Presymptomatic Treatment With Andrographolide Improves Brain Metabolic Markers and Cognitive Behavior in a Model of Early-Onset Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common type of dementia. The onset and progression of this pathology are correlated with several changes in the brain, including the formation of extracellular aggregates of amyloid-beta (Aβ) peptide and the intracellular accumulation of hyperphosphorylated tau protein. In addition, dysregulated neuronal plasticity, synapse loss, and a reduction in cellular energy metabolism have also been described. Canonical Wnt signaling has also been shown to be downregulated in AD. Remarkably, we showed previously that the in vivo inhibition of Wnt signaling accelerates the appearance of AD markers in transgenic (Tg) and wild-type (WT) mice. Additionally, we found that Wnt signaling stimulates energy metabolism, which is critical for the ability of Wnt to promote the recovery of cognitive function in AD. Therefore, we hypothesized that activation of canonical Wnt signaling in a presymptomatic transgenic animal model of AD would improve some symptoms. To explore the latter, we used a transgenic mouse model (J20 Tg) with mild AD phenotype expression (high levels of amyloid aggregates) and studied the effect of andrographolide (ANDRO), an activator of canonical Wnt signaling. We found that presymptomatic administration of ANDRO in J20 Tg mice prevented the reduction in cellular energy metabolism markers. Moreover, treated animals showed improvement in cognitive performance. At the synaptic level, J20 Tg animals showed severe deficiencies in presynaptic function as determined by electrophysiological parameters, all of which were completely restored to normal by ANDRO administration. Finally, an analysis of hippocampal synaptosomes by electron microscopy revealed that the length of synapses was restored with ANDRO treatment. Altogether, these data support the idea that the activation of canonical Wnt signaling during presymptomatic stages could represent an interesting pharmacological strategy to delay the onset of AD.

Astragaloside IV Exerts Cognitive Benefits and Promotes Hippocampal Neurogenesis in Stroke Mice by Downregulating Interleukin-17 Expression via Wnt Pathway

“…Moreover, the pathway enrichment analysis suggested that many DEGs involved in synapse plasticity were up-regulated, like serotonergic, glutamatergic, GABA-ergic, dopaminergic, and cholinergic synapses, which was consistent with the results of Golgi staining ( Figures 1G-J), both in line with our hypothesis that As IV treatment promoted hippocampal neuronal plasticity by downregulating IL-17. Consistently, previous studies reported that Wnt signaling orchestrated expressional changes in genes encoding presynaptic and postsynaptic components in neurons (Martinez et al, 2019) and enhancing Wnt signaling could boost synaptic function during aging, and ameliorate synaptic pathology in AD (Cisternas et al, 2019;Palomer et al, 2019). Besides, in this study, DEGs between IL-17 KO and WT mice were relevant to the nervous and immune system ( Figure 4C) and involved in the regulation of TLR, TNF, and IL-17 pathways ( Figure 4D).…”

Effects of long-lasting social isolation and re-socialization on cognitive performance and brain activity: a longitudinal study in Octodon degus

“…Then, despite that CI-R group stayed additional 6-months for the re-socialization purpose, we considered that all our treatments are comparable in time. According to previous studies in our laboratory, we know that degus can start experimenting biochemical changes and impairment in cognitive performance associated with normal ageing, only > 3 years old 47 , 58 , 76 – 78 . Our treatments were performed during the first 2 years of life, when all animals are considered mature, healthy and biologically similar.…”

Role of Wnt Signaling in Adult Hippocampal Neurogenesis in Health and Disease

“…ANDRO treatment induced proliferation and increased the density of immature neurons in the dentate gyrus of AD mice, concomitantly with an increase in hippocampal levels of β-catenin and NeuroD1 in the hippocampus ( Varela-Nallar et al, 2015 ). Importantly, ANDRO was shown to improve cognitive performance in APPswe/PSEN1ΔE9 mice ( Serrano et al, 2014 ), and in J20 mice expressing human APP with two mutations linked to familial AD ( Cisternas et al, 2019 ). More recently, Valproic acid (VPA), another selective inhibitor of GSK-3β used as an antiepileptic and mood-stabilizing drug, was shown to promote proliferation, increase the density of immature neurons, and improved learning and memory in the dentate gyrus of triple transgenic APPswe/PSEN1ΔE9/Nestin-GFP mice ( Zeng et al, 2019 ).…”