Alpha7 nicotinic acetylcholine receptor-specific agonist DMXBA (GTS-21) attenuates Aβ accumulation through suppression of neuronal γ-secretase activity and promotion of microglial amyloid-β phagocytosis and ameliorates cognitive impairment in a mouse model of Alzheimer's disease

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

“…The therapeutic value of rescuing α7nAChR function is well reported (Lombardo & Maskos, 2015;Yang et al, 2017). For example, activation of α7nAChRs has been shown to counteract Aβ-promoted inhibition of hippocampal LTP (Kroker, Moreth, Kussmaul, Rast, & Rosenbrock, 2013), to significantly improve cognitive performance in the 3xTg-AD mice (Medeiros et al, 2014), to protect against Aβ cytotoxicity (Kaneko et al, 1997), and to attenuate Aβ accumulation (Takata et al, 2018). Therefore, it is not surprising that the α7nAChR has been considered as a molecular target in drug development programmes for AD.…”

Positive Allosteric Modulation of Alpha7 Nicotinic Acetylcholine Receptors Transiently Improves Memory but Aggravates Inflammation in LPS-Treated Mice

“…The increase in α7-bound Aβ(1-42) found 2 months after a single LPS injection can be explained by both the decrease of α7 nAChRs and accumulation of Aβ peptides. Similarly, the effect of PNU282 can be attributed to either up-regulation of α7 nAChRs or decreased production of Aβ peptides, since another α7-selective agonist DMXBA suppressed γ-secretase activity in solubilized fractions of human neuroblastoma cells and transgenic mouse brain (Takata et al, 2018). In contrast, the increase of α7-bound Aβ(1-42) under the effect of nicotine was not related to changes in α7 expression but was possibly due to elevated cellular levels of β-secretase (Ohshima et al, 2018) and accumulation of Aβ peptides in the brain (Liu et al, 2017).…”

High Availability of the α7-Nicotinic Acetylcholine Receptor in Brains of Individuals with Mild Cognitive Impairment: A Pilot Study Using 18F-ASEM PET

“…The kinetics of 18 F-ASEM were modeled using Logan graphical analysis (14) with a metabolite-corrected arterial input function obtained from 90 min of dynamic data, generating a regional 18 F-ASEM total distribution volume, V T (15) . To address the effect of atrophy on 18 F-ASEM binding in the brains of this elderly study population, we report regional V T values that were derived from PET data after partial-volume correction (PVC) using the algorithm of Müller-Gärtner et al (16). V T estimates from images without PVC were secondary binding outcomes.…”

“…Relative to control tissue, a nonsignificant trend toward higher basal forebrain a7-nAChR expression was found in cases of mild cognitive impairment (MCI), a prodromal stage to dementia (6). 18 F-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-18 F-fluorodibenzo[b,d]thiophene 5,5-dioxide) is a PET radioligand for estimating the availability of a7-nAChR in the brain in vivo and has shown high specific binding in receptor blockade studies in mice (7) and baboons (8). 18 F-ASEM PET has been used to study the a7-nAChR in healthy aging (9) and psychosis (10).…”

“…18 F-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-18 F-fluorodibenzo[b,d]thiophene 5,5-dioxide) is a PET radioligand for estimating the availability of a7-nAChR in the brain in vivo and has shown high specific binding in receptor blockade studies in mice (7) and baboons (8). 18 F-ASEM PET has been used to study the a7-nAChR in healthy aging (9) and psychosis (10). In this pilot study, we used 18 F-ASEM PET to test for higher in vivo availability of a7-nAChR in individuals with MCI than in cognitively intact, healthy controls.…”