In this Alzheimer?s disease (AD)-focused administrative supplements for NIH grants that are not focused on AD, will test our hypothesis that novel retinoic acid receptor (RAR) agonists reduce AD pathology by increasing ?-secretase levels and by triggering anti-inflammatory responses. While AD is the most prevalent neurodegenerative disease of aging, currently no treatment is available, and the aetiology of non-familial AD remains unclear, although amyloid-? (A?) accumulation and the associated pro-inflammatory responses are linked to neuronal loss and cognitive decline in both AD patients and the animal models. Our parent grant (R21AA027374) aims to evaluate the neuroprotective effects of RAR agonists/antagonists against alcohol toxicity in the developing brain, because RA plays an important role in the development of embryos and their CNS, and alcohol disturbs retinoid metabolism. Therefore, the parent grant aims to determine if novel retinoid derivatives synthesized by Dr. Bhaskar Das (PI) alleviates alcohol-induced neurotoxicity, using mouse primary cultured cortical neurons and an in vivo mouse model of fetal alcohol spectrum disorders (FASD). The RA signaling pathway is important not only in neural development but also in the maintenance of neural functions. Previous studies have indicated that activation of the RA signaling pathway may attenuate progression of AD, because RA can up-regulate non-amyloidogenic ?-secretase and down-regulate amyloidogenic ?-secretase 1. ?-Secretase cleaves amyloid precursor protein (APP), producing soluble APP? (sAPP?), which elicits neuroprotective effects on synaptic plasticity, memory formation, neurogenesis, and neuritogenesis, while lowering toxic A? peptides and reducing amyloid pathology in the brain. RA is also implicated in exerting anti- inflammatory functions. However, all-trans-RA (a major physiological form of RA) activates various RAR subtypes (RAR?, ?, and ?) with a wide spectrum of effects including both beneficial and detrimental effects. The specific and novel boron-containing RAR agonists developed for alcohol studies in the parent grant can be used to assess the neuroprotective effects of RA signaling activation in AD models. In this supplementary grant we will focus two specific aims.
Aim1 : We will design and synthesize new analogs of our two lead RAR receptor specific agonists BT75 and BT10 and test their efficacy and specificity using in in-vitro binding and luciferase assays, and Aim 2: Examine the efficacy of novel RAR agonists using primary cultured cortical neurons and an AD mouse model. In this aim, new compounds will be assayed in vitro using cultured neurons, and the efficacy of existing two lead compounds (BT75, BT10), which show reduction in A? production and elevation in ?- secretase expression, will be tested in APPSwe/PS1?E9 (APP/PS1) mice to determine the optimal dosing paradigm (doses and dosing time interval) without any evidence of side effects using short-term treatment strategies (1- month treatment). In summary, our proposed studies could identify novel compounds targeted at ?-secretase to prevent AD pathologies and cognitive dysfunction, with a potential to be advanced into human clinical trial.
In this Alzheimer's disease (AD)-focused administrative supplements for NIH grants (R21AA027374) that are not focused on AD, will test our hypothesis that novel retinoic acid receptor (RAR) agonists reduce AD pathology by increasing ?-secretase levels and by triggering anti-inflammatory responses. While AD is the most prevalent neurodegenerative disease of aging, currently no treatment is available, and the aetiology of non-familial AD remains unclear, although amyloid-? (A?) accumulation and the associated pro-inflammatory responses are linked to neuronal loss and cognitive decline in both AD patients and the animal models. We expect our studies will define the mechanism and have potential to identify new entry points for therapeutic intervention of AD. This supplement grant will put foundation to explore and expand in our AD research program targeting RA signaling pathways and gene network.
