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.
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.
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Yohei
Y
Shibuya
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Zhaoyang
Z
Niu
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Elena Y
EY
Bryleva
Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
Brent T
BT
Harris
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Stephanie R
SR
Murphy
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Alireza
A
Kheirollah
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Zachary D
ZD
Bowen
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Electronic address: Catherine.Chang@dartmouth.edu.
Catherine C Y
CCY
Chang
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Electronic address: Ta.Yuan.Chang@dartmouth.edu.
Ta-Yuan
TY
Chang
D000081:Acetamides; D000085:Acetates / Q000494:pharmacology* / Q000627:therapeutic use; D000101:Acetyl-CoA C-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics*; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D055785:Gene Knockdown Techniques; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000378:metabolism* / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D016875:tau Proteins / Q000378:metabolism*
C520671:(2-(4-(2-benzimidazol-2ylthio)ethyl)piperazin-1yl)-N-(2,4-bis(methylthio)-6-methyl-3-pyridyl)acetamide; D000081:Acetamides; D000085:Acetates; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001562:Benzimidazoles; D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; C054369:MAPT protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D013449:Sulfonamides; D013451:Sulfonic Acids; C075222:amyloid beta-protein (1-42); C580804:presenilin 1, mouse; D016875:tau Proteins; C423185:avasimibe; D002784:Cholesterol; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase
ACAT (SOAT); Alzheimer's disease; Autophagy; Neuron; Tauopathy