Can Exposure to Volatile Anesthetics Be a Tipping Point for AD Susceptible Populations?

The relationship between surgery induced Postoperative Cognitive Dysfunction (POCD) and the development of Alzheimer’s disease (AD) later has been a debatable question. Volatile anesthetics represent a potential environmental factor that can change the CNS both acutely and long-term. By interacting with membrane cholesterol to alter signaling in neurons or alter the normally quiescent microglial phenotype, volatile anesthetics are implicated in the development of POCD. The tipping point for triggering AD cyclic pathology may rest with individual AD genetic risk factors combined with the known molecular consequences of anesthetic exposure. This review covers genome wide association studies (GWAS) identifi ed AD risk factors, actions of volatile anesthetics in the development of AD phenotypes and presents some newly discovered pre or post-anesthetic POCD attenuating therapies. Review Article Can Exposure to Volatile Anesthetics Be a Tipping Point for AD Susceptible Populations? Ingrid R Niesman* Department of Cellular & Molecular Medicine, University of California-San Diego, 2880 North Torrey Pines Scenic Drive, CA, USA Dates: Received: 16 December, 2016; Accepted: 21 February, 2017; Published: 22 February, 2017 *Corresponding author: Ingrid R. Niesman, M.S., Ph.D. Senior Research Associate, Department of Cellular & Molecular Medicine, University of California-San Diego, 2880 North Torrey Pines Scenic Drive, La Jolla, CA 92037-0695, USA, Tel: (858) 534-9700; Fax: (858) 2460162; E-mail:


Introduction
As a consequence of modern medicine and healthier living, our population is aging beyond our current understanding of geriatric physiology. One inevitable fact society must face is the growing number of cases of age-related cognitive decline and neurodegenerative diseases. The costs of these conditions in terms of monetary value and in terms of human quality of life are unquantifi able. We have identifi ed numerous genetic and lifestyle risk factors for development of Alzheimer's disease (AD), yet penetrance across populations is sporadic [1,2]. Thus, the actual mechanistic triggers or tipping points to initial the pathological cascades leading to AD or other forms of cognitive decline have remained elusive.
One of the most prominent risk factors for the development of late onset Alzheimer's disease (LOAD) is the presence of heterozygous or homozygous ApoE4 alleles. ApoE and cholesterol have a complex inter-relationship in CNS. Astrocytes are the major producers of cholesterol and neurons are the major consumers, using the cholesterol transported by ApoE particles to build their elegant membrane structures and maintain the synaptic superhighway of information. Therefore, dysfunction in transport, uptake or traffi cking of cholesterol may represent major contributing factors to the development of AD [3][4][5]. Along those lines of reasoning, other factors which potentially disrupt cholesterol biogenesis, synthesis and mechanisms of action, could exacerbate already damaged cells, leading to clinical pathology.
Volatile general anesthetics (vGA) interact directly with cholesterol in the plasma membrane, through an undefi ned mechanism, and alter signal transduction cascades [6]. These effects can be considered acute or chronic [7] depending on the precise protein or receptor affected. However, the actual chemical structure of individual anesthetics may dictate these interactions. Isofl urane (ISO) and sevofl urane (SEVO) have been shown to have opposing effects compared to desfl urane (DES), due to differences in the degradative byproduct trifl uoroacetic acid or the shorter action time [8,9].
Postoperative Cognitive Dysfunction (POCD) is a well described clinical syndrome found in elderly patients following surgery, with duration and symptomology widely varying and found to be associated with use of inhaled anesthetics.
Any combination of AD risk factors and common surgical procedures may be considered a triggering event in the long pathological decline leading to full-blown AD disease. This review will discuss: a) the implications of vGA exposure in the development of cognitive impairment, b) theories supporting vGA as an initiating trigger of AD pathology and c) identify some potential therapeutic targets to attenuate the consequences.

Genetic risk factors and volatile anesthetic interactions
The Alzheimer's Association (Alz.org) currently estimates around 5.3 million AD patients in the US alone and the number will escalate as the percentage of people >65 years increases in the population. Bioinformatics, combined with robust genomic analyses, have identifi ed new cohorts of risk factors associated with development of sporadic Alzheimer's disease (SAD) or LOAD. What we currently lack is an understanding of how the daily human experience and the molecular mechanisms of risk factors genes can synergize, leading to AD clinical manifestations. One signifi cant environmental factor which has the potential to alter physiology both transiently and chronically, is the use of volatile anesthetics during surgical procedures [10]. Anesthetics such as ISO are commonly administered to all age populations and have been linked to early childhood cognitive issues [11] and elderly POCD [8]. Older adults represent a large percentage of surgical patients, with cardiovascular surgery and joint replacements common procedures requiring extensive use of anesthetics. Physiological interactions at a molecular level between variant risk gene proteins and volatile anesthetics may likely determine the initiation of dementia and classical AD pathologies in any number of individuals. Familial Alzheimer's disease (FAD) has a clear genetic component. Mutations and duplications of human amyloid precursor protein (APP) and the presenilins 1 and 2 (PSEN1; PSEN2) have been identifi ed in large family cohorts of patients [12], but, these cases represent only a minor fraction of current clinical presentation. The etiology of the remaining cases is still an open debate. Newly identifi ed AD risk variants, typically single nucleotide polymorphisms -SNPs -form interesting cluster patterns, ranging from cholesterol biology, intracellular traffi cking to neuro infl ammation [1,2,5,[13][14][15][16]. Table 1 lists current information on genes with risk identifi ed SNPs, cell type most affected and the cellular function if defi ned.
Precisely how these variant proteins can alter normal CNS homeostasis and result in AD related cognitive decline or how individuals with these genetic alleles avoid AD pathology are key questions. Until we have a signifi cant pool of fully sequenced humans and a lifetime to study their particular nurturing and environmental interactions, the latter will remain unanswered and unobtainable. However, we have begun to unravel connections between AD risk factors and anesthetic exposure [10]. POCD has been clinically recognized and has clearly defi ned operational criteria [17]. How, when and where the transition or switch from simple POCD to the long pathway of synapse loss, neuronal damage and neuroinfl ammation occurs has been confounded by the use of transgenic AD mouse models, non-human CNS cell cultures and a lack of defi nitive long term human clinical studies.

Known volatile anesthetic effects
Volatile anesthetics interact directly with the lipid bilayer, modifying the local lipid and protein environment. Three theories have been proposed for the interactions of lipids and volatile anaesthetics: 1) direct binding to membrane proteins modifying their conformation and signaling activity; 2) binding to and weakening cholesterol and phospholipid associations which alters plasma membrane localized ion channel activity; and 3) binding specifi cally to lipid raft domains, modifying their lateral organization, interfering with many required protein-protein interaction in signal transduction pathways [18].
As the chemical structures of this class of anesthetics are diverse, the interactions with lipids and proteins are likely to differ and have differential effects. ISO has a weakening effect on cholesterol-phospholipid interaction in lipid raft domains, suggesting that ISO acts as a "replacement" or substitute for cholesterol [19,20]. Propofol (PPF), on the other hand, can interact with raft or non-raft domains and when PPF induced metabolic changes, after exposure, were compared to SEVO post-exposure, distinct differences in fatty acid or glucose oxidation were seen. SEVO increases fatty acid transport and PPF increases pyruvate dehydrogenase activity without affecting GLUT4 [20].
Within the CNS, these volatile anesthetics can interact differentially within the membrane environment based on phospholipid composition and differentially with local areas of membrane specialization, such as the pre or postsynaptic zones or lipid rafts. vGA effects may also be temporally different throughout lifespans. We are now realizing the profound phenotypic differences between young glia and old glia in terms of priming, cytoskeletal integrity and mitochondrial function. The same can be said for neuronal phenotypes; young cells are highly plastic, while older neurons have a myriad of dysfunctional cell operations, such as autophagy [21].

How volatile general anesthetics (vGA) can induce AD pathology
The hallmark pathology of AD has long been considered extracellular deposition of toxic A -amyloid plaques -and/ or the intracellular accumulation of oligomerized tau protein, known as neurofi brillary tangles (NFT), but this concept is currently challenged [22]. Still, the controversy rages on and recent data clearly suggests that these pathologies are probably symptomatic not causative [23]. vGAs have the capacity to increase A processing [10,24,25]. Importantly, 2% ISO treatment for six hours drives −secretase activity over −secretase activity, increasing the A 1-42 toxic cleavage product, leading to aggregation over short time points [24,26].
When these cell culture studies are repeated in transgenic AD mouse models however, inconsistent data is found across compounds. In their 2011 review, Papon et al, conclude that although it appears little differences in APP processing occurs in normal mice following vGA exposures, transgenic mice with known increased A plaque formation are at increased risk for increased aberrant APP processing following exposures [27].
Tau protein is a small molecular weight microtubule- loses functionality -reviewed by [28]. Tau is continually phosphorylated on multiple serine and threonine residues -hyperphosphorylation -an initiating step in the pretangle stages of tau aggregation [29,30]. vGA can accelerate this process by increasing pS and pThr sites directly [31]  The search for an intervention when a mechanism is not yet fully elucidated: POCD to AD Armed with the idea that neuroinfl ammation may be the underlying condition fueling POCD and ultimately AD, several groups have begun exploring novel anesthetic preor post-treatments to reduce the activation of microglia in the hippocampus and other brain regions, reviewed by [39].
Berberine is a natural isoquinoline alkaloid, with known anti- required for full microglial activation [44]. They found that they were able to stave off microglia activation by oxidative stress mechanisms, using deferoxamine, and were also able to prevent the associated neurotoxicity and cognitive defi cits.
Two studies, published in early 2017, have intriguing data on other possible selective targets and pathways to mitigate POCD. The fi rst study attenuates POCD associated neurodegeneration in aged mice with PPAR activation using the agonist pioglitazone prior to ISO exposure. Antagonizing the receptor reverses the positive benefi ts of pre-treatment [45]. The already approved pioglitazone treatment for diabetes lowers blood sugar levels but has potential cardiac risks with long-term treatment. However, the suggestion that short term or acute administration prior to surgery can provide behavioural benefi ts makes this pathway an attractive target and well worth investigating in clinical trials. Since vGA exposure -SEVO in particular -increases p-tau/t-tau ratios and inhibits the autophagy pathway through mTOR [34,35], a compound that targets both p-tau generation and moderates autophagy pathways is another method worth investigating. The nutriceutical selenomethionine (Se-Met) has shown effi cacy in the retention of cognitive function in mouse transgenic AD models [46]. This compound reduces p-tau by modulation of the key GSK-3/PP2A pathway and concomitantly activates the AMPK-mTOR axis to enhance autophagic clearance. Animals were treated for 3-month, not short term, and the effects were modest but as proof of concept studies, they establish the basis to screen for other similar compounds with faster kinetics and pharmacodynamics.   Once differentiation is confi rmed, the cells are exposed to Vga and readouts for AD pathology and neuroinflammation are assessed.