Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models.
Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNA-dependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 alpha and caspase 12 activation induced by amyloid beta peptide1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 alpha were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid beta peptide(1-42)-infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid beta peptide(1-42)-infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 alpha is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.
Choi
Yoori
Y
Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul, South Korea.
Kim
Hye-Sun
HS
Shin
Ki Young
KY
Kim
Eun-Mee
EM
Kim
Minji
M
Kim
Hyun-Soo
HS
Park
Cheol Hyoung
CH
Jeong
Yun Ha
YH
Yoo
Jongman
J
Lee
Jean-Pyo
JP
Chang
Keun-A
KA
Kim
Seonghan
S
Suh
Yoo-Hun
YH
D000544:Alzheimer Disease / Q000139:chemically induced / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D016923:Cell Death / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016716:PC12 Cells / Q000187:drug effects; D010446:Peptide Fragments; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D020932:Nerve Growth Factor; D008911:Minocycline