Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia

Abstract

Alzheimer's disease and other tauopathies are characterized by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated, insoluble tau. General anesthesia has been shown to be associated with increased risk of Alzheimer's disease, and we have previously demonstrated that anesthesia induces hypothermia, which leads to overt tau hyperphosphorylation in the brain of mice regardless of the anesthetic used. To investigate whether anesthesia enhances the long-term risk of developing pathological forms of tau, we exposed a mouse model with tauopathy to anesthesia and monitored the outcome at two time points-during anesthesia, or 1 wk after exposure. We found that exposure to isoflurane at clinically relevant doses led to increased levels of phospho-tau, increased insoluble, aggregated forms of tau, and detachment of tau from microtubules. Furthermore, levels of phospho-tau distributed in the neuropil, as well as in cell bodies increased. Interestingly, the level of insoluble tau was increased 1 wk following anesthesia, suggesting that anesthesia precipitates changes in the brain that provoke the later development of tauopathy. Overall, our results suggest that anesthesia-induced hypothermia could lead to an acceleration of tau pathology in vivo that could have significant clinical implications for patients with early stage, or overt neurofibrillary tangle pathology.

The Unexpected Capability of Melanin to Split the Water Molecule and the Alzheimer’s Disease

“…We lose our capacity to perform the photosynthesis function at its peak during adulthood (which is less than that of embryonic period) at an approximate rate of 10% with each decade of life after the mid-twenties, and when we reach our fifties it goes into free fall. The potential risk factor for sporadic Alzheimer's disease, general anesthesia, promotes tau insolubility and Aβ oligomerization [9,10], and that is congruent with our findings because the water dissociation capacity in the human body is very sensitive to agents with an elevated apparent distribution volume, such as anesthesia agents and antidepressants.…”

Early Improved and Late Defective Cognition Is Reflected by Dendritic Spines in Tau.P301L Mice

“…Immunohistochemistry (IHC) for phosphorylated protein Tau with antibody AT8 benchmarks the pathological progression of AD (Braak and Braak, 1991). Of note, operational implementation of AT8 in pathology does not define the specified phosphorylations as pathological because AT8 reaction is evident physiologically in development and the adult brain, in humans and animals, and in normal conditions, hibernation, and hypothermia (Kenessey and Yen, 1993;Takuma et al, 2003;Härtig et al, 2005Härtig et al, , 2007Planel et al, 2009;Braak and Del Tredici, 2011;Duyckaerts, 2011).…”

Perioperative Cognitive Decline in the Aging Population

“…93 Anesthetic-induced Aβ accumulation also is associated with caspase activation and apoptosis, 94 and anesthesia-induced hypothermia has been shown to induce tau protein phosphorylation. 89,95 However, the anesthetic propofol can also directly increase tau protein phosphorylation. 96 Alternative findings that suggest that anesthesia is not associated with neurodegenerative diseases and/or that anesthetics do not promote neurodegeneration are summarized in 2 recent reviews.…”

“…9 Evidence from animal models and cell culture studies suggests that exposure to anesthetics induces pathologic changes normally associated with AD, including increase in Aβ peptide and β-actin cleavage enzyme 88 ; anesthesia-induced hypothermia also increased tau hyperphosphorylation by decreasing phosphatase 2A activity. 95 In a transgenic mouse model of AD, exposure to halothane increased Aβ plaque deposition but was not associated with further deterioration of cognitive function. 100 Anesthesia also appeared to have no effect on APP transcription and expression.…”