Icariside II Effectively Reduces Spatial Learning and Memory Impairments in Alzheimer’s Disease Model Mice Targeting Beta-Amyloid Production

Abstract

Icariside II (ICS II) is a broad-spectrum anti-cancer natural compound extracted from Herba Epimedii Maxim. Recently, the role of ICS II has been investigated in central nervous system, especially have a neuroprotective effect in Alzheimer’s disease (AD). In this study, we attempted to investigate the effects of ICS II, on cognitive deficits and beta-amyloid (Aβ) production in APPswe/PS1dE9 (APP/PS1) double transgenic mice. It was found that chronic ICS II administrated not only effectively ameliorated cognitive function deficits, but also inhibited neuronal degeneration and reduced the formation of plaque burden. ICS II significantly suppressed Aβ production via promoting non-amyloidogenic APP cleavage process by up-regulating a disintegrin and metalloproteinase domain 10 (ADAM10) expression, inhibited amyloidogenic APP processing pathway by down-regulating amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1) expression in APP/PS1 transgenic mice. Meanwhile, ICS II attenuated peroxisome proliferator-activated receptor-γ (PPARγ) degradation as well as inhibition of eukaryotic initiation factor α phosphorylation (p-eIF2α) and PKR endoplasmic reticulum regulating kinase phosphorylation (p-PERK). Moreover, phosphodiesterase type 5 inhibitors (PDE5-Is) have recently emerged as a possible therapeutic target for cognitive enhancement via inhibiting Aβ levels, and we also found that ICS II markedly decreased phosphodiesterase-5A (PDE5A) expression. In conclusion, the present study demonstrates that ICS II could attenuate spatial learning and memory impairments in APP/PS1 transgenic mice. This protection appears to be due to the increased ADAM10 expression and decreased expression of both APP and BACE1, resulting in inhibition of Aβ production in the hippocampus and cortex. Inhibition of PPARγ degradation and PERK/eIF2α phosphorylation are involved in the course, therefore suggesting that ICS II might be a promising potential compound for the treatment of AD.

Icariside II, a PDE5 Inhibitor, Suppresses Oxygen-Glucose Deprivation/Reperfusion-Induced Primary Hippocampal Neuronal Death Through Activating the PKG/CREB/BDNF/TrkB Signaling Pathway

“…Also encouragingly, our previous studies revealed that ICS II not only ameliorated the neurological dysfunction and decreased infarct volume after middle cerebral artery occlusion-induced cerebral I/R injury in rats (Deng et al, 2016) but also effectively protected against streptozotocininduced cognitive deficits in rats through decreasing Ab deposition (Yin et al, 2016). Furthermore, ICS II significantly improved the functions of learning and memory in Alzheimer's disease (AD) mice and upregulated BDNF/TrkB signaling in paralleled vitro study (Yan et al, 2017;Liu et al, 2018). Therefore, it is reasonable to assume that ICS II may contribute to restore learning and memory impairments after cerebral I/R insult.…”

“…Herba Epimedii, a TCM, has a long history of use in improving sexual performance. It is worth noting that ICS II has also been proven to exhibit salutary effects on ED, as well as neurological disorders (Wang et al, 2015;Yan et al, 2017). Interestingly, although the inhibitory effect of ICS II on PDE5 activity is just half of SIL (Dell'agli et al, 2008), it effectively inhibits melanoma according to recent reports (Wu et al, 2013;Wu et al, 2015).…”

Human-Induced Pluripotent Stem Cells and Herbal Small-Molecule Drugs for Treatment of Alzheimer’s Disease

“…This cleavage generates a neuroprotective APP-derived short fragment (C83) and attenuates the production of Aβ peptides [87]. The mechanism of icariside in the treatment of Alzheimer's disease involves increased ADAM10 expression and decreased expression of both APP and BACE1, resulting in reduced production of Aβ [88].…”

CZ2HF mitigates β-amyloid 25-35 fragment-induced learning and memory impairment through inhibition of neuroinflammation and apoptosis in rats

“…Morris water maze test. The Morris water maze test (MWM) was performed in order to determine the learning and memory function of the rats from the 7 groups as described in our previous study (19). The rats were trained and exposed to 4 successive memory acquisition trials in the MWM to analyze their capacity to escape and find the platform, which was performed daily between days 11 and 16 after the Aβ [25][26][27][28][29][30][31][32][33][34][35] injection.…”

“…The sections were subsequently treated with dAB substrate solution and washed again with PBS. A total of 3 images were captured randomly for each section and counted using a fluorescent microscope as described in our previous study (19).…”