Abstract

To date, there is no effective Alzheimer's disease (AD)-modifying therapy. Nonetheless, combination therapy holds promise, and nutraceuticals (natural dietary compounds with therapeutic properties) and their synthetic derivatives are well-tolerated candidates. We tested whether combination therapy with octyl gallate (OG) and ferulic acid (FA) improves cognition and mitigates AD-like pathology in the presenilin-amyloid β-protein precursor (PSAPP) transgenic mouse model of cerebral amyloidosis. One-year-old mice with established β-amyloid plaques received daily doses of OG and FA alone or in combination for 3 months. PSAPP mice receiving combination therapy had statistically significant improved cognitive function versus OG or FA single treatment on some (but not all) measures. We also observed additional statistically significant reductions in brain parenchymal and cerebral vascular β-amyloid deposits as well as brain amyloid β-protein abundance in OG- plus FA-treated versus singly-treated PSAPP mice. These effects coincided with enhanced nonamyloidogenic amyloid β-protein precursor (APP) cleavage, increased α-secretase activity, and β-secretase inhibition. We detected elevated expression of nonamyloidogenic soluble APP-α and the α-secretase candidate, a disintegrin and metalloproteinase domain-containing protein 10. Correspondingly, amyloidogenic β-carboxyl-terminal APP fragment and β-site APP-cleaving enzyme 1 expression levels were reduced. In parallel, the ratio of β- to α-carboxyl-terminal APP fragment was decreased. OG and FA combination therapy strikingly attenuated neuroinflammation, oxidative stress, and synaptotoxicity. Co-treatment afforded additional statistically significant benefits on some, but not all, of these outcome measures. Taken together, these data provide preclinical proof-of-concept for AD combination therapy.

Highlights

  • To date, there is no effective Alzheimer’s disease (AD)-modifying therapy

  • We tested whether combination therapy with octyl gallate (OG) and ferulic acid (FA) improves cognition and mitigates AD-like pathology in the presenilin-amyloid ␤-protein precursor (PSAPP) transgenic mouse model of cerebral amyloidosis

  • We previously reported that OG promotes nonamyloidogenic processing of both human wild-type (WT) and “Swedish” mutant forms of APP via estrogen receptor-mediated a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) activation

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Summary

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FA is generated by the metabolism of phenylalanine and tyrosine, and it is found both in free form and covalently linked to lignin and other biopolymers The compound has both anti-inflammatory and anti-oxidant properties [15], and our previous report showed that oral FA treatment for 6 months remediates behavioral impairment, reduces amyloidogenic APP metabolism by modulating ␤-secretase, and mitigates AD-like pathology in the PSAPP transgenic mouse model of cerebral amyloidosis [11]. Both OG and FA have low molecular weights, are cell-permeable, and are highly bioavailable. For some (but not all) measures, results showed additional benefit afforded by combination therapy

Results
Discussion
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