TY  - JOUR
AB  - BACKGROUND: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-β (Aβ) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. OBJECTIVE: In the present study, we want to detail the interactions of inhalational anesthetics with Aβ-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aβ oligomerization and Aβ-mediated neurotoxicity on processes related to cognition. METHODS: Oligomerization of Aβ 1-42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aβ 1-42, Aβ 1-40, pyroglutamate-modified amyloid-(AβpE3), and nitrated Aβ (3NTyrAβ), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aβ plaque burden in transgenic AD mice (ArcAβ) after anesthesia. RESULTS: Whereas isoflurane and sevoflurane did not affect Aβ 1-42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AβpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aβ 1-42-induced spine density attenuation. In the presence of Aβ 1-40 and AβpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aβ 1-42 or 3NTyrAβ, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAβ mice. CONCLUSION: None of the anesthetics aggravated Aβ-derived AD pathology in vivo. However, Aβ and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aβ 1-42 aggregation, LTP, and spine density.
AU  - Hofmann, C.*
AU  - Sander, A.*
AU  - Wang, X.X.*
AU  - Buerge, M.*
AU  - Jungwirth, B.*
AU  - Borgstedt, L.*
AU  - Kreuzer, M.*
AU  - Kopp, C.*
AU  - Schorpp, K.K.
AU  - Hadian, K.
AU  - Wotjak, C.T.*
AU  - Ebert, T.*
AU  - Ruitenberg, M.*
AU  - Parsons, C.G.*
AU  - Rammes, G.*
C1  - 63466
C2  - 51543
CY  - Nieuwe Hemweg 6b, 1013 Bg Amsterdam, Netherlands
SP  - 1193-1218
TI  - Inhalational anesthetics do not deteriorate amyloid-β-derived pathophysiology in alzheimer's disease: Investigations on the molecular, neuronal, and behavioral level.
JO  - J. Alzheimers Dis.
VL  - 84
IS  - 3
PB  - Ios Press
PY  - 2021
SN  - 1387-2877
ER  - 

TY  - JOUR
AB  - A breakthrough in Alzheimer's disease (AD) research came with the discovery of the link between activity-dependent release of amyloid-β (Aβ) from neurons and formation of amyloid plaques. Along with elucidating the cellular basis of behavioral-dependent fluctuations in Aβ levels in the brain, insights have been gained toward understanding the mechanisms that warrant selective vulnerability of various forebrain circuits to amyloid pathology. The notion of elevated activity as a source of excessive Aβ production and plaque formation is, however, in conflict with ample electrophysiological data, which demonstrate exceedingly intense activity (both intrinsic and synaptic) of neurons in several brain regions that are spared or marginally affected by amyloid plaques of AD. Thus, the link between the functional load of brain circuits and their vulnerability to amyloidosis, while evident, is also complex and remains poorly understood. Here, we discuss emerging data suggestive of a major role for super-intense synchronous activity of cortical and limbic networks in excessive Aβ production and plaque formation. It is proposed that dense recurrent wiring of associative areas prone to epileptic seizures might be of critical relevance to their higher susceptibility to plaque pathology and related functional impairments.
AU  - Ovsepian, S.V.*
AU  - O'Leary, V.B.
C1  - 47165
C2  - 39126
SP  - 13-19
TI  - Neuronal activity and amyloid plaque pathology: An update.
JO  - J. Alzheimers Dis.
VL  - 49
IS  - 1
PY  - 2015
SN  - 1387-2877
ER  - 

TY  - JOUR
AB  - Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
AU  - Gerrish, A.*
AU  - Russo, G.*
AU  - Richards, A.*
AU  - Moskvina, V.*
AU  - Ivanov, D.*
AU  - Harold, D.*
AU  - Sims, R.*
AU  - Abraham, R.*
AU  - Hollingworth, P.*
AU  - Chapman, J.*
AU  - Hamshere, M.*
AU  - Pahwa, J.S.*
AU  - Dowzell, K.*
AU  - Williams, A.*
AU  - Jones, N.*
AU  - Thomas, C.*
AU  - Stretton, A.*
AU  - Morgan, A.R.*
AU  - Lovestone, S.*
AU  - Powell, J.*
AU  - Proitsi, P.*
AU  - Lupton, M.K.*
AU  - Brayne, C.*
AU  - Rubinsztein, D.C.*
AU  - Gill, M.*
AU  - Lawlor, B.*
AU  - Lynch, A.*
AU  - Morgan, K.*
AU  - Brown, K.S.*
AU  - Passmore, P.A.*
AU  - Craig, D.*
AU  - McGuinness, B.*
AU  - Todd, S.*
AU  - Johnston, J.A.*
AU  - Holmes, C.*
AU  - Mann, D.*
AU  - Smith, A.D.*
AU  - Love, S.*
AU  - Kehoe, P.G.*
AU  - Hardy, J.*
AU  - Mead, S.*
AU  - Fox, N.*
AU  - Rossor, M.*
AU  - Collinge, J.*
AU  - Maier, W.*
AU  - Jessen, F.*
AU  - Kölsch, H.*
AU  - Heun, R.*
AU  - Schürmann, B.*
AU  - Bussche, H.*
AU  - Heuser, I.*
AU  - Kornhuber, J.*
AU  - Wiltfang, J.*
AU  - Dichgans, M.*
AU  - Frölich, L.*
AU  - Hampel, H.*
AU  - Hüll, M.*
AU  - Rujescu, D.*
AU  - Goate, A.M.*
AU  - Kauwe, J.S.*
AU  - Cruchaga, C.*
AU  - Nowotny, P.*
AU  - Morris, J.C.*
AU  - Mayo, K.*
AU  - Livingston, G.*
AU  - Bass, NJ.*
AU  - Gurling, H.*
AU  - McQuillin, A.*
AU  - Gwilliam, R.*
AU  - Deloukas, P.*
AU  - Davies, G.*
AU  - Harris, S.E.*
AU  - Starr, J.M.*
AU  - Deary, I.J.*
AU  - Al-Chalabi, A.*
AU  - Shaw, C.E.*
AU  - Tsolaki, M.*
AU  - Singleton, A.B.*
AU  - Guerreiro, R.*
AU  - Mühleisen, T.W.*
AU  - Nöthen, M.M.*
AU  - Moebus, S.*
AU  - Jöckel, K.-H.*
AU  - Klopp, N.
AU  - Wichmann, H.-E.
AU  - Carrasquillo, M.M.*
AU  - Pankratz, V.S.*
AU  - Younkin, S.G.*
AU  - Jones, L.*
AU  - Holmans, P.A.*
AU  - O'Donovan, M.C.*
AU  - Owen, M.J.*
AU  - Williams, J.*
C1  - 7223
C2  - 29526
SP  - 377-387
TI  - The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.
JO  - J. Alzheimers Dis.
VL  - 28
IS  - 2
PB  - IOS Press
PY  - 2012
SN  - 1387-2877
ER  -