Browsing by Subject "Hyperphosphorylated tau protein"

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    Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules
    (Springer Nature, 2019-04) Falcon, Benjamin; Zivanov, Jasenko; Zhang, Wenjuan; Murzin, Alexey G.; Garringer, Holly J.; Vidal, Ruben; Crowther, R. Anthony; Newell, Kathy L.; Ghetti, Bernardino; Goedert, Michel; Scheres, Sjors H.W.; Pathology & Laboratory Medicine, IU School of Medicine
    Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1-3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4-7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro12-15. Similar to Alzheimer's disease12,14,16-18, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.
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    PAA, a novel metal chelator and metalloproteinase inhibitor significantly reduced amyloid plaque burden in an APP/tau mouse model of Alzheimer’s disease (AD)
    (Wiley, 2025-01-09) Schmued, Larry; Schmued, Calvert; Maloney, Bryan; Lahiri, Debomoy K.; Psychiatry, School of Medicine
    Background: Major contributors to AD pathogenesis include aggregates of amyloid‐β (Aβ) peptides, hyperphosphorylated tau protein, and neuroinflammation. No currently approved treatment stops or significantly slows the progression of AD. Nevertheless, one class of agents that has shown promise is metal chelators. For the assessment of a novel effect of oral administration of 1,10‐Phenanthroline‐5‐amine (PAA) on the severity of amyloid plaque load, we used a transgenic (Tg) mouse model with inserted human autosomally dominant (familial) AD genes: amyloid‐beta (Aβ) protein precursor (APP) and tau protein. Method: APP/Tau transgenic mice that model AD were allotted into one of two groups. The control group received no treatment while the experimental group received 1,10‐phenanthroline‐5‐amine (PAA) in their drinking water, starting at 4 months. All animals were sacrificed at 1 year of age, and their brains were stained with 2 different markers of amyloid plaques, Amylo‐Glo+ and HQ‐O, as we have recently described (Schmued et al, 2023). Result: PAA administered as a daily oral dose for 9 months resulted in no changes in weight or behavior and resulted in no observed pathologies. Control animals exhibited numerous dense core plaques throughout the neo‐ and allo‐cortical brain regions. PAA administered as a daily dose for 9 months resulted in roughly 2/3 the amyloid plaque burden compared to untreated transgenic mice. Conclusion: Oral daily dosing with PAA significantly reduced the amyloid plaque burden in transgenic AD model mice. The mode of action of PAA may be attributed to its ability to chelate transition metals and to inhibit either metalloprotease enzymes or the metal‐seeded auto aggregation of Aβ. The underlying mechanism for this protection is not fully known; one possible mechanism would be to inhibit the “metal‐seeding” of Aβ. Dyshomeostasis of certain transition metals in brain microenvironment contributes to amyloidosis. Although this dysregulation may be attributable to impaired metal transporter function, there exists no known treatment that would modify such dysfunction. Further research is underway to confirm these results in another mouse model of AD (APP/PS1). Altogether, reducing regional metal levels via chelation with PAA may be a feasible and viable strategy for suppressing the formation of amyloid plaques in AD patients.