Loss of synapses has been correlated with dementia in Alzheimer's disease (AD) as an early event during the disease progression. Hence, synaptogenesis and neurogenesis in adulthood could serve as a therapeutic target for the prevention and treatment of AD. Recently, we have demonstrated enhanced hippocampal neurogenesis by oral administration of Ginkgo biloba extract (EGb 761) to a mouse model of AD. This study aims to identify the constituents that contribute to EGb 761-induced neurogenesis. Among the constituents tested, bilobalide and quercetin significantly increased cell proliferation in the hippocampal neurons in a dose-dependent manner. Bilobalide and quercetin also enhanced phosphorylation of cyclic-AMP Response Element Binding Protein (CREB) in these cells, and elevated the levels of pCREB and, brain-derived neurotrophic factor in mice brain. Immunofluorescence staining of synaptic markers shows remarkable dendritic processes in hippocampal neurons treated with either quercetin or bilobalide. Furthermore, both constituents restored amyloid-beta oligomers (also known as ADDL)-induced synaptic loss and phosphorylation of CREB. The present findings suggest that enhanced neurogenesis and synaptogenesis by bilobalide and quercetin may share a common final signaling pathway mediated by phosphorylation of CREB. Despite a recent report showing that EGb 761 was insufficient in prevent dementia, its constituents still warrant future investigation.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that shows cognitive deficits and memory impairment. Extract from the leaves of Gotu Kola (Centella Asiatica) have been used as an alternative medicine for memory improvement in Indian Ayurvedic system of medicine for a long time. Although several studies have revealed its effect in ameliorating the cognitive impairment in rat models of AD and stimulating property on neuronal dendrites of hippocampal region, the molecular mechanism of Gotu Kola on neuroprotection still remains to be elucidated. In this study, we report that phosphorylation of cyclic AMP response element binding protein (CREB) is enhanced in both a neuroblastoma cell line expressing amyloid beta 1-42 (Aβ) and in rat embryonic cortical primary cell culture. In addition, the contribution of two major single components to the enhanced CREB phosphorylatioin was examined. Furthermore, inhibitors were applied in this study revealing that ERK/RSK signaling pathway might mediate this effect of Gotu Kola extract. Taken together, we provide a possible molecular mechanism for memory enhancing property of Gotu Kola extract for the first time.

Heat shock response, mediated by heat shock proteins, is a highly conserved physiological process in multicellular organisms for reestablishment of cellular homeostasis. Expression of heat shock factors and subsequent heat shock protein plays a role in protection against proteotoxicity in invertebrate and vertebrate models. Proteotoxicity due to β-amyloid peptide (Aβ) oligomerization has been linked to the pathogenesis of Alzheimer's disease. Previously, we demonstrated that progressive paralysis induced by expression of human Aβ 1-42 in transgenic C. elegans was alleviated by Aβ oligomer inhibitors ginkgo biloba extract and its constituents (Wu, et al., J. Neurosci 2006, 26:13102-13). In this study, we apply a protective heat shock to the transgenic C. elegans and demonstrate: 1) a remarkable delay in paralysis, 2) increased expression of small heat shock protein HSP16.2, and 3) significant reduction of Aβ oligomers in a heat shock timedependent manner. These results suggest that transient heat shock lessens Aβ toxicity by diminishing Aβ oligomerization, which provide a link between up regulation of endogenous chaperone proteins and protection against Aβ proteotoxicity in vivo.

Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are key angiogenic stimulators during normal development and wound healing, as well as in a variety of pathological conditions. Recent studies have demonstrated a synergistic effect of VEGF and PlGF in pathological angiogenesis and suggest a role for PlGF in amplifying VEGF action in endothelial cells. We show here in the mouse model of oxygen-induced retinopathy that VEGF is significantly increased (P < 0.01) in the retina at both the mRNA and protein levels. In this mouse model, PlGF was significantly upregulated in the retina at the protein level (P < 0.01) without a corresponding change in mRNA levels. In cultured human retinal and umbilical vein endothelial cells, VEGF induced the production of PlGF protein by over 10-fold (P < 0.01) in a dose-dependent manner through a post-transcriptional mechanism. The increased PlGF expression upon VEGF treatment was significantly reduced by inhibition of the protein kinase C (PKC) and MEK signaling pathways, as well as by treatment with the calcium ionophore A23187. Taken together, our findings demonstrate that VEGF can amplify its effects on endothelial cells by inducing the production of PlGF via a post-transcriptional mechanism in a PKC-dependent manner, and provide a potential link between PKC inhibition and amelioration of vascular complications in the development of angiogenic diseases.