Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease

Lilek, Jaclyn; Ajroud, Kaouther; Feldman, Alexander; Krishnamachari, Sesha; Ghourchian, Shadi; Gefen, Tamar; Spencer, Callen; Kawles, Allegra; Mao, Qinwen; Tranovich, Jessica F.; Jack, Clifford R.; Mesulam, M-Marsel; Reichard, R. Ross; Zhang, Hui; Murray, Melissa E.; Knopman, David S.; Dickson, Dennis W.; Petersen, Ronald C.; Smith, Benjamin R.; Ashe, Karen H.; Mielke, Michelle M.; Nelson, Kathryn M.; Flanagan, Margaret E.

doi:10.3233/jad-220848

Cited by 8 publications

(6 citation statements)

References 59 publications

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“…To characterize the effects of Nanoligomer treatment on tau, we performed immunohistochemistry on hippocampus and frontal cortex sections from control and treated rTg4510 mice. We imaged and quantified two insoluble tau residues (phosphorylated at threonine-181 and threonine-231), which have been associated with AD pathology and progression [35,36]. We found that these tau species increased in hippocampus and cortex of rTg4510 mice, similar to what others have reported in other tauopathy models [37,38], and that this effect was attenuated with Nanoligomer treatment (Figure 4).…”

Section: Broad Nanoligomer-induced Reductions In Neuroinflammation Co...supporting

confidence: 81%

“…First, we found that reduced neuroinflammation with NF-κB/NLRP3-targeting Nanoligomers was associated with reductions in phosphorylated tau in the rTg4510 mouse hippocampus. These insoluble tau residues (phosphorylated at threonine-181 and threonine-231) have been associated with cognitive dysfunction and AD pathology/progression [35, 36]. Because aggressive, transgene-driven expression of tau occurs in rTg4510 mice at young ages, our findings may suggest that the treatment protected against tau-induced NF-κB/NLRP3 activation that further promotes pathology in these animals.…”

Section: Discussionmentioning

confidence: 88%

“…Importantly, tau pathology can both activate and be exacerbated by NF-κB and NLRP3 [34][35][36], driving cycles of inflammation-mediated tau propagation and toxicity [37], and phosphorylated (activated) tau is closely associated with cognitive dysfunction [38]. To characterize the effects of Nanoligomer treatment on tau, we performed immunohistochemistry for two insoluble tau residues (phosphorylated at threonine-181 and threonine-231) that have been associated with AD pathology and progression [39,40]. We found that these tau species increased in hippocampus and cortex of rTg4510 mice, similar to what others have reported in other tauopathy models [41,42], and that this effect was attenuated with Nanoligomer treatment (Figure 4A).…”

Section: Reductions In Phosphorylated Tau With Nanoligomer Treatmentmentioning

confidence: 99%

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Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Wahl,

Risen,

Osburn

et al. 2024

Preprint

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Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. Here, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old wildtype mice, and in a mouse model of tauopathy. We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and tauopathy mice. These effects of NF-κB/NLRP3-targeting Nanoligomer treatment were associated with reduced glial cell activation in old wildtype mice, less pathology in tauopathy mice, favorable changes in transcriptome signatures of inflammation (reduced) and neuronal health (increased) in both mouse models, and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting NF-κB/NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegenerative disease.

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Section: Broad Nanoligomer-induced Reductions In Neuroinflammation Co...supporting

confidence: 81%

Section: Discussionmentioning

confidence: 88%

Section: Reductions In Phosphorylated Tau With Nanoligomer Treatmentmentioning

confidence: 99%

See 1 more Smart Citation

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Wahl,

Risen,

Osburn

et al. 2024

Preprint

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“…Different Tau species (oligomeric, misfolded and phosphorylated) colocalize with PSD-95 at the postsynaptic site in human postmortem samples 29 . Consistent with these findings, colocalization of phosphorylated Tau and PSD-95 increases during Alzheimer’s disease progression across clinically stratified groups (normal, mild cognitive impairment, Alzheimer’s disease) in the frontal cortex 30 . Additionally, signals of AT8, AT100, and AT180 antibodies, which recognize phosphoepitopes that are abundant in pathological aggregated and filamentous Tau of Alzheimer’s disease, are elevated in Tau transgenic mice, in particular in PSD fractions 31 .…”

Section: Introductionsupporting

confidence: 72%

Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density

Shen,

Sun,

Savastano

et al. 2023

Nat Commun

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Alzheimer’s disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer’s disease has been associated with the localization of the microtubule-associated protein Tau at the postsynapse. However, the correlation between Tau at the postsynapse and synaptic dysfunction remains unclear. Here, we show that Tau arrests liquid-like droplets formed by the four postsynaptic density proteins PSD-95, GKAP, Shank, Homer in solution, as well as NMDA (N-methyl-D-aspartate)-receptor-associated protein clusters on synthetic membranes. Tau-mediated condensate/cluster arrest critically depends on the binding of multiple interaction motifs of Tau to a canonical GMP-binding pocket in the guanylate kinase domain of PSD-95. We further reveal that competitive binding of a high-affinity phosphorylated peptide to PSD-95 rescues the diffusional dynamics of an NMDA truncated construct, which contains the last five amino acids of the NMDA receptor subunit NR2B fused to the C-terminus of the tetrameric GCN4 coiled-coil domain, in postsynaptic density-like condensates/clusters. Taken together, our findings propose a molecular mechanism where Tau modulates the dynamic properties of the postsynaptic density.

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“…The increase in its levels ranged from 2-fold in plasma and serum to up to 5-fold in CSF [76]. Lilek et al [115] showed evidence that p-tau231 primarily accumulates at the postsynaptic density, and this occurs in an early, often presymptomatic stage of the disease. The study of Montoliu-Gaya et al [108] indicated that p-tau231 increased significantly along the AD continuum and that its levels did not increase in MCI and demented patients without AD pathology.…”

Section: P-tau231 Is Probably the Earliest Ad Biomarkermentioning

confidence: 99%

Evaluating p-tau217 and p-tau231 as Biomarkers for Early Diagnosis and Differentiation of Alzheimer’s Disease: A Narrative Review

Jarek,

Mizerka,

Nuszkiewicz

et al. 2024

Biomedicines

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The escalating prevalence of Alzheimer’s disease (AD) highlights the urgent need to develop reliable biomarkers for early diagnosis and intervention. AD is characterized by the pathological accumulation of amyloid-beta plaques and tau neurofibrillary tangles. Phosphorylated tau (p-tau) proteins, particularly p-tau217 and p-tau231, have been identified as promising biomarker candidates to differentiate the disease progression from preclinical stages. This narrative review is devoted to a critical evaluation of the diagnostic accuracy, sensitivity, and specificity of p-tau217 and p-tau231 levels in the detection of AD, measured in plasma, serum, and cerebrospinal fluid, compared to established biomarkers. Additionally, the efficacy of these markers in distinguishing AD from other neurodegenerative disorders is examined. The significant advances offered by p-tau217 and p-tau231 in AD diagnostics are highlighted, demonstrating their unique utility in early detection and differential diagnosis. This comprehensive analysis not only confirms the excellent diagnostic capabilities of these markers, but also deepens the understanding of the molecular dynamics of AD, contributing to the broader scientific discourse on neurodegenerative diseases. This review is aimed to provide key information for researchers and clinicians across disciplines, filling interdisciplinary gaps and highlighting the role of p-tau proteins in revolutionizing AD research and clinical practice.

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Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease

Cited by 8 publications

References 59 publications

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density

Evaluating p-tau217 and p-tau231 as Biomarkers for Early Diagnosis and Differentiation of Alzheimer’s Disease: A Narrative Review

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