Chronic treatment with anesthetic propofol attenuates β-amyloid protein levels in brain tissues of aged mice
- Yiying Zhang†1,
- Haijun Shao†1, 2,
- Yuanlin Dong1,
- Celeste A Swain1,
- Buwei Yu2,
- Weiming Xia3 and
- Zhongcong Xie1Email author
© Zhang et al.; licensee BioMed Central Ltd. 2014
Received: 3 February 2014
Accepted: 1 April 2014
Published: 11 April 2014
Alzheimer’s disease (AD) is the most common form of dementia. At the present time, however, AD still lacks effective treatments. Our recent studies showed that chronic treatment with anesthetic propofol attenuated brain caspase-3 activation and improved cognitive function in aged mice. Accumulation of β-amyloid protein (Aβ) is a major component of the neuropathogenesis of AD dementia and cognitive impairment. We therefore set out to determine the effects of chronic treatment with propofol on Aβ levels in brain tissues of aged mice. Propofol (50 mg/kg) was administrated to aged (18 month-old) wild-type mice once a week for 8 weeks. The brain tissues of mice were harvested one day after the final propofol treatment. The harvested brain tissues were then subjected to enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Here we report that the propofol treatment reduced Aβ (Aβ40 and Aβ42) levels in the brain tissues of the aged mice. Moreover, the propofol treatment decreased the levels of β-site amyloid precursor protein cleaving enzyme (the enzyme for Aβ generation), and increased the levels of neprilysin (the enzyme for Aβ degradation) in the brain tissues of the aged mice. These results suggested that the chronic treatment with propofol might reduce brain Aβ levels potentially via decreasing brain levels of β-site amyloid precursor protein cleaving enzyme, thus decreasing Aβ generation; and via increasing brain neprilysin levels, thus increasing Aβ degradation. These preliminary findings from our pilot studies have established a system and postulated a new hypothesis for future research.
KeywordsAging Alzheimer’s disease Neurodegeneration β-amyloid peptide Anesthesia Propofol
Alzheimer disease (AD) is an insidious and progressive neurodegenerative disorder accounting for the vast majority of dementia, and is characterized by global cognitive decline and the robust accumulation of amyloid deposits and neurofibrillary tangles in the brain (reviewed in ). However, there is still a lack of effective treatments for AD, and many studies aim to find new and novel drugs to treat and/or prevent AD.
β-Amyloid protein (Aβ) is a main component of the plaques found in brains of AD patients and is the hallmark of AD dementia and cognitive impairment (reviewed in ). Accumulation and deposition of β-amyloid protein (Aβ) has been reported as one of the main aspects of AD neuropathogenesis ([2–4], reviewed in ). Aβ was isolated from meningovascular amyloid deposits in AD and Down’s syndrome [2, 5]. These findings led to the cloning of the gene encoding amyloid precursor protein (APP) as one of the AD genes [6, 7] and consequently, the further studies of APP processing and Aβ metabolism.
APP is hydrolyzed by aspartyl protease β-site APP-cleaving enzyme (BACE) or β-secretase, a type I transmembrane, glycosylated aspartyl protease found in post-Golgi membranes and at the cell surface [8–11], and then is cleaved by γ-secretase [12–14] to generate Aβ. Finally, Aβ can be degraded by enzyme insulin degrading enzyme (IDE) and neprilysin (NEP) ([15–19]; reviewed in ).
Propofol (2, 6-disopropylphenol) is an intravenous anesthetic. It has been shown that propofol can attenuate the caspase-3 activation and Aβ oligomerization induced by the anesthetic isoflurane . Our recent studies have shown that chronic treatment with propofol (50 mg/kg, once per week for 8 weeks) in aged mice (e.g., 18 month-old) can improve the cognitive function and attenuate the caspase-3 activation . Given Aβ accumulation can lead to cognitive impairment [reviewed in ), we set out in the present pilot studies to establish a system and to test a hypothesis that the chronic treatment with propofol can decrease Aβ levels in the brain tissues of aged mice via inhibiting its generation and/or promoting its degradation. The findings from these proof of concept studies would promote more research to further determine the effects of anesthetic propofol on AD neuropathogenesis.
Materials and methods
Mice and propofol treatment
The animal protocol was approved by the Standing Committee on Animals at Massachusetts General Hospital, Boston, Massachusetts. The maintenance and handling of mice were consistent with the guideline of National Institute of Health, and all of the efforts were made to minimize the number of animals in the studies. Wild-type mice (C57BL/6 J, The Jackson Lab, Bar Harbor, ME) were used in the study. There were 10 mice in the propofol treatment group and 10 mice in the saline control group. The mice, at the age of 18 months-old, were randomized by weight and gender into experimental groups, which received propofol (APP Pharmaceuticals, Inc, Schaumburg, IL) treatment [50 mg/kg, intraperitoneal (IP) injection], and control groups, which received the same volume of saline (IP), once a week every Saturday for 8 weeks.
One day after the last propofol or saline treatment, mice were decapitated, and the brain tissues were harvested. The harvested brain tissues were homogenized on ice with an immunoprecipitation buffer (10 mM Tris–HCl, pH 7.4, 150 mM NaCl, 2 mM ethylenediaminetetraacetic acid, 0.5% Nonidet P-40) plus protease inhibitors (1 μg/ml aprotinin, 1 μg/ml leupeptin, 1 μg/ml pepstatin A). The lysates were centrifuged at 14,000 rpm for 15 minutes, and quantified for total protein concentration by a bicinchoninic acid protein assay kit (Pierce, Iselin, NJ). The harvested brain tissues were subjected to Enzyme-linked immunosorbent assay (ELISA) or Western blot analyses as described in our previous studies [21, 23, 24].
ELISA determination of A β
The mouse Aβ40 (KMB3481) and Aβ42 (KMB3441) immunoassay Kits (Invitrogen, San Francisco, CA) were used to determine the Aβ40 and Aβ42 levels in the brain tissues of the aged mice, respectively. The brain tissues were homogenized in TBS buffer (including 50 mM Tris, and 150 mM NaCl, pH 8.0) with protease inhibitor (1 mg/ml aprotinin, 1 mg/ml leupeptin, 1 mg/ml pepstatin A), and then centrifuged for 45 minutes at 65,000 rounds per minute (RPM) at 4 degrees Celsius. The supernatants were removed. The pellets were resuspended by sonication in a homogenization buffer containing 1% SDS, and spun again (15 minutes at 18,000 RPM). We collected the supernatants and measured the total protein amount of each sample. We obtained 110 μg of protein from each harvested mouse brain sample or standard, and placed the sample into each well coated with a monoclonal antibody to the NH2-terminus of mouse Aβ. The samples and the antibody were incubated overnight at 4 degrees Celsius. After washing 4 times, a rabbit monoclonal antibody specific for the COOH-terminus of the Aβ sequence (1–40 or 1–42) was added and incubated in room temperature for one hour. After another 4 washes, horseradish peroxidase-labeled anti-rabbit antibody was added to the wells, and incubated for a half hour at room temperature. Wells were then developed with tetramethylbenzidine (TMB) reagent in dark and the well absorbance was measured at 450 nm. Aβ40 and Aβ42 levels in test samples were determined by comparison with the signals from the standard spiked with known quantities of Aβ40 or Aβ42.
Western blot analysis
BACE antibody (1:1,000 dilution; Abcam, Cambridge, MA, Cat. Number: ab2077) was used to recognize BACE (65 kDa). Anti-neprilysin (NEP) antibody (1:1,000 dilution, Millipore, Temecula, CA) was used to detect protein levels of NEP (86 kDa). Antibody anti-β-Actin (1:10,000, Sigma, St. Louis, MO) was used to detect β-Actin (42 kDa). Each band in the Western blot represented an independent experiment. The results were averaged from 6–10 independent experiments. We quantified the Western blots in two steps as described in our previous studies . First, we used β-Actin levels to normalize protein levels (e.g., determining the ratio of BACE to β-Actin amount) and control for loading differences in the total protein amount. Second, we presented protein level changes in the brain tissues of mice treated with propofol as a percentage of those in the saline control group. 100% of protein level changes refer to control levels for the purpose of comparison to experimental conditions.
Immunoblot detection of Aβ
Immunoblot detection of Aβ in brain tissues was measured as described in previous studies [25–27]. Specifically, brain samples were homogenized (150 mM NaCl with protease inhibitor cocktail in 50 mM Tris, pH of 8.0) and centrifuged (65,000 rpm × 45 minutes), and the supernatant was removed. The pellet was then resuspended by sonication in homogenization buffer containing 1% SDS. Following the pelleting of insoluble material (18,000 rpm × 15 minutes), the SDS-extract was electrophoresed on SDS-PAGE (4-12% Bis-Tris polyacrylamide gel from Invitrogen, Carlsbad, CA), blotted to PVDF membrane and probed with a 1:200 dilution of 6E10 (Covance).
Data were expressed as mean ± standard deviation (SD). The number of samples varied from 6 to 10, and the samples were normally distributed (tested by normality test). Student-t test was used to analyze the difference in Aβ, BACE, and NEP levels between the brain tissues of the propofol-treated mice and the brain tissues of the saline-treated mice. Prism 6 software (La Jolla, CA) was used to analyze the data.
Propofol treatment reduced the Aβ levels in the brain tissues of aged mice
Our recent studies  showed that chronic treatment with anesthetic propofol (50 mg/kg, once a week for 8 weeks) was able to improve cognitive function and attenuated the aging-associated caspase-3 activation. Both caspase-3 activation and Aβ have been reported to contribute to AD neuropathogenesis and cognitive impairment (, reviewed in ). Therefore, we set out to determine whether the chronic propofol treatment could also reduce the Aβ levels in the brain tissues of mice.
Next, we performed Western blot analysis of Aβ to further determine the effects of the propofol treatment on the Aβ levels in the brain tissues of the aged mice. The immunoblotting of Aβ showed that there was a visible reduction in the levels of bands representing Aβ (4 kDa) in the brain tissues of mice following the propofol treatment as compared to those of mice following the saline treatment (Figure 1C). There was no significant difference in the β-Actin levels between the brain tissues of mice following the propofol treatment and the brain tissues of mice following the saline treatment. The quantification of the Western blot, based on the ratio of Aβ to β-Actin, showed that the propofol treatment (black bar) decreased the Aβ levels as compared to the saline treatment (white bar): 43% versus 100%, P = 0.001 (Figure 1D). Taken together, these data suggested that the chronic treatment with 50 mg/kg propofol weekly for 8 weeks was able to decrease Aβ levels in the brain tissues of aged mice.
Propofol treatment reduced the BACE levels in the brain tissues of aged mice
Propofol treatment increased the NEP levels in the brain tissues of aged mice
Our recent studies have shown that a weekly treatment with 50 mg/kg propofol for 8 weeks is able to improve the cognitive function in the aged mice, and reduces caspase-3 activation in the brain tissues of the mice . Aβ accumulation also contributes to cognitive impairment [reviewed in ). Therefore, in the current study, we assessed the effects of the chronic treatment of propofol on the levels of Aβ, as well as its generation enzyme BACE and degradation enzyme NEP. Note that the main objective in this proof of concept study is to establish a pre-clinical model for future large scale studies.
We found that the weekly treatment of propofol for 8 weeks in the aged mice was able to attenuate the Aβ levels in the brain tissues of the mice (Figure 1). These data suggested that it was possible that the anesthetic propofol might improve cognitive function in aged mice by reducing the Aβ levels in the brain tissues of the mice. However, the cause-effect relationship of the propofol-induced reduction in brain Aβ levels of aged mice and the propofol-induced improvement of cognitive function in aged mice remain to be determined. Such studies would illustrate the functional outcomes of the propofol-induced reduction in brain Aβ levels of aged mice and are warranted to perform in the future.
Moreover, the propofol treatment decreased BACE levels in the brain tissues of the aged mice (Figure 2). These results showed the potential underlying mechanism of the propofol-induced reduction in Aβ levels, and suggested that propofol might decrease the Aβ levels by inhibiting its generation in the brain tissues of the mice.
Finally, the propofol treatment increased the NEP levels in the brain tissues of the aged mice (Figure 3). These findings demonstrated a different underlying mechanism of the propofol-induced reduction in Aβ levels, and suggested that propofol might decrease the Aβ levels by enhancing its degradation in the brain tissues of the mice.
A recent study has shown that AD patients may have an age-dependent decrease of gamma-aminobutyric acid (GABA) currents in the AD brain, and this reduction is associated with decreased mRNA and protein levels of GABA receptor subunits . These findings suggest that reduced GABA neurotransmission could also contribute to AD neuropathogenesis. Propofol is a GABA receptor agonist , and it has been shown in a preliminary clinical study that propofol may improve cognitive function in humans . Our current studies showed that the chronic propofol treatment might decrease BACE levels (the generation enzyme) and increase NEP levels (the degradation enzyme), leading to reduction in Aβ levels in brain tissues of aged mice. Furthermore, our recently published work  suggested that the same chronic propofol treatment was able to attenuate caspase-3 activation in the brain tissues of aged mice and improved cognitive function in the mice. Taken together, these findings suggest the potential association between GABA neurotransmission with caspase activation, Aβ metabolism and cognitive function. Future studies may use different GABA receptor agonist(s) to further test this hypothesis. These findings may promote more research, leading to new concepts of AD neuropathogenesis and new intervention(s) of AD.
Moreover, these findings demonstrated the possibility that the anesthetic propofol could be used to prevent or treat neurological disorders, e.g., AD. Pending further studies, the chronic treatment with propofol would be used to attenuate the neuropathogenesis of AD and to improve the cognitive function in AD patients. These studies would promote further investigations, in both pre-clinical and clinical settings, to seek innovative uses of current anesthetics for the interventions of other disorders.
Some anesthetics, e.g., isoflurane, have been shown to induce neurotoxicity and neurobehavioral deficits in vitro and in vivo[25, 33–46]. Therefore, the current findings that propofol attenuated Aβ levels in brain tissues of mice suggested that more studies are needed to assess whether propofol could be a better choice when providing anesthesia care for AD patients or senior patients who are vulnerable to develop postoperative cognitive dysfunction.
Note that propofol is a short acting anesthetic agent. The observed reductions in the levels of Aβ and BACE, and increases in the NEP levels were likely not the acute effects of propofol. The exactly mechanism by which the chronic treatment of propofol alters the levels of Aβ, BACE, and NEP remains unknown at the current time. We have postulated that the weekly treatment with 50 mg/kg propofol for 8 weeks may regulate the functional status of GABA receptor, which then leads to the changes in the levels of Aβ, BACE, and NEP. Future studies to test this hypothesis are warranted.
The studies have several limitations. First, we did not determine the dose or time-dependent effects of propofol on Aβ levels in the brain tissues of the aged mice. Different treatments of propofol may be neurotoxic [47–49] or neuroprotective [50–52]. Therefore, it is possible that propofol treatment with different doses or administered at different times may have different effects on brain Aβ levels. Nevertheless, the outcomes from the current studies have established a system and proposed a new concept to further determine the effects of propofol on brain function. Second, we did not assess the effects of propofol on the levels of other enzymes involving in Aβ metabolism, e.g., γ-secretase and/or insulin degradation enzyme (IDE). However, the main objective of the current studies was to determine whether anesthetic propofol could decrease brain Aβ levels in aged mice. We will systematically investigate the underlying mechanism by which propofol affects brain Aβ levels using our established system in the future.
In conclusion, we found that chronic treatment with the anesthetic propofol was able to reduce Aβ (both Aβ40 and Aβ42) levels in the brain tissues of aged mice. Furthermore, the chronic propofol treatment might reduce the brain Aβ levels by decreasing brain BACE levels (decreasing Aβ generation) and increasing brain NEP levels (increasing Aβ degradation). The findings from these concept and hypothesis generation studies will promote more research to systematically determine the effect of chronic treatment of propofol or other anesthetics on Aβ levels and the associated behavioral changes, which would ultimately lead to the development of new therapeutic strategies for aging- and/or AD-associated cognitive impairment and of better anesthesia care for senior and AD patients.
Amyloid β precursor protein
β-site amyloid precursor protein cleaving enzyme
This research was supported by R21AG038994, R01 GM088801 and R01 AG041274 from National Institutes of Health, Bethesda, Maryland, Investigator-initiated Research grant from Alzheimer’s Association, Chicago, Illinois, and Cure Alzheimer’s Fund, Wellesley, Massachusetts to Zhongcong Xie. The cost of the anesthetic propofol was generously provided by the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
- Querfurth HW, LaFerla FM: Alzheimer's disease. N Engl J Med 2010, 362(4):329-344. 10.1056/NEJMra0909142View ArticlePubMedGoogle Scholar
- Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J: Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1991, 349(6311):704-706. 10.1038/349704a0View ArticlePubMedGoogle Scholar
- Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K: Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 1985, 82(12):4245-4249. 10.1073/pnas.82.12.4245PubMed CentralView ArticlePubMedGoogle Scholar
- Selkoe DJ, Podlisny MB, Joachim CL, Selkoe DJ, Podlisny MB, Joachim CL, Selkoe DJ, Podlisny MB, Joachim CL, Vickers EA, Lee G, Fritz LC, Oltersdorf T: Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci U S A 1988, 85(19):7341-7345. 10.1073/pnas.85.19.7341PubMed CentralView ArticlePubMedGoogle Scholar
- Glenner GG, Wong CW: Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 1984, 122(3):1131-1135. 10.1016/0006-291X(84)91209-9View ArticlePubMedGoogle Scholar
- Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL: Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 1987, 235(4791):880-884. 10.1126/science.2949367View ArticlePubMedGoogle Scholar
- Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Müller-Hill B: The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987, 325(6106):19-25. 733–6View ArticleGoogle Scholar
- Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M: Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999, 286(5440):735-741. 10.1126/science.286.5440.735View ArticlePubMedGoogle Scholar
- Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G: Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 1999, 14(6):419-427. 10.1006/mcne.1999.0811View ArticlePubMedGoogle Scholar
- Sinha S, Lieberburg I: Cellular mechanisms of beta-amyloid production and secretion. Proc Natl Acad Sci U S A 1999, 96(20):11049-11053. 10.1073/pnas.96.20.11049PubMed CentralView ArticlePubMedGoogle Scholar
- Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME: Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 1999, 402(6761):533-537. 10.1038/990107View ArticlePubMedGoogle Scholar
- Gu Y, Misonou H, Sato T, Dohmae N, Takio K, Ihara Y: Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch. J Biol Chem 2001, 276(38):35235-35238. 10.1074/jbc.C100357200View ArticlePubMedGoogle Scholar
- Sastre M, Steiner H, Fuchs K, Capell A, Multhaup G, Condron MM, Teplow DB, Haass C: Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2001, 2(9):835-841. 10.1093/embo-reports/kve180PubMed CentralView ArticlePubMedGoogle Scholar
- Yu C, Kim SH, Ikeuchi T, Xu H, Gasparini L, Wang R, Sisodia SS: Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment gamma. Evidence for distinct mechanisms involved in gamma -secretase processing of the APP and Notch1 transmembrane domains. J Biol Chem 2001, 276(47):43756-43760. 10.1074/jbc.C100410200View ArticlePubMedGoogle Scholar
- Eckman EA, Eckman CB: Abeta-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention. Biochem Soc Trans 2005, 33(Pt 5):1101-1105.PubMedGoogle Scholar
- Higuchi M, Iwata N, Saido TC: Understanding molecular mechanisms of proteolysis in Alzheimer's disease: progress toward therapeutic interventions. Biochim Biophys Acta 2005, 1751(1):60-67. 10.1016/j.bbapap.2005.02.013View ArticlePubMedGoogle Scholar
- Wang DS, Dickson DW, Malter JS: beta-Amyloid degradation and Alzheimer's disease. J Biomed Biotechnol 2006, 2006(3):58406.PubMed CentralPubMedGoogle Scholar
- Miners JS, Baig S, Palmer J, Palmer LE, Kehoe PG, Love S: Abeta-degrading enzymes in Alzheimer's disease. Brain Pathol 2008, 18(2):240-252. 10.1111/j.1750-3639.2008.00132.xView ArticlePubMedGoogle Scholar
- Bates KA, Verdile G, Li QX, Ames D, Hudson P, Masters CL, Martins RN: Clearance mechanisms of Alzheimer's amyloid-beta peptide: implications for therapeutic design and diagnostic tests. Mol Psychiatry 2009, 14(5):469-486. 10.1038/mp.2008.96View ArticlePubMedGoogle Scholar
- Qiu WQ, Folstein MF: Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol Aging 2006, 27(2):190-198. 10.1016/j.neurobiolaging.2005.01.004View ArticlePubMedGoogle Scholar
- Zhang Y, Zhen Y, Dong Y, Xu Z, Yue Y, Golde TE, Tanzi RE, Moir RD, Xie Z: Anesthetic propofol attenuates the isoflurane-induced caspase-3 activation and abeta oligomerization. PLoS One 2011, 6(11):e27019. 10.1371/journal.pone.0027019PubMed CentralView ArticlePubMedGoogle Scholar
- Shao H, Zhang Y, Dong Y, Yu B, Xia W, Xie Z: Chronic treatment with anesthetic propofol improves cognitive function and attenuates caspase activation in both aged and Alzheimer's disease transgenic mice. J Alzheimers Dis 2014. In PressGoogle Scholar
- Zhang Y, Dong Y, Wu X, Lu Y, Xu Z, Knapp A, Yue Y, Xu T, Xie Z: The mitochondrial pathway of anesthetic isoflurane-induced apoptosis. J Biol Chem 2010, 285(6):4025-4037. 10.1074/jbc.M109.065664PubMed CentralView ArticlePubMedGoogle Scholar
- Xu Z, Dong Y, Wang H, Culley DJ, Marcantonio ER, Crosby G, Tanzi RE, Zhang Y, Xie Z: Age-dependent postoperative cognitive impairment and Alzheimer-related neuropathology in mice. Sci Rep 2014, 4: 3766.PubMed CentralPubMedGoogle Scholar
- Xie Z, Culley DJ, Dong Y, Zhang G, Zhang B, Moir RD, Frosch MP, Crosby G, Tanzi RE: The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo. Ann Neurol 2008, 64(6):618-627. 10.1002/ana.21548PubMed CentralView ArticlePubMedGoogle Scholar
- Nagano S, Huang X, Moir RD, Payton SM, Tanzi RE, Bush AI: Peroxidase activity of cyclooxygenase-2 (COX-2) cross-links beta-amyloid (Abeta) and generates Abeta-COX-2 hetero-oligomers that are increased in Alzheimer's disease. J Biol Chem 2004, 279(15):14673-14678. 10.1074/jbc.M313003200View ArticlePubMedGoogle Scholar
- Dong Y, Zhang G, Zhang B, Moir RD, Xia W, Marcantonio ER, Culley DJ, Crosby G, Tanzi RE, Xie Z: The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels. Arch Neurol 2009, 66(5):620-631.PubMed CentralView ArticlePubMedGoogle Scholar
- Haijun Shao YZ, Yuanlin D, Buwei Y, Weiming Xia Zhongcong X: Chronic treatment with anesthetic propofol improves cognitive function and attenuates caspase activation in both aged and Alzheimer’s disease transgenic mice. J Alzheimers Dis In Press
- Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL, Joseph B: Caspase signalling controls microglia activation and neurotoxicity. Nature 2011, 472(7343):319-324. 10.1038/nature09788View ArticlePubMedGoogle Scholar
- Limon A, Reyes-Ruiz JM, Miledi R: Loss of functional GABA(A) receptors in the Alzheimer diseased brain. Proc Natl Acad Sci U S A 2012, 109(25):10071-10076. 10.1073/pnas.1204606109PubMed CentralView ArticlePubMedGoogle Scholar
- Hales TG, Lambert JJ: The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones. Br J Pharmacol 1991, 104(3):619-628.PubMed CentralView ArticlePubMedGoogle Scholar
- Pryor K, Blackstock Bernstein AS, Feiler D, Vortsman E, Root JC: Administration of Propofol After Learning Improves Memory Performance in Human Subjects Via Loss of Competitive Consolidation: Evidence That Propofol Amnesia Occurs at the Induction of Consolidation. Anesthesiol 2012. ASA AbstractGoogle Scholar
- Eckenhoff RG, Johansson JS, Wei H, Carnini A, Kang B, Wei W, Pidikiti R, Keller JM, Eckenhoff MF: Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiol 2004, 101(3):703-709. 10.1097/00000542-200409000-00019View ArticleGoogle Scholar
- Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, Dissen GA, Creeley CE, Olney JW: Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology 2010, 112(4):834-841. 10.1097/ALN.0b013e3181d049cdPubMed CentralView ArticlePubMedGoogle Scholar
- Xie Z, Dong Y, Maeda U, Alfille P, Culley DJ, Crosby G, Tanzi RE: The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid beta protein levels. Anesthesiol 2006, 104(5):988-994. 10.1097/00000542-200605000-00015View ArticleGoogle Scholar
- Xie Z, Dong Y, Maeda U, Moir R, Inouye SK, Culley DJ, Crosby G, Tanzi RE: Isoflurane-induced apoptosis: a potential pathogenic link between delirium and dementia. J Gerontol A Biol Sci Med Sci 2006, 61(12):1300-1306. 10.1093/gerona/61.12.1300View ArticlePubMedGoogle Scholar
- Wei H, Kang B, Wei W, Liang G, Meng QC, Li Y, Eckenhoff RG: Isoflurane and sevoflurane affect cell survival and BCL-2/BAX ratio differently. Brain Res 2005, 1037(1–2):139-147.View ArticlePubMedGoogle Scholar
- Loop T, Dovi-Akue D, Frick M, Roesslein M, Egger L, Humar M, Hoetzel A, Schmidt R, Borner C, Pahl HL, Geiger KK, Pannen BH: Volatile anesthetics induce caspase-dependent, mitochondria-mediated apoptosis in human T lymphocytes in vitro. Anesthesiol 2005, 102(6):1147-1157. 10.1097/00000542-200506000-00014View ArticleGoogle Scholar
- Wei H, Liang G, Yang H, Wang Q, Hawkins B, Madesh M, Wang S, Eckenhoff RG: The common inhalational anesthetic isoflurane induces apoptosis via activation of inositol 1,4,5-trisphosphate receptors. Anesthesiol 2008, 108(2):251-260. 10.1097/01.anes.0000299435.59242.0eView ArticleGoogle Scholar
- Xie Z, Dong Y, Maeda U, Moir RD, Xia W, Culley DJ, Crosby G, Tanzi RE: The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. J Neurosci 2007, 27(6):1247-1254. 10.1523/JNEUROSCI.5320-06.2007View ArticlePubMedGoogle Scholar
- Shu Y, Zhou Z, Wan Y, Sanders RD, Li M, Pac-Soo CK, Maze M, Ma D: Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain. Neurobiol Dis 2012, 45(2):743-750. 10.1016/j.nbd.2011.10.021View ArticlePubMedGoogle Scholar
- Zhao X, Yang Z, Liang G, Wu Z, Peng Y, Joseph DJ, Inan S, Wei H: Dual Effects of Isoflurane on Proliferation, Differentiation, and Survival in Human Neuroprogenitor Cells. Anesthesiol 2013, 118(3):537-549. 10.1097/ALN.0b013e3182833faeView ArticleGoogle Scholar
- Sanders RD, Hassell J, Davidson AJ, Robertson NJ, Ma D: Impact of anaesthetics and surgery on neurodevelopment: an update. British J Anaesthesia 2013, 110(Suppl 1):i53-72. 10.1093/bja/aet054View ArticleGoogle Scholar
- Jevtovic-Todorovic V, Absalom AR, Blomgren K, Brambrink A, Crosby G, Culley DJ, Fiskum G, Giffard RG, Herold KF, Loepke AW, Ma D, Orser BA, Planel E, Slikker W Jr, Soriano SG, Stratmann G, Vutskits L, Xie Z, Hemmings HC Jr: Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar. British J Anaesthesia 2013, 111(2):143-151. 10.1093/bja/aet177View ArticleGoogle Scholar
- Zhang B, Tian M, Zhen Y, Yue Y, Sherman J, Zheng H, Li S, Tanzi RE, Marcantonio ER, Xie Z: The effects of isoflurane and desflurane on cognitive function in humans. Anesth Analg 2012, 114(2):410-415. 10.1213/ANE.0b013e31823b2602PubMed CentralView ArticlePubMedGoogle Scholar
- Zhang Y, Xu Z, Wang H, Dong Y, Shi HN, Culley DJ, Crosby G, Marcantonio ER, Tanzi RE, Xie Z: Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory. Ann Neurol 2012, 71(5):687-698. 10.1002/ana.23536PubMed CentralView ArticlePubMedGoogle Scholar
- Pearn ML, Hu Y, Niesman IR, Patel HH, Drummond JC, Roth DM, Akassoglou K, Patel PM, Head BP: Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation. Anesthesiol 2012, 116(2):352-361. 10.1097/ALN.0b013e318242a48cView ArticleGoogle Scholar
- Whittington RA, Virag L, Marcouiller F, Papon MA, El Khoury NB, Julien C, Morin F, Emala CW, Planel E: Propofol directly increases tau phosphorylation. PLoS One 2011, 6(1):e16648. 10.1371/journal.pone.0016648PubMed CentralView ArticlePubMedGoogle Scholar
- Krzisch M, Sultan S, Sandell J, Demeter K, Vutskits L, Toni N: Propofol Anesthesia Impairs the Maturation and Survival of Adult-born Hippocampal Neurons. Anesthesiology 2013, 118(3):602-610. 10.1097/ALN.0b013e3182815948View ArticlePubMedGoogle Scholar
- Bayona NA, Gelb AW, Jiang Z, Wilson JX, Urquhart BL, Cechetto DF: Propofol neuroprotection in cerebral ischemia and its effects on low-molecular-weight antioxidants and skilled motor tasks. Anesthesiol 2004, 100(5):1151-1159. 10.1097/00000542-200405000-00017View ArticleGoogle Scholar
- Zhang Y, Dong Y, Xu Z, Xie Z: Propofol and magnesium attenuate isofluraneinduced caspase-3 activation via inhibiting mitochondrial permeability transition pore. Med Gas Res 2012, 2(1):20. 10.1186/2045-9912-2-20PubMed CentralView ArticlePubMedGoogle Scholar
- Rossaint J, Rossaint R, Weis J, Fries M, Rex S, Coburn M: Propofol: neuroprotection in an in vitro model of traumatic brain injury. Crit Care 2009, 13(2):R61. 10.1186/cc7795PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.