The Beneficial Effects of Combining Anti-Aß Antibody NP106 and Curcumin Analog TML-6 on the Treatment of Alzheimer's Disease in APP/PS1 Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with a multifactorial etiology. A multitarget treatment that modulates multifaceted biological functions might be more effective than a single-target approach. Here, the therapeutic efficacy of combination treatment using anti-Aß antibody NP106 and curcumin analog TML-6 versus monotherapy was investigated in an APP/PS1 mouse model of AD. Our data demonstrate that both combination treatment and monotherapy attenuated brain Aß and improved the nesting behavioral deficit to varying degrees. Importantly, the combination treatment group had the lowest Aß levels, and insoluble forms of Aß were reduced most effectively. The nesting performance of APP/PS1 mice receiving combination treatment was better than that of other APP/PS1 groups. Further findings indicate that enhanced microglial Aß phagocytosis and lower levels of proinflammatory cytokines were concurrent with the aforementioned effects of NP106 in combination with TML-6. Intriguingly, combination treatment also normalized the gut microbiota of APP/PS1 mice to levels resembling the wild-type control. Taken together, combination treatment outperformed NP106 or TML-6 monotherapy in ameliorating Aß pathology and the nesting behavioral deficit in APP/PS1 mice. The superior effect might result from a more potent modulation of microglial function, cerebral inflammation, and the gut microbiota. This innovative treatment paradigm confers a new avenue to develop more efficacious AD treatments.

Protective Effects of Dietary Supplementation with a Combination of Nutrients in a Transgenic Mouse Model of Alzheimer's Disease.

OBJECTIVE: This study investigated the effects of intervention with a combination of nutrients in the amyloid precursor protein-presenilin (APP-PSN) C57BL/6J double transgenic mouse model of Alzheimer's disease (AD). METHODS: A total of 72 2-month-old APP-PSN mice were randomly assigned to three groups. The model group (MG) was fed regular, unsupplemented chow, while the low- and high-dose treatment groups (LG and HG, respectively) were given a combination of nutrients that included phosphatidylserine, blueberry extracts, docosahexaenoic acid, and eicosapentaenoic acid as part of their diet. An additional 24 wild-type littermates that were fed unsupplemented chow served as the negative control group (NG). After 3 and 7 months of treatment, the cognitive performance was assessed with the Morris water maze and the shuttle box escape/avoidance task, and the biochemical parameters and oxidative stress were evaluated in both the blood and brain. RESULTS: An improvement in antioxidant capacity was observed in the treatment groups relative to the MG at 3 months, while superior behavioral test results were observed in the mice of the HG and NG groups. In the MG, pycnosis was detected in neuronal nuclei, and a loss of neurons was observed in the cerebral cortex and the hippocampus. At 7 months, the ß-amyloid1-42 peptide accumulation was significantly elevated in the MG but was markedly lower in the mice fed the nutrient combination. The antioxidant capacity and behavioral test scores were also higher in these mice. CONCLUSIONS: Early intervention with a combination of nutrients should be considered as a strategy for preventing cognitive decline and other symptoms associated with AD.

Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice.

The present study investigated the relationships among oxidative stress, beta-amyloid and cognitive abilities in the APP/PSEN1 double-transgenic mouse model of Alzheimer's disease. In two experiments, long-term dietary supplements were given to aged APP/PSEN1 mice containing vitamin C alone (1 g/kg diet; Experiment 1) or in combination with a high (750 IU/kg diet, Experiments 1 and 2) or lower (400 IU/kg diet, Experiment 2) dose of vitamin E. Oxidative stress, measured by F(4)-neuroprostanes or malondialdehyde, was elevated in cortex of control-fed APP/PSEN1 mice and reduced to wild-type levels by vitamin supplementation. High-dose vitamin E with C was less effective at reducing oxidative stress than vitamin C alone or the low vitamin E+C diet combination. The high-dose combination also impaired water maze performance in mice of both genotypes. In Experiment 2, the lower vitamin E+C treatment attenuated spatial memory deficits in APP/PSEN1 mice and improved performance in wild-type mice in the water maze. Amyloid deposition was not reduced by antioxidant supplementation in either experiment.