Correction: Smart Soup, a Traditional Chinese Medicine Formula, Ameliorates Amyloid Pathology and Related Cognitive Deficits.

[This corrects the article DOI: 10.1371/journal.pone.0111215.].

Polysaccharides from Ganoderma lucidum Promote Cognitive Function and Neural Progenitor Proliferation in Mouse Model of Alzheimer's Disease.

Promoting neurogenesis is a promising strategy for the treatment of cognition impairment associated with Alzheimer's disease (AD). Ganoderma lucidum is a revered medicinal mushroom for health-promoting benefits in the Orient. Here, we found that oral administration of the polysaccharides and water extract from G. lucidum promoted neural progenitor cell (NPC) proliferation to enhance neurogenesis and alleviated cognitive deficits in transgenic AD mice. G. lucidum polysaccharides (GLP) also promoted self-renewal of NPC in cell culture. Further mechanistic study revealed that GLP potentiated activation of fibroblast growth factor receptor 1 (FGFR1) and downstream extracellular signal-regulated kinase (ERK) and AKT cascades. Consistently, inhibition of FGFR1 effectively blocked the GLP-promoted NPC proliferation and activation of the downstream cascades. Our findings suggest that GLP could serve as a regenerative therapeutic agent for the treatment of cognitive decline associated with neurodegenerative diseases.

ß-arrestin-1 contributes to brown fat function and directly interacts with PPARα and PPARγ.

The peroxisome proliferator-activated receptor (PPAR) family plays central roles in brown adipose tissue (BAT) adipogenesis and contributes to body temperature maintenance. The transcriptional activity of PPAR family has been shown to be tightly controlled by cellular signal networks. ß-arrestins function as major secondary messengers of G protein-coupled receptors (GPCR) signaling by functional interactions with diverse proteins. Here, we report that ß-arrestin-1 knock-out mice show enhanced cold tolerance. We found that ß-arrestin-1 directly interacts with PPARα and PPARγ through a LXXXLXXXL motif, while D371 in PPARα and L311/N312/D380 in PPARγ are required for their interactions with ß-arrestin-1. Further mechanistic studies showed that ß-arrestin-1 promotes PPARα- but represses PPARγ-mediated transcriptional activities, providing potential regulatory pathway for BAT function.

γ-Secretase Modulators and Inhibitors Induce Different Conformational Changes of Presenilin 1 Revealed by FLIM and FRET.

Elucidation of γ-secretase structure and dynamic conformational changes is of importance to drug discovery targeting this enzyme. Electron microscopy analyses provided important structural information, but the dynamic changes of γ-secretase in cells need to be explored further. We found that PS1 internal fluorescence resonance energy transfer (FRET) probes can incorporate into γ-secretase complex and possess secretase activity. Our results from fluorescence lifetime image microscopy (FLIM) and acceptor photobleaching FRET show different PS1 internal FRET when PS1 fluorescent probes expressed alone or with other secretase subunits Aph1aL, Nicastrin, and Pen2, indicating that PS1 internal FRET could be applied for probing conformational change of γ-secretase complex. Further, we accessed whether γ-secretase activity interfering compounds induced different conformational changes of PS1. Our results show that both γ-secretase modulators and inhibitors affect PS1 internal FRET but in different manners. These results demonstrate that FLIM and acceptor photobleaching FRET could be applied to monitor different PS1 conformational changes in γ-secretase.

Smart Soup, a traditional Chinese medicine formula, ameliorates amyloid pathology and related cognitive deficits.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes substantial public health care burdens. Intensive efforts have been made to find effective and safe disease-modifying treatment and symptomatic intervention alternatives against AD. Smart Soup (SS), a Chinese medicine formula composed of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP), is a typical prescription against memory deficits. Here, we assessed the efficacy of SS against AD. Oral administration of SS ameliorated the cognitive impairment of AD transgenic mice, with reduced Aß levels, retarded Aß amyloidosis and reduced Aß-induced gliosis and neuronal loss in the brains of AD mice. Consistently, SS treatment reduced amyloid-related locomotor dysfunctions and premature death of AD transgenic Drosophila. Mechanistic studies showed that RP reduced Aß generation, whereas AT and PRP exerted neuroprotective effects against Aß. Taken together, our study indicates that SS could be effective against AD, providing a practical therapeutic strategy against the disease.

ß-arrestin1 regulates γ-secretase complex assembly and modulates amyloid-ß pathology.

Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease in which the γ-secretase-mediated amyloid-ß (Aß) pathology plays an important role. We found that a multifunctional protein, ß-arrestin1, facilitated the formation of NCT/APH-1 (anterior pharynx-defective phenotype 1) precomplex and mature γ-secretase complex through its functional interaction with APH-1. Deficiency of ß-arrestin1 or inhibition of binding of ß-arrestin1 with APH-1 by small peptides reduced Aß production without affecting Notch processing. Genetic ablation of ß-arrestin1 diminished Aß pathology and behavioral deficits in transgenic AD mice. Moreover, in brains of sporadic AD patients and transgenic AD mice, the expression of ß-arrestin1 was upregulated and correlated well with neuropathological severity and senile Aß plaques. Thus, our study identifies a regulatory mechanism underlying both γ-secretase assembly and AD pathogenesis, and indicates that specific reduction of Aß pathology can be achieved by regulation of the γ-secretase assembly.