Browsing by Author "Schmued, Larry"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    Treatment with 1, 10 Phenanthroline-5-Amine Reduced Amyloid Burden in a Mouse Model of Alzheimer’s Disease
    (IOS Press, 2024) Schmued, Larry; Maloney, Bryan; Schmued, Calvert; Lahiri, Debomoy K.; Psychiatry, School of Medicine
    Background: Alzheimer's disease (AD) is the most prevalent age-related dementia, and, despite numerous attempts to halt or reverse its devastating progression, no effective therapeutics have yet been confirmed clinically. However, one class of agents that has shown promise is certain metal chelators. Objective: For the novel assessment of the 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-β protein precursor (AβPP) and tau. Methods: AβPP/Tau transgenic mice that model AD were allotted into one of two groups. The control group received no treatment while the experimental group received PAA in their drinking water starting at 4 months of age. All animals were sacrificed at 1 year of age and their brains were stained with two different markers of amyloid plaques, Amylo-Glo+ and HQ-O. Results: The control animals exhibited numerous dense core plaques throughout the neo- and allo- cortical brain regions. The experimental group treated with PAA, however, showed 62% of the amyloid plaque burden seen in the control group. Conclusions: Oral daily dosing with PAA will significantly reduce the amyloid plaque burden in transgenic mice that model AD. The underlying mechanism for this protection is not fully known; however, one proposed mechanism involves inhibiting the "metal-seeding" of Aβ.