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Amyloid-β (Aβ) accumulation caused by an imbalance of the production and clearance of Aβ in the brain is associated with the development of Alzheimer's disease (ad). Apolipoprotein E (ApoE) (the strongest genetic risk factor) enhances Aβ clearance, preventing Aβ deposition. Sirtuin 2 (Sirt2) is an NAD+-dependent histone deacetylase and its inhibition has been reported to ameliorate memory impairment in ad -like model mice. However, the role of Sirt2 in ApoE secretion is unknown. Here, we found that inhibition of Sirt2 activity in primary cultured astrocytes and BV2 cells decreased ApoE secretion, resulting in the accumulation of intracellular ApoE and inhibiting extracellular Aβ degradation. However, the reduction of Sirt2 protein level by Sirt2 siRNA decreased ApoE protein level, which ultimately reduces ApoE secretion. In addition, the knockdown of Sirt2 in the HEK293-APP cells also decreased levels of intracellular ApoE leading to reduction of its secretion, which is accompanied by increased Aβ levels without altering APP and APP processing enzymes. Our findings provide a novel role of Sirt2 in ApoE secretion. [ABSTRACT FROM AUTHOR]

We previously demonstrated that the Alzheimer's disease (AD)-like model mice, Tg2576, housed at a high ambient temperature of 30 °C for 13 months, exhibited increased body temperature, which increased amyloid-β (Aβ) levels and tau stability, leading to tau phosphorylation and ultimately inducing memory impairment. Here, we aimed to exclude the possible effect of environmental factors associated with the difference in ambient temperature (23 °C vs. 30 °C) and to further clarify the effects of elevated body temperature on AD-like pathologies. We generated uncoupling protein 1 (UCP1) deletion in Tg2576 mice, Tg2576/UCP1−/−, because UCP1 deletion mice show a sustained rise in body temperature at normal room temperature. As expected, the body temperature in Tg2576/UCP1−/− mice was higher than that in Tg2576/ UCP1+/+ mice at 23 °C, which was accompanied by upregulated Aβ levels due to increased β-secretase (BACE1) and decreased neprilysin (NEP) protein levels in the brains of Tg2576/UCP1−/− mice compared with those in the Tg2576/ UCP1+/+ mice. Elevated body temperature also increased total tau levels, leading to enhanced phosphorylation, heat shock protein induction, and activated tau kinases. Furthermore, elevated body temperature enhanced glial activation and decreased synaptic protein levels in the brain. Taken together, these findings demonstrate that elevated body temperatures exacerbate AD-like pathologies. [ABSTRACT FROM AUTHOR]

Lactoferrin (LF) is present in senile plaques and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients and amyloid-β protein precursor transgenic (AβPP-Tg) mice. LF has anti-inflammatory and antioxidant functions, which exert neuroprotective effects against AD. However, its effects on memory impairment and AD pathogenesis have not been fully examined. In this study, we examined the effects of LF on memory impairment and AD pathogenesis in AβPP-Tg mice (J20 mice). Nine-month-old J20 mice were fed with control, 2% lactoferrin-containing (LF), and 0.5% pepsin-hydrolyzed lactoferrin-containing (LF-hyd) diets for 3 months. We found that both the LF and LF-hyd diets attenuated memory impairment in J20 mice and decreased brain Aβ40 and Aβ42 levels through the inhibition of amyloidogenic processing of AβPP, as it decreased β-site amyloid protein precursor cleaving enzyme 1 (BACE1) levels. Furthermore, we found for the first time that LF and LF-hyd treatments increased both ApoE secretion and ATP-binding cassette A1 (ABCA1) protein levels in the brains of J20 mice and in primary astrocyte cultures. Moreover, LF and LF-hyd promoted extracellular degradation of Aβ in primary astrocyte cultures. These findings indicate that the reduction in Aβ levels in the brains of mice fed with both the LF and LF-hyd diets may also be mediated by increased ApoE secretion and ABCA1 protein levels, which in turn leads to the enhanced degradation of Aβ in the brains of J20 mice. Our findings suggest that LF and LF-hyd can be used for the treatment and/or prevention of the development of AD. [ABSTRACT FROM AUTHOR]