PPARγ Dysfunction in the Medial Prefrontal Cortex Mediates High-Fat Diet-Induced Depression.

Epidemiological studies suggest a bidirectional association between depression and obesity; however, the biological mechanisms that link the development of depression to a metabolic disorder remain unclear. Even though nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) agonists show anti-depressive effect, and high-fat diet-(HFD)-induced PPARγ dysfunction is involved in the pathogenesis of metabolic disorders, the neuronal PPARγ has never been studied in HFD-induced depression. Thus, we aimed to investigate the effect of neuronal PPARγ on depressive-like behaviors in HFD-induced obese mice.We fed male C57BL/6 J mice with HFD to generate obese mice and conducted a series of behavioral tests to assess the effects of HFD feeding on depression. We generated neuron-specific PPARγ knockout mice (NKO) to determine whether neuronal PPARγ deficiency was correlated with depressive-like behaviors. To further prove whether PPARγ in the medial prefrontal cortex (mPFC) neurons is involved in depressive-like behaviors, we applied AAV- CaMKIIα-Cre approach to specifically knockout PPARγ in the mPFC neurons of LoxP mice and used AAV-syn-PPARγ vectors to overexpress PPARγ in the mPFC neurons of NKO mice.We observed a low mPFC PPARγ level and an increase in depressive-like behaviors in the HFD-fed mice. Moreover, neuronal-specific PPARγ deficiency in mice induced depressive-like behaviors, which could be abolished by imipramine. Furthermore, overexpressing PPARγ in the mPFC reversed the depressive-like behaviors in HFD-fed mice as well as in neuronal-specific PPARγ knockout mice.These results implicate that dysregulation of neuronal PPARγ in the mPFC may contribute to an increased risk for depression in obese populations.

Toxic amyloid-ß oligomers induced self-replication in astrocytes triggering neuronal injury.

BACKGROUND: Soluble amyloid-ß oligomer (AßO) induced deleterious cascades have recently been considered to be the initiating pathologic agents of Alzheimer's disease (AD). However, little is known about the neurotoxicity and production of different AßOs. Understanding the production and spread of toxic AßOs within the brain is important to improving understanding of AD pathogenesis and treatment. METHODS: Here, PS1V97L transgenic mice, a useful tool for studying the role of AßOs in AD, were used to identify the specific AßO assembly that contributes to neuronal injury and cognitive deficits. Then, we investigated the production and spread of toxic Aß assemblies in astrocyte and neuron cultures, and further tested the results following intracerebroventricular injection of AßOs in animal model. FINDINGS: The results showed that cognitive deficits were mainly caused by the accumulation of nonameric and dodecameric Aß assemblies in the brains. In addition, we found that the toxic AßOs were duplicated in a time-dependent manner when BACE1 and apolipoprotein E were overexpressed, which were responsible for producing redundant Aß and forming nonameric and dodecameric assemblies in astrocytes, but not in neurons. INTERPRETATION: Our results suggest that astrocytes may play a central role in the progression of AD by duplicating and spreading toxic AßOs, thus triggering neuronal injury. FUND: This study was supported by the Key Project of the National Natural Science Foundation of China; the National Key Scientific Instrument and Equipment Development Project; Beijing Scholars Program, and Beijing Brain Initiative from Beijing Municipal Science & Technology Commission.

Sulforaphane Inhibits the Generation of Amyloid-ß Oligomer and Promotes Spatial Learning and Memory in Alzheimer's Disease (PS1V97L) Transgenic Mice.

Abnormal amyloid-ß (Aß) aggregates are a striking feature of Alzheimer's disease (AD), and Aß oligomers have been proven to be crucial in the pathology of AD. Any intervention targeting the generation or aggregation of Aß can be expected to be useful in AD treatment. Oxidative stress and inflammation are common pathological changes in AD that are involved in the generation and aggregation of Aß. In the present study, 6-month-old PS1V97L transgenic (Tg) mice were treated with sulforaphane, an antioxidant, for 4 months, and this treatment significantly inhibited the generation and aggregation of Aß. Sulforaphane also alleviated several downstream pathological changes that including tau hyperphosphorylation, oxidative stress, and neuroinflammation. Most importantly, the cognition of the sulforaphane-treated PS1V97L Tg mice remained normal compared to that of wild-type mice at 10 months of age, when dementia typically emerges in PS1V97L Tg mice. Pretreating cultured cortical neurons with sulforaphane also protected against neuronal injury caused by Aß oligomers in vitro. These findings suggest that sulforaphane may be a potential compound that can inhibit Aß oligomer production in AD.

Brain Amyloid-ß Plays an Initiating Role in the Pathophysiological Process of the PS1V97L-Tg Mouse Model of Alzheimer's Disease.

Amyloid-ß (Aß) aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation are major pathophysiological events in Alzheimer's disease (AD). However, the relationships among these processes and which first exerts an effect are unknown. In the present study, we investigated age-dependent behavioral changes and the sequential pathological progression from the brain to the periphery in AD transgenic (PS1V97L-Tg) mice and their wild-type littermates. We discovered that the brain Aß significantly increased at 6 months old, the increased brain Aß caused memory dysfunction, and the ability of Aß to induce tau hyperphosphorylation might be due to oxidative stress and neuroinflammatory reactions. The levels of Aß42, total tau (t-tau), oxidative stress parameters, and proinflammatory cytokines in plasma can be used to differentiate between PS1V97L-Tg mice and their wild-type littermates at different time points. Collectively, our findings support the hypothesis that Aß is a trigger among these pathophysiological processions and show that plasma biomarkers can reflect the condition of the AD brain.