Neurotoxicity of different amyloid beta subspecies in mice and their interaction with isoflurane anaesthesia

Abstract

Background The aim of this study was to assess different amyloid beta subspecies’ effects on behaviour and cognition in mice and their interaction with isoflurane anaesthesia. Methods After governmental approval, cannulas were implanted in the lateral cerebral ventricle. After 14 days the mice were randomly intracerebroventricularly injected with Aβ 1–40 (Aβ40), Aβ 1–42 (Aβ42), 3NTyr10-Aβ (Aβ nitro), AβpE3-42 (Aβ pyro), or phosphate buffered saline. Four days after the injection, 30 mice (6 animals per subgroup) underwent general anaesthesia with isoflurane. A “sham” anaesthetic procedure was performed in another 30 mice (6 animals per subgroup, 10 subgroups in total). During the next eight consecutive days a blinded assessor evaluated behavioural and cognitive performance using the modified hole-board test. Following the testing we investigated 2 brains per subgroup for insoluble amyloid deposits using methoxy staining. We used western blotting in 4 brains per subgroup for analysis of tumour-necrosis factor alpha, caspase 3, glutamate receptors NR2B, and mGlu5. Data were analysed using general linear modelling and analysis of variance. Results Aβ pyro improved overall cognitive performance (p = 0.038). This cognitive improvement was reversed by isoflurane anaesthesia (p = 0.007), presumably mediated by decreased exploratory behaviour (p = 0.022 and p = 0.037). Injection of Aβ42 was associated with increased anxiety (p = 0.079). Explorative analysis on a limited number of brains did not reveal insoluble amyloid deposits or differences in the expression of tumour-necrosis factor alpha, NR2B, mGlu5, or caspase 3. Conclusions Testing cognitive performance after intracerebroventricular injection of different amyloid beta subspecies revealed that Aβ pyro might be less harmful, which was reversed by isoflurane anaesthesia. There is minor evidence for Aβ42-mediated neurotoxicity. Preliminary molecular analysis of biomarkers did not clarify pathophysiological mechanisms.

Isoflurane has no effect on cognitive or behavioral performance in a mouse model of early-stage Alzheimer’s disease

“…The day following general anesthesia or sham procedure, respectively, mice were tested for cognitive and motor function as well as behavior using the mHBT. This test is a combination of a classical hole-board with an open field test, according to an established protocol ( Gordan et al, 2012 ; Borgstedt et al, 2020 ). With this test, a total of 16 different parameters can be observed simultaneously.…”

Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology

“…(3) The complexity of Aβ itself. All the following factors matter in Aβ functions: length of fragments [ 248 ], concentration, intracellular or extracellular localization, and aggregation state [ 47 ]. For instance, nanomolar concentrations of intra-axonal oligomeric Aβ42 (o Aβ42), but not oAβ40 or extracellular oAβ42, acutely inhibit synaptic transmission in squid [ 6 ].…”

In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer’s Disease

“…Another enzyme is the beta-secretase 1 (BACE1), which is a transmembrane aspartic protease, which cleaves amyloid precursor protein (APP) and produces Aβ 1-42 [ 12 , 13 ]. The Aβ 1-42 can aggregate and produce neurotoxicity, thus, inhibiting BACE1 can help in the treatment of AD [ 14 , 15 ]. In this context, in 2020 the Food and Drug Administration (FDA) approved the use of an antibody (Aduhelm from Biogen) to reduce the amyloid beta plaques in the brain as a treatment for AD [ 16 , 17 ].…”