The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer's Disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation.



The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown.



Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid β.



JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro-inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month-old 3xTg mice.



Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation.
Marco
M
Magistri
Dmitry
D
Velmeshev
Madina
M
Makhmutova
Prutha
P
Patel
Gregory C
GC
Sartor
Claude-Henry
CH
Volmar
Claes
C
Wahlestedt
Center for Therapeutic Innovation & Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Ave, BRB 508, Miami, FL 33136, USA. mohammad.ali.faghihi@gmail.com.
Mohammad Ali
MA
Faghihi
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009929:Organ Size; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism*
C561695:(+)-JQ1 compound; D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D001381:Azepines; C558298:Mapt protein, mouse; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D014230:Triazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins