Age-associated metabolic risk factor(s) or nutritional imbalances, such as excessive fat and cholesterol intake or hypovitaminosis, are often linked to increased amyloidogenesis, as seen in late-onset sporadic Alzheimer's disease (SAD). Elevated expression of beta-secretase BACE1 is observed in SAD brains. In cultured neuronal models, we show that BACE1 transcription is upregulated through metabolic risk factors. Overexpression of the PPARgamma coactivator (PGC-1) a key metabolic regulator or all-trans retinoid acid (atRA) can reduce the elevated BACE1 expression resulting from inflammation induced by a high fat high cholesterol diet (HFD). Markedly increased RNA and protein levels of BACE1 were also found in the mouse forebrains fed HFD for 2 months;2-months of treatment with atRA restored BACE1 mRNA and expression after HFD feeding. Given the increasingly recognized importance of retinoid signaling in AD and the promise of retinoid-based therapies, our long-term goal is to fully characterize the beneficial effects and the underlying molecular mechanisms of atRA in mitigating neuroinflammation and amyloidogenesis. In this application, we will test the hypotheses first that atRA suppresses BACE1 expression via recruitment of liganded RARs to the promoter, secondly that coregulators including PGC-1 and nuclear corepressors participate in the transcriptional repression and finally that atRA and RARs interfere with the NF-gammaB mediated induction of BACE1.
Two aims are proposed to investigate 1) the molecular mechanism underlying the negative regulation of BACE1 transcription by atRA and 2) the mechanisms by which atRA modulates NF-gammaB activity upon inflammation. We will employ both in vitro cellular (TNFalpha +LPS) as well as animal models representing acute and chronic neuroinflammation (systemic LPS, HFD etc). Given the emerging role of aberrantly activated NF-gammaB in AD pathogenesis, studying atRA's regulation of this molecule is of potential broad impact not only for BACE1 gene regulation but also in large cohorts of NF-gammaB-sensitive genes in AD brains. Although BACE1 regulation has been extensively studied under hypoxic and metabolic stressed conditions including ROS, its upregulation under neuroinflammatory conditions is largely understudied. Hence, our focus of investigating its negative regulation by nuclear receptors upon inflammation is of high novelty. Successful completion of this project will be instrumental for future pursuing potential combination therapy between agents promoting retinoid signaling and insulin- sensitization (PPARgamma agonists etc).
Retinoid-based therapy is emerging as a promising option for preventing and treating AD. This project proposes to further investigate its effect in blunting neuroinflammation as well as the molecular mechanism underlying BACE1 suppression a diet-induced sporadic AD mouse model.
