Evaluation of the Therapeutic Potentials of Herb Extracts in Alzheimer’S Neuroinflammatory Cell and Animal Models

Alzheimer’s disease (AD) is the most prevalent form of dementia associated with progressive cognitive decline and memory loss. Currently effective treatment for modifying AD progression is still lacking. Compelling evidence has demonstrated the role of microglia-mediated neuroinflammation in the pathogenesis of AD. In pathology, AD is characterized by abnormal accumulation of β-amyloid (Aβ). Aβ accumulation activates microglia, which secrete pro-inflammatory factors that are associated with Aβ clearance impairment and cause neurotoxicity, forming a vicious cycle between Aβ accumulation, activated microglia, and microglial inflammatory mediators. Blocking this vicious cycle by inhibition of microglial activation may be a therapeutic strategy for AD. Previously we identified three plant extracts (Hyptis brevipes, Oenanthe javanica, and Flemingia philippinensis; provided by ITRI), which possessed not only aggregates-inhibitory effects on Aβ aggregation model but also anti-inflammatory effects on RAW 264.7 macrophage inflammatory model. Here we aim to apply AD-specific neuroinflammatory cell and animal models to further examine their potentials for AD treatment. The specific aims include: Aim 1: Applying Aβ-activated BV2 microglial AD model to investigate the anti-neuroinflammatory potentials of plant extracts (year 1). The anti-neuroinflammatory potentials of plant extracts (Hyptis brevipes, Oenanthe javanica, and Flemingia philippinensis) and their relevant active constituents will be identified by Aβ-activated BV2 microglial cells. Aim 2: Constructing in vitro neuroinflammatory neuronal AD model for evaluating the neuroprotective effects of plant extracts (years 1 ~2). To mimic neuroinflammatory environment in AD, we will treat Tet-on Aβ SH-SY5Y with medium conditioned by Aβ-activated BV2 microglia. The anti-neuroinflammatory and neuroprotective effects of plant extracts (Hyptis brevipes, Oenanthe javanica, and Flemingia philippinensis)/constituents will be evaluated by this neuronal model. Several candidates (leading candidates) will be selected for further testing in Aim 3 and Aim 4. Aim 3: Using human AD-iPSC model to evaluate the therapeutic potential of plant extracts (years 2 ~ 3). The neuroprotective potentials of leading candidates will be explored by an APPD678H-mutated AD-induced pluripotent stem cell (AD-iPSC)-derived neurons under the treatment with Aβ-activated BV2 cell conditioned medium. Aim 4: Testing the therapeutic potential of plant extracts by APP/PS1/tau triple transgenic mouse model (year 3). The in vivo effects of the leading candidates will be examined by APP/PS1/tau triple transgenic mouse model. Studies from this proposal will provide new insights into the herb medicine for the treatment of AD.

Project ID:PC10608-1468
External Project ID:MOST106-2314-B182-037-MY2