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.