Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer's disease mouse and reduces human P301L-tau content at the presymptomatic stage

Abstract 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-coenzyme A (Acyl-CoA):cholesterol acyltransferase 1 (ACAT1) diminished amyloidopathy and...

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Bibliographic Details
Published in:Neurobiology of aging 2015-07, 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
Subjects:
ACAT (SOAT)
Acetates - pharmacology
Acetates - therapeutic use
Acetyl-CoA C-Acetyltransferase - antagonists & inhibitors
Acetyl-CoA C-Acetyltransferase - genetics
Acetyl-CoA C-Acetyltransferase - physiology
Alzheimer Disease - drug therapy
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Alzheimer's disease
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - metabolism
Animals
Autophagy
Autophagy - drug effects
Autophagy - genetics
Benzimidazoles - pharmacology
Benzimidazoles - therapeutic use
Brain - metabolism
Brain - pathology
Cells, Cultured
Cholesterol - metabolism
Cholesterol Esters - metabolism
Disease Models, Animal
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Gene Knockdown Techniques
Internal Medicine
Mice, Inbred C57BL
Mice, Transgenic
Molecular Targeted Therapy
Neurology
Neuron
Neurons - metabolism
Neurons - physiology
Peptide Fragments - metabolism
Presenilin-1 - metabolism
Sulfonic Acids - pharmacology
Sulfonic Acids - therapeutic use
tau Proteins - metabolism
Tauopathy
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Summary:Abstract 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-coenzyme A (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 mice that express mutant forms of amyloid precursor protein, presenilin-1, 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 triple transgenic 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.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2015.04.002