Isoflurane anesthesia promotes cognitive impairment by inducing expression of β-amyloid protein-related factors in the hippocampus of aged rats.

Shuai Zhang,Wei Guan,Bei Li,Qichao Tang,Honggang Fan,Li Luan,Xueyuan Hu,Cristoforo Scavone

doi:10.1371/journal.pone.0175654

Abstract

Isoflurane anesthesia has been shown to be responsible for cognitive impairment in Alzheimer’s disease (AD) and development of AD in the older age groups. However, the pathogenesis of AD-related cognitive impairments induced by isoflurane anesthesia remains elusive. Thus, this study was designed to investigate the mechanism by which isoflurane anesthesia caused AD-related cognitive impairments. Aged Wistar rats were randomly divided into 6 groups (n = 12), 1 control group (CONT) and 5 isoflurane treated (ISO) groups (ISO 0, ISO 0.5D, ISO 1D, ISO 3D and ISO 7D). The CONT group inhaled 30% O2 for 2 h without any anesthesia. ISO groups were placed under anesthesia with 3% isoflurane and then exposed to 1.5% isoflurane delivered in 30% O2 for 2 h. Rats in each ISO group were then analyzed immediately (ISO 0) or at various time points (0.5, 1, 3 or 7 day) after this exposure. Cognitive function was assessed using the Morris water maze test. Protein levels of amyloid precursor protein (APP), β-site APP cleavage enzyme-1 (BACE-1) and Aβ42 peptide were analyzed in hippocampal samples by Western blot. β-Amyloid (Abeta) plaques were detected in hippocampal sections by Congo red staining. Compared with controls, all ISO groups showed increased escape latency and impaired spatial memory. Isoflurane increased APP mRNA expression and APP protein depletion, promoting Aβ42 overproduction, oligomerization and accumulation. However, isoflurane did not affect BACE-1 expression. Abeta plaques were observed only in those ISO groups sacrificed at 3 or 7 d. Our data indicate that aged rats exposed to isoflurane had increased APP mRNA expression and APP protein depletion, with Aβ42 peptide overproduction and oligomerization, resulting in formation of Abeta plaques in the hippocampus. Such effects might have contributed to cognitive impairments, including in spatial memory, observed in these rats after isoflurane anesthesia.

Highlights

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease
We explored effects of isoflurane anesthesia on cognitive impairment in aged rats
We examined the relationship between these cognitive impairments and certain AD-associated β-amyloid protein-related properties in the hippocampi of these animals

Summary

Introduction

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease. It is primarily characterized by deleterious changes in orientation, judgment and personality, as well as social and cognitive abilities. A major molecular etiology of AD involves overproduction and accumulation of β-amyloid (Aβ) peptides. APP was mainly through the non-amyloidogenic pathway and cleaved by α- and γ-secretases, which did not generate Aβ peptides. APP was primarily by the amyloidogenic pathway and cleaved by β-secretase (BACE-1), which generated Aβ peptides. Amyloid plaques consist primarily of Aβ42 and Aβ40, peptides generated by the amyloidogenic processing of APP [6]. Levels of Aβ40 in the brain are higher than those of Aβ42, Aβ42 has greater neuronal toxicity because it more readily generates the large oligomers that form plaque-like deposits on the cell membrane surface [7,8,9]. The overproduction, oligomerization and accumulation of Aβ have become regarded as central to the pathogenesis of AD [11, 12]

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