Abstract
Several plant-derived compounds have demonstrated efficacy in pre-clinical Alzheimer's disease (AD) rodent models. Each of these compounds share a gallic acid (GA) moiety, and initial assays on this isolated molecule indicated that it might be responsible for the therapeutic benefits observed. To test this hypothesis in a more physiologically relevant setting, we investigated the effect of GA in the mutant human amyloid β-protein precursor/presenilin 1 (APP/PS1) transgenic AD mouse model. Beginning at 12 months, we orally administered GA (20 mg/kg) or vehicle once daily for 6 months to APP/PS1 mice that have accelerated Alzheimer-like pathology. At 18 months of age, GA therapy reversed impaired learning and memory as compared with vehicle, and did not alter behavior in nontransgenic littermates. GA-treated APP/PS1 mice had mitigated cerebral amyloidosis, including brain parenchymal and cerebral vascular β-amyloid deposits, and decreased cerebral amyloid β-proteins. Beneficial effects co-occurred with reduced amyloidogenic and elevated nonamyloidogenic APP processing. Furthermore, brain inflammation, gliosis, and oxidative stress were alleviated. We show that GA simultaneously elevates α- and reduces β-secretase activity, inhibits neuroinflammation, and stabilizes brain oxidative stress in a pre-clinical mouse model of AD. We further demonstrate that GA increases abundance of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10, Adam10) proprotein convertase furin and activates ADAM10, directly inhibits β-site APP cleaving enzyme 1 (BACE1, Bace1) activity but does not alter Adam10 or Bace1 transcription. Thus, our data reveal novel post-translational mechanisms for GA. We suggest further examination of GA supplementation in humans will shed light on the exciting therapeutic potential of this molecule.
Highlights
Alzheimer’s disease (AD) irreversibly affects memory and cognition in the elderly, beginning with brain changes decades before dementia
That has anti-inflammatory and anti-oxidant properties [11], and we were interested in gallic acid (GA) because this moiety is present in other nutraceuticals that we have shown to be therapeutic in preclinical AD model mice [2,3,4,5]
We tested if administering oral GA therapy from 6 to 12 months of age to amyloid b-protein precursor/presenilin 1 (APP/PS1) mice modified cognitive function and AD-like pathology
Summary
Repeated-measures ANOVA followed by post hoc testing showed statistically significant differences between APP/PS1-V mice and the other three mouse groups (Fig. 1E; **, p , 0.01 for errors and *, p , 0.05 for escape latency). Mitigation of cerebral amyloid pathology by long-term GA oral treatment could be owed to 1) shifting equilibrium toward brain-to-blood Ab efflux [30], 2) decreasing expression of APP or PS1 transgenes, or 3) modulating APP cleavage To begin addressing these possibilities, we assayed plasma Ab1-40 and Ab1-42 species in peripheral blood samples from each APP/PS1 mouse group, but did not detect between-groups differences (data not shown). Was comparable between-groups, densitometry disclosed significantly elevated nonamyloidogenic APP processing to sAPPa in brain homogenates from GA- versus vehicle-treated APP/ PS1 mice (Fig. 4, A and B; ***, p , 0.001). We observed positive immunostaining for the astrocytic activation marker, glial fibrillary acidic protein (GFAP), and the structural marker of activated microglia, ionized calcium-binding adapter molecule 1 (Iba1), in glial somata and processes
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