Rosmarinic acid and ursolic acid alleviate deficits in cognition, synaptic regulation and adult hippocampal neurogenesis in an Aß1-42-induced mouse model of Alzheimer's disease.

BACKGROUND: Rosmarinus officinalis, commonly known as rosemary, is a medicinal herb that presents significant biological properties such as antimicrobial, antioxidant, anti-inflammatory, anti-diabetic and anti-depressant activities. Recent findings correlate impaired adult neurogenesis, which is crucial for the maintenance of synaptic plasticity and hippocampal functioning, synaptic regulation with the pathological hallmarks of Alzheimer's disease (AD). These observations call for the need to developing compounds that promote neurogenesis and alleviates deficits in cognition and synaptic regulation. PURPOSE AND STUDY DESIGN: The present study was conducted to determine the proneurogenic effects of R. officinalis and its active compounds (ursolic acid and rosmarinic acid) in comparison to Donepezil in an Aß1-42-induced mouse model of AD. METHODS: BALB/c mice were divided into ten groups. Half were injected with Aß1-42 in the hippocampus through stereotaxic surgery to generate the disease groups. The other half received control injections. Each set of five groups were administered orally with vehicle, an ethanolic extract of R. officinalis, ursolic acid, rosmarinic acid or donepezil. Behavior analysis included the Morris water maze test, the novel object recognition test and the Elevated plus maze. The mice were then sacrificed and the hippocampal tissue was processed for immunohistochemistry and gene expression analysis. RESULTS: The results show a protective effect by rosmarinic acid and ursolic acid in reversing the deficits in spatial and recognition memory as well as changes in anxiety induced by Aß1-42. The neuronal density and the expression levels of neurogenic (Ki67, NeuN and DCX) and synaptic (Syn I, II, III, Synaptophysin and PSD-95) markers were also normalized upon treatment with rosmarinic and ursolic acid. CONCLUSION: Our findings indicate the potential of R. officinalis and its active compounds as therapeutic agents against Aß1-42-induced neurotoxicity in AD.

Amyloid-beta Induced Neurotoxicity Impairs Cognition and Adult Hippocampal Neurogenesis in a Mouse Model for Alzheimer's Disease.

BACKGROUND: Neurogenesis, the key mechanism to generate new neurons from existing stem cell niches continues throughout the life in the adult mammalian brain, although decelerate with aging or the progression of neurodegenerative disorders like Alzheimer's disease (AD). In the past few years, impaired adult hippocampal neurogenesis emerged as a contributing hallmark of AD pathophysiology along with amyloid beta (Aß) and tau hyper phosphorylation-induced neurotoxicity. However, no conclusive evidence exists that indicates the up/down-regulation of adult hippocampal neurogenesis during the course of AD progression. METHODS: In this study, we examined alterations in adult hippocampal neurogenesis and cognitive deficits using Aß(1-42)-induced mouse model of AD. RESULTS: Our results demonstrate that Aß administration induces an anxiety like behavior and impairs spatial and non-spatial memory and learning in BALB/c mice. Extensive neuronal loss was also evident in the dentate gyrus (DG), CA1, CA2 and CA3 regions of hippocampus in Aß-treated animals. Furthermore, Aß-exposure markedly reduced the real-time expression of markers of cell proliferation and migration i.e. Ki67 and DCX, whereas immunohistochemistry analysis revealed a substantial reduction in the expression levels of Ki67 and NeuN. CONCLUSION: Our findings highlight the association of Aß-induced neurotoxicity with altered neurogenesis and memory formation; however further insight is warranted to explore the underlying molecular pathway(s). Moreover, the treatment strategies aiming to repair the adult hippocampal neurogenesis hold potential as AD therapeutics.