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J Alzheimers Dis
2026 Feb 09;:13872877261416524. doi: 10.1177/13872877261416524.
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Regional correlates of tau pathology and synaptic function in primary age-related tauopathy.
Kadamangudi S, Sanchez-Sanchez L, Limon A, Taglialatela G.
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BackgroundEmerging studies implicate the microtubule-associated protein tau as a key modulator of neuronal excitability and synaptic dysfunction in human tauopathies. How distinct tau forms influence synaptic excitability across brain regions with differing susceptibility to tau accumulation remains unclear. Primary age-related tauopathy (PART), defined by hippocampal-restricted tau pathology in the absence of amyloid-β, offers a tractable model to investigate tau-specific effects on synaptic physiology.ObjectiveTo determine how regionally enriched tau species in PART relate to synaptic excitation-inhibition balance and to identify molecular pathways linking tau oligomers to synaptic dysfunction.MethodsAutopsy-derived hippocampal and superior middle temporal gyrus tissues from neuropathologically validated PART specimens were analyzed. Tau species, including monomers, oligomers, and paired helical filaments (PHFs), were quantified by western blot. Synaptic function was assessed by microtransplantation of synaptosomal membranes into Xenopus laevis oocytes, followed by electrophysiological recordings of glutamatergic (kainate-evoked AMPAR) and GABAergic (GABAAR) currents to calculate the synaptic excitation-to-inhibition (sE/I) ratio. Proteomic and enrichment analyses of brain-derived tau oligomer (BDTO) interactomes from PART hippocampi were performed.ResultsPART specimens showed hippocampal accumulation of aggregation-prone tau assemblies (oligomeric and PHF-tau) that were negatively correlated with sE/I. Proteins within the BDTO interactome linked to reduced sE/I were enriched for pathways related to vesicle-mediated transport, synaptic endocytosis, and neurotransmitter receptor regulation.ConclusionsIn PART, oligomeric and fibrillar tau are associated with shift toward synaptic inhibition, predominantly within the hippocampus. Proteomic correlates implicate vesicle trafficking pathways as mediators of tau oligomer-associated alterations in synaptic function, providing mechanistic insight into early-stage tauopathy.
Figure 1. Schematic of experimental design and techniques. Overview of the experimental workflow used to investigate associations between tau pathology and synaptic function in PART brain specimens. Frozen autopsy-derived hippocampal and superior middle temporal gyrus (SMTG) samples were processed for either synaptosome isolation (right pathway) or tissue lysate preparation (left pathway). Left pathway: western blot analysis was performed to quantify tau oligomers (O), monomers (M), and total tau (T) using antibodies targeting AT180, PHF13.6, Tau5, and Tau13. Right pathway: Synaptosomes isolated from individual brain specimens were microtransplanted into Xenopus laevis oocytes. Two-electrode voltage-clamp (TEVC) recordings were used to measure ligand-gated synaptic currents using kainate (E), GABA (I) as agonists and to calculate sE/I ratio. Bottom: Correlations between tau measures and synaptic function were performed with brain regions (hippocampus and SMTG) pooled or analyzed separately. (Color figure available online).
Figure 2. Regional differences in tau pathology in PART brain specimens. Tissue lysates from PART patients (n = 7) were analyzed via western blot to compare tau burden between the hippocampus and SMTG. Each lane (15 μg of protein) represents an individual patient, with paired comparisons across brain regions (lanes 1–7: hippocampus; lanes 8–14: SMTG from the same patient). Tau species were delineated using antibodies against hyperphosphorylated tau (AT180), PHF-tau (PHF13.6), and total tau (Tau13, Tau5). Specific areas of quantification (AOQ) were applied to distinguish tau oligomers (red), monomers (green), and total tau (blue), as outlined in the figure legend. Quantifications (right) display relative abundance for oligomeric (O), monomeric (M), and total (T) tau normalized to β-Actin. Phospho-tau signals (AT180, PHF13.6) were further normalized to total tau (Tau5 or Tau13). Normality was assessed using the Shapiro-Wilk test (Supplemental Table 3), and statistical significance was determined using paired t-tests or Wilcoxon signed-rank tests (α = 0.05), with *p < 0.05 indicating significant differences. (Color figure available online).
Figure 3. Regional differences in synaptic excitation and inhibition in PART brain specimens. TEVC recordings of glutamatergic and GABAergic synaptic responses in hippocampal and SMTG synaptosomes from PART (f – j; n = 7) patients. (Top) Representative traces depict ligand-gated currents evoked by kainate [100 µM] and GABA [1 mM] in Xenopus oocytes microtransplanted with human synaptic receptors. (Bottom) Quantification of kainate-activated AMPAR and GABA-activated GABAAR currents, along with the sE/I ratio, in hippocampal and SMTG samples. Paired comparisons reflect interregional differences within each patient. Normality was assessed using the Shapiro-Wilk test, two-tailed (Supplemental Table 3), and statistical significance was determined using paired t-tests or Wilcoxon signed-rank tests (α = 0.05), with *p < 0.05 indicating significance.
Figure 4. Associations between tau and synaptic function in PART. Correlation analyses were conducted to assess the relationship between tau burden and sE/I ratio in PART cases. a, b. Correlations using pooled data from both hippocampus and SMTG; c, d. Region-specific correlations analyzed separately for hippocampus and SMTG. Data points are color-coded by region (Hippo.—pink, SMTG—green), with solid lines indicating best-fit correlations. Only significant correlations (and their regional counterparts) are shown; all others are reported in Supplemental Table 5. The sE/I ratio is plotted against relevant tau correlates, namely a. Tau5-O, b. PHF-M. The correlation coefficient (r or ρ based on respective normality measures; Supplemental Table 3) and p-values are displayed for each analysis, with significant correlations (p < 0.05) marked by an orange asterisk. (Color figure available online).
Figure 5. Pathway enrichment and protein-protein interaction analysis of sE/I-associated proteins in the PART BDTO interactome. Enrichment analysis of 38 proteins identified from the protein interactome of brain-derived tau oligomers (BDTO), isolated from individual PART hippocampal specimens (n = 4), that were associated with decreased sE/I. Proteins included in the analysis were those negatively correlated with excitatory currents, positively correlated with inhibitory currents, or negatively correlated with the sE/I ratio. The complete list of proteins is provided in Supplemental Table 6. a. Pathway enrichment analysis using Metascape, incorporating GO terms from multiple databases. Bars represent the most significantly enriched pathways, ranked by -log10(p-value). b. Protein-protein interaction (PPI) network analysis of sE/I-associated proteins constructed using the STRING database via Metascape. Nodes represent individual proteins, and edges represent known interactions. (Right) The top three most significantly enriched pathways within the PPI network, with pathway descriptions and log10(p-value) scores. C. Functional enrichment analysis via SynGO, specifically assessing synapse-related biological processes and cellular components. Sunburst plots represent hierarchical enrichment, with ‘top-level terms’ in the innermost ring with subcategories (i.e., ‘second-level terms’) radiating outward. Color-coded segments indicate significantly enriched synaptic compartments and pathways associated with BDTO. Individual proteins comprising enriched pathways are listed within dashed boxes. (Color figure available online).
