurons exhibited high sensitivity to tau in the very early stages of the disease (Braak Stage 0), accounting for a large proportion of ptau-positive cells in the ADN region (64.3%).
    • This finding highlights the significant impact of tau pathology in subcortical regions during Alzheimer’s Disease progression. The cell subtype specificity of the study provides potential new avenues for early targeted therapy for Alzheimer’s disease.

Conclusion

This study confirms the subtype and synapse-specific tau pathology in the ADN region during the early stages of Alzheimer’s disease, particularly at VGluT2-positive presynaptic axon terminals. The research demonstrates the progressive accumulation and spread of tau pathology during Alzheimer’s disease and suggests that the ADN may be a primary hub for early tau pathology. This finding is significant for a deeper understanding of the mechanisms of early-stage Alzheimer’s Disease and its systemic effects on other systems.

Comments and Prospects

This study makes a significant contribution to understanding the mechanisms of Alzheimer’s disease pathology in subcortical regions and highlights the special role of VGluT2-positive synapses in disease propagation. This provides new directions for future therapeutic strategies, which may involve early intervention by targeting these early affected neuron subtypes, potentially having significant clinical applications.