Alzheimer's Disease and Anesthesia

Cognitive disorders such as postoperative cognitive dysfunction, confusion, and delirium, are common following anesthesia in the elderly, with symptoms persisting for months or years in some patients. Alzheimer's disease (AD) patients appear to be particularly at risk of cognitive deterioration following anesthesia, and some studies suggest that exposure to anesthetics may increase the risk of AD. Here, we review the literature linking anesthesia to AD, with a focus on the biochemical consequences of anesthetic exposure on AD pathogenic pathways

Propofol Directly Increases Tau Phosphorylation

In Alzheimer's disease (AD) and other tauopathies, the microtubule-associated protein tau can undergo aberrant hyperphosphorylation potentially leading to the development of neurofibrillary pathology. Anesthetics have been previously shown to induce tau hyperphosphorylation through a mechanism involving hypothermia-induced inhibition of protein phosphatase 2A (PP2A) activity. However, the effects of propofol, a common clinically used intravenous anesthetic, on tau phosphorylation under normothermic conditions are unknown. We investigated the effects of a general anesthetic dose of propofol on levels of phosphorylated tau in the mouse hippocampus and cortex under normothermic conditions. Thirty min following the administration of propofol 250 mg/kg i.p., significant increases in tau phosphorylation were observed at the AT8, CP13, and PHF-1 phosphoepitopes in the hippocampus, as well as at AT8, PHF-1, MC6, pS262, and pS422 epitopes in the cortex. However, we did not detect somatodendritic relocalization of tau. In both brain regions, tau hyperphosphorylation persisted at the AT8 epitope 2 h following propofol, although the sedative effects of the drug were no longer evident at this time point. By 6 h following propofol, levels of phosphorylated tau at AT8 returned to control levels. An initial decrease in the activity and expression of PP2A were observed, suggesting that PP2A inhibition is at least partly responsible for the hyperphosphorylation of tau at multiple sites following 30 min of propofol exposure. We also examined tau phosphorylation in SH-SY5Y cells transfected to overexpress human tau. A 1 h exposure to a clinically relevant concentration of propofol in vitro was also associated with tau hyperphosphorylation. These findings suggest that propofol increases tau phosphorylation both in vivo and in vitro under normothermic conditions, and further studies are warranted to determine the impact of this anesthetic on the acceleration of neurofibrillary pathology

Dimethyl Sulfoxide Induces Both Direct and Indirect Tau Hyperphosphorylation

Dimethyl sulfoxide (DMSO) is widely used as a solvent or vehicle for biological studies, and for treatment of specific disorders, including traumatic brain injury and several forms of amyloidosis. As Alzheimer’s disease (AD) brains are characterized by deposits of β-amyloid peptides, it has been suggested that DMSO could be used as a treatment for this devastating disease. AD brains are also characterized by aggregates of hyperphosphorylated tau protein, but the effect of DMSO on tau phosphorylation is unknown. We thus investigated the impact of DMSO on tau phosphorylation in vitro and in vivo. One hour following intraperitoneal administration of 1 or 2 ml/kg DMSO in mice, no change was observed in tau phosphorylation. However, at 4 ml/kg, tau was hyperphosphorylated at AT8 (Ser202/Thr205), PHF-1 (Ser396/Ser404) and AT180 (Thr231) epitopes. At this dose, we also noticed that the animals were hypothermic. When the mice were maintained normothermic, the effect of 4 ml/kg DMSO on tau hyperphosphorylation was prevented. On the other hand, in SH-SY5Y cells, 0.1% DMSO induced tau hyperphosphorylation at AT8 and AT180 phosphoepitopes in normothermic conditions. Globally, these findings demonstrate that DMSO can induce tau hyperphosphorylation indirectly via hypothermia in vivo, and directly in vitro. These data should caution researchers working with DMSO as it can induce artifactual results both in vivo and in vitro

Effect of DMSO on tau kinases in mouse hippocampal tissue 1 h following the administration of DMSO (4 ml/kg i.p.).

<p>Hippocampal protein extracts were separated by SDS-PAGE and levels of kinases were determined using antibodies directed at activated or total kinases as follow: (A) phospho-ERK/total ERK ratio, (β) total ERK, (C) phospho-JNK/total JNK ratio, (D) total JNK, (E) GSK-3β phospho-S9/total GSK-3β ratio, (F) total GSK-3β, (G) phospho-CaMKII/total CaMKII ratio, (H) total CaMKII, (I) phospho-P38/total P38 ratio, (J) total P38, (K) CDK5, and (L) p35. Relative immunoreactive band intensities are expressed as a percent of control (0 ml/kg of DMSO) and are displayed for each epitope. For each condition, 2 representative data are displayed with controls (0 ml/kg; n  = 5), 1 ml/kg (n  = 5), 2 ml/kg (n  = 5) and 4 ml/kg (n  = 5). Data are expressed as mean ± SD. *, **, *** denote <i>p</i><0.05, <i>p</i><0.01, <i>p</i><0.001 versus control; ANOVA with Newman-Keuls <i>post hoc</i> test.</p

Body temperature follow-up following 0 (n = 4–22), 1 (n = 4–10), 2 (n = 4–10) and 4 ml/kg (n = 4–28) of DMSO i.p administration.

<p>Data are expressed as mean ± SEM. **, *** denote <i>p</i><0.01, <i>p</i><0.001 versus control (0 ml/kg of DMSO); ANOVA with Newman-Keuls <i>post hoc</i> for each time point.</p

Regional anatomical localization of phosphorylated tau protein in DMSO treated mice at 5X (A-B, G-H, M-N), 20X (C-D, I-J, O-P) and 40X magnification (E-F, K-L, Q-R).

<p>Fluorescent photomicrographs of hippocampal sagittal sections are shown with AT8 (Red, A-F), Total Tau (Green, G-L), or merged with DAPI (M-R), for the following groups: control (A, C, E, G, I, K, M, O, Q) or DMSO-treated mice (B, D, F, H, J, L, N, P, R).</p

Effect of DMSO on tau phosphorylation in 3R human tau transfected SH-SY5Y cells following 1 h exposure.

<p>Cell lysate protein extracts were separated by SDS-PAGE and levels of tau phosphorylation were determined using antibodies directed at the (A) AT8, (B) PHF-1, or (C) AT180 phosphoepitopes, and (D) total tau. Relative immunoreactive band intensities are expressed as a percent of control from a total Tau ratio and are displayed for each phosphoepitope and total tau. For each condition, 2 representative data are displayed with control (n  = 9) and 0.1% DMSO (n  = 9). Data are expressed as mean ± SD. *, ** denote <i>p</i><0.05 and <i>p</i><0.01, versus control, respectively; Student’s t test.</p

Tau phosphorylation in mouse hippocampal tissue 1 h following the administration of DMSO at 0, 1, 2, and 4 ml/kg i.p.

<p>Hippocampal protein extracts were separated by SDS-PAGE and levels of tau phosphorylation were determined using antibodies directed at the (A) AT8 (pSer²⁰²/pThr²⁰⁵), (B) PHF-1 (pSer³⁹⁶/pSer⁴⁰⁴), (C) AT180 (pThr²³¹/pSer²³⁵) phophoepitopes, or (D) total Tau. For each phosphoepitope, relative immunoreactive band intensities are expressed as a ratio to total tau and are displayed as a percentage of control (0 ml/kg of DMSO). For each condition, 2 representative data are displayed with controls (0 ml/kg; n  = 5), 1 ml/kg (n  = 5), 2 ml/kg (n  = 5) and 4 ml/kg (n  = 5). Data are expressed as mean ± SD. *, **, *** denote <i>p</i><0.05, <i>p</i><0.01 and <i>p</i><0.001 versus control, respectively; ANOVA with Newman-Keuls <i>post hoc</i> test.</p

Tau phosphorylation in mouse hippocampal tissue 1 h following the administration of DMSO (4 ml/kg i.p.) under hypothermic (Hypo) and normothermic (Normo) conditions.

<p>Hippocampal protein extracts were separated by SDS-PAGE and levels of tau phosphorylation were determined using antibodies directed at the (A) AT8 (pSer²⁰²/pThr²⁰⁵), (B) PHF-1 (pSer³⁹⁶/pSer⁴⁰⁴), (C) AT180 (pThr²³¹/pSer²³⁵) phophoepitopes, or (D) total Tau. For each phosphoepitope, relative immunoreactive band intensities are expressed as a ratio to total tau and are displayed as a percentage of control (0 ml/kg of DMSO). For each condition, 2 representative data are displayed with controls (0 ml/kg; n  = 5), 4 ml/kg DMSO in hypothermic conditions (n  = 5), and 4 ml/kg DMSO in normothermic conditions (n  = 6). Data are expressed as mean ± SD. **, *** denote <i>p</i><0.01, <i>p</i><0.001 versus control, respectively; ANOVA with Newman-Keuls <i>post hoc</i> test.</p