The walking system of the stick insect is one of the most thoroughly described invertebrate systems. We know a lot about the role of sensory input in the control of stepping of a single leg. However, the neuronal organization and connectivity of the central neural networks underlying the rhythmic activation and coordination of leg muscles still remain elusive. It is assumed that these networks can couple in the absence of phasic sensory input due to the observation of spontaneous recurrent patterns (SRPs) of coordinated motor activity equivalent to fictive stepping-phase transitions. Here we sought to quantify the phase of motor activity within SRPs in the isolated and interconnected meso- and meta-thoracic ganglia. We show that SRPs occur not only in the meso-, but also in the metathoracic ganglia of the stick insect, discovering a qualitative difference between them. We construct a network based on neurophysiological data capable of reproducing the measured SRP phases to investigate this difference. By comparing network output to the biological measurements we confirm the plausibility of the architecture and provide a hypothesis to account for these qualitative differences. The neural architecture we present couples individual central pattern generators to reproduce the fictive stepping-phase transitions observed in deafferented stick insect preparations after pharmacological activation, providing insights into the neural architecture underlying coordinated locomotion.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease of the brain causing either familial or sporadic dementia. We have previously administered the modified C5a receptor agonist (EP67) for a short period to a transgenic mouse model of AD (5XFAD) and have observed not only reduction in β-amyloid deposition and gliosis but also improvement in cognitive impairment. Inquiring, however, on the effects of EP67 in an already heavily burdened animal, thus representing a more realistic scenario, we treated 6-month-old 5XFAD mice for a period of 14 weeks. We recorded a significant decrease in both fibrillar and pre-fibrillar β-amyloid as well as remarkable amelioration of cognitive impairment. Following proteomic analysis and pathway association, we postulate that these events are triggered through the upregulation of β-adrenergic and GABAergic signaling. In summary, our results reveal how inflammatory responses can be employed in inducing tangible phenotype improvements even in advanced stages of AD.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the most common type of dementia. Although a considerably large amount of money has been invested in drug development for AD, no disease modifying treatment has been detected so far. In our previous work, we developed a computational method to highlight stage-specific candidate repurposed drugs against AD. In this study, we tested the effect of the top 13 candidate repurposed drugs that we proposed in our previous work in a severity stage-specific manner using an in vitro BACE1 assay and the effect of a top-ranked drug from the list of our previous work, tetrabenazine (TBZ), in the 5XFAD as an AD mouse model. From our in vitro screening, we detected 2 compounds (clomiphene citrate and Pik-90) that showed statistically significant inhibition against the activity of the BACE1 enzyme. The administration of TBZ at the selected dose and therapeutic regimen in 5XFAD in male and female mice showed no significant effect in behavioral tests using the Y-maze and the ELISA immunoassay of Aβ40. To our knowledge, this is the first time the drug tetrabenazine has been tested in the 5XFAD mouse model of AD in a sex-stratified manner. Our results highlight 2 drugs (clomiphene citrate and Pik-90) from our previous computational work for further investigation.

Alzheimer’s disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease’s progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy (CAA). CAA is a condition manifesting as amyloid deposits in the cerebral vasculature, eventually leading to microhemorrhage. Here, we have treated the CRND8 mouse model with the C5a agonist (EP67) in order to observe the effects on cerebral amyloidosis, CAA, and hyperphosphorylated tau. EP67 attaches to the C5a receptor on phagocytes and stimulates the engulfment and digestion of fibrillar and prefibrillar amyloid while exhibiting minimal inflammation. Older CRND8 mice and their respective controls were treated with EP67 for a prolonged period of time. Following treatment, the CRND8 mice displayed improved spatial memory, while both amyloid deposition and tau hyperphosphorylation were found to be diminished. (c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).