Role of ABeta in neural synapse and circuit remodeling following general anesthes

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Nearly 40% of surgical procedures are performed on patients 65 years of age or older and cognitive complications are common. General anesthesia has been implicated and seniors worry that the anesthesia might cause permanent memory problems or even dementia. Clinical studies are inconclusive but preclinical studies show that some general anesthetic agents produce prolonged memory impairment and promote Alzheimer's disease (AD)-like biochemical changes in the brain. In particular, the commonly used volatile anesthetic isoflurane rapidly increases amyloid ? (A?), a protein strongly implicated in the neuropathogenesis of Alzheimer's disease, and causes long-lasting memory impairment, whereas desflurane, also widely used, does neither. Further, the biochemical changes are exaggerated in AD transgenic mice that have elevated levels of cerebral Abeta at baseline, implying pre-existing cerebral amyloid may be a vulnerability factor for anesthetic-induced cognitive decline. Mounting evidence indicates AD is primarily a disease of progressive synaptic dysfunction and loss that results in both synaptic depression and aberrant patterns of neuronal network activity, with oligomeric Abeta playing a major role in the process. However, no studies have investigated the impact of an anesthetic- induced increase in Abeta on neural synapses and networks. We propose to do so here, using isoflurane and desflurane anesthesia and Arc::dVenus reporter mice and Arc:dVenus/PS1 AD transgenic mice as models, respectively, of the 'normal' and Abeta-burdened brain. Arc is an immediate early gene that is a central regulator of dendritic spine dynamics and experience-dependent plasticity and Arc:dVenus mice overexpress destabilized Venus (dVenus) under control of the Arc promoter, allowing experience-evoked activity in spines and neurons to be directly visualized by fluorescence microscopy. We hypothesize that an increase in Abeta after isoflurane anesthesia has different consequences in the healthy vs. Abeta-burdened brain. We propose that an isoflurane-induced increase in Abeta causes collapse of dendritic spines (Aim 1) and 2. Generates abnormal patterns of experienced-evoked activity in hippocampal neural circuits (Aim 2) when the pre-existing amyloid burden is high but not otherwise, and that desflurane has no effect. This research is significant scientifically because it will clarify the functional consequences of anesthetic-induced increases in Abeta. Furthermore, because 1 in 3 older adults without cognitive symptoms, and most of those with mild cognitive impairment (MCI) or AD, have elevated amyloid at baseline, this work could have vast clinical implications for improving anesthetic care and reducing cognitive morbidity in geriatric surgical patients.