Acyl-CoA:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer’s disease mouse and reduces human P301L-tau content at the pre-symptomatic stage

• Published in: Neurobiology of aging 2015-04, Vol.36 (7), p.2248-2259
• Main Authors: Shibuya, Yohei, Niu, Zhaoyang, Bryleva, Elena Y., Harris, Brent T., Murphy, Stephanie R., Kheirollah, Alireza, Bowen, Zachary D., Chang, Catherine C.Y., Chang, Ta-Yuan
• Format: Article
• Language: English
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2015.04.002

Patients with Alzheimer’s disease (AD) display amyloidopathy and tauopathy. In mouse models of AD, pharmacological inhibition using small molecule enzyme inhibitors, or genetic inactivation of Acyl-CoA: cholesterol acyltransferase 1 (ACAT1) diminished amyloidopathy and restored cognitive deficits. In microglia, ACAT1 blockage increases autophagosome formation and stimulates amyloid β peptide1–42 degradation. Here we hypothesize that in neurons ACAT1 blockage augments autophagy and increases autophagy-mediated degradation of P301L-tau protein. We tested this possibility in murine neuroblastoma cells ectopically expressing human tau, and in primary neurons isolated from triple transgenic AD (3XTg-AD) mice that express mutant forms of APP, PS1, and human tau. The results show that ACAT1 blockage increases autophagosome formation and decreases P301L-tau protein content without affecting endogenous mouse tau protein content. In vivo , lacking Acat1 decreases P301L-tau protein content in the brains of young 3XTg-AD mice but not in those of old mice, where extensive hyperphosphorylations and aggregation of P301L-tau take place. These results suggest that, in addition to ameliorating amyloidopathy in both young and old AD mice, ACAT1 blockage may benefit AD by reducing tauopathy at early stage.