Our results demonstrated that myelin injury was an early event in 5XFAD mice even prior to emergence of deposition of Aβ. Intervention with the LINGO-1 antibody could attenuate impaired spatial memory deficits by remyelination, which suggested that myelin injury was involved in spatial memory deficits and remyelination may be a potential therapeutic strategy in early stage of AD or mild cognitive impairments.

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Dysfunction of neuronal activity is a major and early contributor to cognitive impairment in Alzheimer's disease (AD). To investigate neuronal activity alterations at early stage of AD, we encompassed behavioral testing and in vivo manganese-enhanced magnetic resonance imaging (MEMRI) in 5XFAD mice at early ages (1-, 2-, 3- and 5-month). The 5XFAD model over-express human amyloid precursor protein (APP) and presenilin 1 (PS1) harboring five familial AD mutations, which have a high APP expression correlating with a high burden and an accelerated accumulation of the 42 amino acid species of amyloid-β. In the Morris water maze, 5XFAD mice showed longer escape latency and poorer memory retention. In the MEMRI, 5XFAD mice showed increased signal intensity in the brain regions involved in spatial cognition, including the entorhinal cortex, the hippocampus, the retrosplenial cortex and the caudate putamen. Of note, the observed alterations in spatial cognition were associated with increased MEMRI signal intensity. These findings indicate that aberrant increased basal neuronal activity may contribute to the spatial cognitive function impairment at early stage of AD, and may further suggest the potential use of MEMRI to predict cognitive impairments. Early intervention that targets aberrant neuronal activity may be crucial to prevent cognitive impairment.

The animal model for depressive behavior due to chronic unpredicted mild stress (CUMS) is commonly used to evaluate antidepressant treatments. The CUMS model has faced some criticism because of the heterogeneity of behavioral effects. Spadin and SID1900 are TREK1 blockers with a quick antidepressant effect. However, to date, their effectiveness and the long-term therapeutic mechanisms are not known. We hypothesize that early intervention with TREK1 blockers can fully reverse depressive-like behaviors, that the chronic administration of TREK1 blockers has a more pronounced effect than the SSRI fluoxetine, and that its long-term therapeutic effects may be mediated by improvement of impaired neurogenesis. Furthermore, we optimized the use of the CUMS model for increased homogeneity by screening the rats after the CUMS induction procedure. Depressive-like behavior was assessed by a forced swimming test, sucrose preference, and open field tests. To evaluate neurogenesis, cell proliferation and newly generated cell apoptosis were measured in the hippocampal dentate gyrus. Of 32 rats that underwent the CUMS procedure, 26 rats that exhibited depressive-like behaviors were grouped as CUMS sensitive rats (CUMSS), while six that did not were grouped as CUMS resistant ones (CUMSR). The CUMSR rats exhibited minor neurogenesis impairments, while the CUMSS rats had a more pronounced effect. Treatment with TREK1 blockers could reverse depressive-like behaviors at least 1 week earlier than that of fluoxetine. Chronic administration of both the TREK1 blockers and fluoxetine could restore neurogenesis impairments. This study underlines the importance of model validation by determination of CUMS sensitivity. The TREK1 blockers were found to have an effect that was more rapid and more pronounced than that of fluoxetine. Therapeutic benefits after chronic administration were associated with a restoration of impaired neurogenesis.

Constitutive photomorphogenesis 9 subunit 6 might be a new potential biomarker for breast cancer. However, the underlying mechanisms of constitutive photomorphogenesis 9 subunit 6's involvement are still unclear.