{'fraction_non_alphanumeric': 0.023534635879218474, 'fraction_numerical': 0.008880994671403197, 'mean_word_length': 5.953703703703703, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Leptin alleviates the saturated fatty acid‐induced increase in BACE1 expression and Amyloid‐β production ‐ Relevance to Alzheimer's disease pathogenesis

Epidemiological studies implicate diets rich in saturated free fatty acids (sFFA) as a potential risk factor for developing Alzheimer's disease (AD). In particular, high plasma levels of the sFFA palmitic acid (palmitate) have been shown to inversely correlate with cognitive function. AD is histo‐pathologically characterized by the deposition of aggregated Amyloid‐β (Aβ) peptide as extracellular amyloid plaques and the intracellular accumulation of aggregated hyper‐phosphorylated tau protein as neurofibrillary tangles. Our recent studies have demonstrated that palmitate‐enriched diet increases Amyloid‐β (Aβ) genesis in the hippocampus by increasing the expression and activity of the aspartyl protease BACE1 which catalyzes the rate limiting step in Aβ (Marwarha et al. 2017, Ghribi & Marwarha 2017). We have also shown that palmitate‐enriched diet decreases the expression of leptin, an adipokine that functions as a key neurotrophic cytokine in the brain (Marwarha et al. 2016). However, the role of palmitate‐induced mitigation in leptin expression and dysregulation of leptin signaling in the palmitate‐induced increase in BACE1 expression and the ensuing Aβ genesis has not been examined. Herein, we determined the role of leptin in modulating the palmitate‐induced increase in BACE1 expression and the ensuing Aβ genesis in human neuroblastoma SH‐SY5Y cells. Concomitant treatment of the cells with exogenous recombinant leptin significantly decreased the exogenous palmitate‐induced increase in BACE1 expression and enzymatic activity that culminated into a reduction in intracellular and secreted Aβ levels. Additionally, human SH‐SY5Y neuroblastoma cells stably overexpressing endogenous leptin, exhibited a lower increase in BACE1 expression and enzymatic activity as well as the ensuing Aβ accumulation in response to exogenous palmitate. Our unprecedented study illuminates a novel role of leptin in the brain and provides a unique insight into the mechanisms that underlie palmitate induced effects on molecular players involved in the etio‐pathogenesis of Alzheimer's disease.