Repression of Alzheimer's beta-Secretase

(AD) is one of the most devastating neuro-degenerative disorders characterized by the two pathological hallmarks of amyloid plaques and neurofibrillary tangles. Multiple environmental factors, such as diet and life style, along with genetic factors are all significant contributors. In addition, classic cardio-metabolic factors such as hypertension, stroke, diabetes and hypercholesterolemia increase the risk of AD. Epidemiological, clinical and experimental evidence strongly link metabolic defects with functional alterations associated with AD pathogenesis. Amyloid peptides (Aβ), the major constituent of plaques, are generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) via β-secretase (BACE1) and the γ-secretase. The selectively affected regions in the frontal brains of AD patients are often found to not only display high accumulation of Aβ peptides but also aberrant metabolic states (impaired homeostasis of lipid, glucose and energy metabolism) and chronic neuroinflammation. Together, these events trigger ultimate neuronal loss and cognitive deficit. BACE1 is the rate-limiting enzyme in APP processing and Aβ generation and thus remains one of the most favored therapeutic targets for treating AD. BACE1 expression is tightly regulated at multiple levels including transcription, post-transcription, translation and post-translation (Vassar et al. BACE1 is a stress-inducible protease. Multiple conditions including oxidative stress, inflammation, hypoxia/ischemia and traumatic conditions induce BACE1 expression primarily via transcriptional activation. We have recently reported differential regulation of BACE1 by oxidative and nitrosative signals (Kwak et al. Mol Neurodegener. 2011 ; 6:17) and by metabolic stress conditions (Wang et al. Cell Metab. 2013; 17:685). The peroxisome proliferator-activated receptor-γ (PPAR γ) is a prototypic ligand-activated nuclear receptor (NR) that utilizes PPARγ coactivator (PGC-1α) as its coactivator to coordinate lipid, glucose and mitochondrial metabolism. Based on the ability of PPARγ agonists to elicit anti-amyloidogenic, anti-inflammatory and insulin-sensitizing effects, rosiglitazone and several non-steroidal anti-inflammatory Editorial drugs (NSAIDs) are being evaluated in AD clinical trials (Heneka et al. 5:481). We recently investigated this PPARγ-PGC-1 axis in BACE1 regulation under various metabolic stress conditions and made several previously unappreciated observations. We discovered that 1) feeding mice high-fat-diets upregulate BACE1 transcription while fasting suppress BACE1, 2) up-or down-regulation of PGC-1α reciprocally regulate BACE1 transcription, 3) full activity of PPARγ and PGC-1α are required for suppressing BACE1 and both rely on a SIRT1-mediated deacetylation, and 4) the role of PPARγ-PGC-1α in transcriptional repression of BACE1 appears to represent a unique noncanonical mechanism which is not dependent on its ligand rosiglitazone but rather involves recruitment of a corepressor NCoR. To …