Alzheimer's disease (AD) is the leading cause of cognitive impairment in the geriatric population. Deposition of the beta-amyloid peptide (Abeta) in the brain parenchyma and cerebral blood vessel walls is one of the distinguishing neuropathological features of AD. Abeta has been hypothesized to be the primary culprit triggering the neurodegenerative changes responsible for the memory loss and behavioral changes in AD. Increased Abeta production and deposition occurs with mutations in all three genes linked to early onset AD, the amyloid precursor protein, Presenilin 1 and Presenilin 2. Doubly transgenic mice with mutations in the amyloid precursor protein and Presenilin 1 rapidly develop AD-like changes in the brain including fibrillar Abeta deposits, glial reactivity and dystrophic neurites and will provide a means of screening treatments that alter AD production or which ameliorate its effects in the brain. Centella asiatica (Syn. Gota Cola, Luei Gong Gen, Indian Pennywort) is an ethnophytotherapeutic agent reputed to have a beneficial effect on cognition. However, the mode of action of Centella asiatica has not been fully established. The object of this application is to test the central hypothesis that Centella asiatica extract (CAE) may exert a therapeutic effect on both cognition and neuropathology in a doubly transgenic mouse model of AD by modulating amyloid deposition in the brain.
Specific aims : 1) Determine the effect of 3 different doses of CAE on learning and memory performance at young (3 month), mature (6 month), and aging (12 month) old doubly transgenic mice when treatment is started prior to onset of Abeta deposition (2 months). 2) Assay the effect of CAE on the production and deposition of Abeta 40 and 42 isoforms using ELISA as well as antibodies to Abeta and standard histological techniques known to detect fibrillar amyloid at each of the three age groups tested. 3) Perform secondary analysis of neuronal loss, dystrophic neurite formation, glial activation and markers of oxidative stress to test the neuronal and glial response to both AD and CAE treatment with aging. The efficacy of CAE to improve working and spatial memory will be studied using the object recognition task that has previously been shown to discriminate between transgenic mice carrying mutations linked to early onset AD and controls. Expected results are improvement in performance of CAE-treated group in the behavioral task, and reduction in the levels of Abeta(3 deposition in the brain. Our proposal meets the criteria of R21 application of NCCAM that will generate preliminary data on possible mechanism of action of a traditional herbal drug for Alzheimer's disease with eventual development of a therapeutic agent.
| Dhanasekaran, Muralikrishnan; Holcomb, Leigh A; Hitt, Angie R et al. (2009) Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer's disease animal model. Phytother Res 23:14-9 |
