Abstract
"Nutraceuticals" are well-tolerated natural dietary compounds with drug-like properties that make them attractive as Alzheimer's disease (AD) therapeutics. Combination therapy for AD has garnered attention following a recent National Institute on Aging mandate, but this approach has not yet been fully validated. In this report, we combined the two most promising nutraceuticals with complementary anti-amyloidogenic properties: the plant-derived phenolics (-)-epigallocatechin-3-gallate (EGCG, an α-secretase activator) and ferulic acid (FA, a β-secretase modulator). We used transgenic mice expressing mutant human amyloid β-protein precursor and presenilin 1 (APP/PS1) to model cerebral amyloidosis. At 12 months of age, we orally administered EGCG and/or FA (30 mg/kg each) or vehicle once daily for 3 months. At 15 months, combined EGCG-FA treatment reversed cognitive impairment in most tests of learning and memory, including novel object recognition and maze tasks. Moreover, EGCG- and FA-treated APP/PS1 mice exhibited amelioration of brain parenchymal and cerebral vascular β-amyloid deposits and decreased abundance of amyloid β-proteins compared with either EGCG or FA single treatment. Combined treatment elevated nonamyloidogenic soluble APP-α and α-secretase candidate and down-regulated amyloidogenic soluble APP-β, β-C-terminal APP fragment, and β-secretase protein expression, providing evidence for a shift toward nonamyloidogenic APP processing. Additional beneficial co-treatment effects included amelioration of neuroinflammation, oxidative stress, and synaptotoxicity. Our findings offer preclinical evidence that combined treatment with EGCG and FA is a promising AD therapeutic approach.
Highlights
We further reported that FA reverses cognitive/behavioral deficits and mitigates Alzheimer’s disease (AD)-like pathology after 6 months of oral treatment in a transgenic mouse model of cerebral amyloidosis, and it alters amyloidogenic -secretase amyloid -protein precursor (APP) cleavage in mutant APP-overexpressing neuron-like cells [10]
APP/PS1EGCG/FA mice presented with additional reductions across all three plaque sizes and brain regions compared with either single treatment (Fig. 3, D–F; Tables S7–S9; †, p Ͻ 0.05; ††, p Ͻ 0.01); effects were independent of sex
Combination therapy exhibited further reduction compared with EGCG or FA treatment alone (Fig. 9, C–E; Table S14; †††, p Ͻ 0.001). These results demonstrate that EGCG plus FA combination therapy stabilizes neuroinflammation and oxidative stress in APP/presenilin 1 (PS1) mouse brains
Summary
Co-treatment with EGCG and FA reverses learning and memory impairment in APP/PS1 mice. Lowed by post hoc testing revealed statistically significant differences for total arm entries between APP/PS1-V mice and the other seven mouse groups (Fig. 1B, left; Table S2; *, p Ͻ 0.05). One-way ANOVA followed by post hoc testing showed statistically significant differences on Y-maze spontaneous alternation between APP/PS1-V mice and the other seven mouse groups (Fig. 1B, right; Table S2; *, p Ͻ 0.05). Repeated-measures ANOVA followed by post hoc assessment disclosed statistically significant differences between APP/PS1-V mice and the other seven mouse groups (Fig. 1, C and D, left; Tables S3 and S5; *, p Ͻ 0.05 for both errors and escape latency). APP/PS1EGCG/FA mice presented with additional reductions across all three plaque sizes and brain regions compared with either single treatment (Fig. 3, D–F; Tables S7–S9; †, p Ͻ 0.05; ††, p Ͻ 0.01); effects were independent of sex (data not shown). All three mouse treatment groups had decreased reactive astrocytes and microglia, and sAPP-α/APP ratio
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