The protective innate immune response of β-amyloid peptide (Aβ) has been indicated as a risk factor for Alzheimer\'s disease (AD) due to the rapid amyloidosis. In order to obtain molecular-level insights into the protective and pathogenic roles of Aβ, the binding modes between Aβ1-42 and the envelop glycoprotein D (gD) of Herpes simplex virus-1 (HSV-1)/Aβ1-42 were theoretically investigated by using molecular docking, molecular dynamics (MD) simulations and binding free energy decomposition methods in the present study. The Aβ1-42 stably binds to the envelop gD via intermolecular hydrogen bonds and van der Waals (vdW) interactions. The Aβ1-42 acquires its equilibrium with higher fluctuation amplitude and a better structured C-terminal in the HSV-1 gD-Aβ1-42 complex comparing to that in the Aβ1-42-Aβ1-42 complex. The amino acid residues of Aβ1-42 involved in the formation of the Aβ1-42 dimer are fully free and accessible in the HSV-1 gD-Aβ1-42 complex. It is favorable for the Aβ1-42 monomer to interact with the HSV-1 gD-Aβ1-42 complex. It may be responsible for the rapid amyloidosis which entraps the herpesvirus as well as causing AD.

Growing evidence has suggested the poor correlation between brain amyloid plaque and Alzheimer\'s disease (AD). Presenilin1 (PS1) and presenilin2 (PS2) conditional double knockout (cDKO) mice exhibited the reduced 42-amino acid amyloid-β peptide (Aβ1-42) level and AD-like symptoms, indicating a different pathological mechanism from the amyloid cascade hypothesis for AD. Here we found that exogenous synthetic Aβ1-42 monomers could improve the impaired memory not only in cDKO mice without Aβ1-42 deposition but also in the APP/PS1/Tau triple transgenic 3 × Tg-AD mice with Aβ1-42 deposition, which were mediated by α7-nAChR. Our findings demonstrate for the first time that reduced soluble Aβ1-42 level is the main cause of cognitive dysfunction in cDKO mice, and support the opinions that low soluble Aβ1-42 level due to Aβ1-42 deposition may also cause cognitive deficits in 3 × Tg-AD mice. Therefore, \"loss-of-function\" of Aβ1-42 should be avoided when designing therapies aimed at reducing Aβ1-42 burden in AD.

Alzheimer\'s disease (AD) and type 2 diabetes mellitus (T2DM) have a common pathology. Both diseases are characterized by local deposition of amyloid proteins in the brain or islet organ, but their phenotypes and clinical manifestation vary widely. Although the sources of islet amyloid polypeptide (IAPP) and amyloid beta (Aβ) are independent, their fibrillar sequences are highly homologous. The prevalence of AD in T2DM populations is considerably higher than that in the normal population, but a mechanistic linkage remains elusive. Therefore, the present study aimed to explore the effects of Aβ42 deposition in the brain on the persistently expression of human IAPP (hIAPP). Additionally, cognitive ability, synaptic plasticity, the state of neural stem cells and mitochondrial function were evaluated at 2 or 6 months after stereotaxically injected the oligomer Aβ1-42 into the dentate gyrus of hIAPP (-/+) mice or the wild-type littermates. We found that Aβ42 and amylin were co-located in hippocampus and Aβ42 levels increased when Aβ1-42 was injected in hIAPP transgenic mice compared with that of the wild-type littermates. Furthermore, at 6 months after Aβ1-42 injection in hIAPP (-/+) mice, it exhibits exacerbated AD-related pathologies including Aβ42 deposition, cognitive impairment, synapse reduction, neural stem cells exhaustion and mitochondrial dysfunction. Our present study suggested that hIAPP directly implicated the Aβ42 production and deposition as an important linkage between T2DM and AD.

Emerging evidence indicates that the enhancement of microglial autophagy inhibits the NLRP3 inflammasome mediated neuroinflammation in Alzheimer\'s disease (AD). Meanwhile, low density lipoprotein receptor-related protein 1 (LRP1) highly expressed in microglia is able to negatively regulate neuroinflammation and positively regulate autophagy. In addition, we have previously reported that an active lychee seed fraction enriching polyphenol (LSP) exhibits anti-neuroinflammation in Aβ-induced BV-2 cells. However, its molecular mechanism of action is still unclear. In this study, we aim to investigate whether LSP inhibits the NLRP3 inflammasome mediated neuroinflammation and clarify its molecular mechanism in Aβ-induced BV-2 cells and APP/PS1 mice. The results showed that LSP dose- and time-dependently activated autophagy by increasing the expression of Beclin 1 and LC3II in BV-2 cells, which was regulated by the upregulation of LRP1 and its mediated AMPK signaling pathway. In addition, both the Western blotting and fluorescence microscopic results demonstrated that LSP could significantly suppress the activation of NLRP3 inflammasome by inhibiting the expression of NLRP3, ASC, the cleavage of caspase-1, and the release of IL-1β in Aβ(1-42)-induced BV-2 cells. In addition, the siRNA LRP1 successfully abolished the effect of LSP on the activation of AMPK and its mediated autophagy, as well as the inhibition of NLRP3 inflammasome. Furthermore, LSP rescued PC-12 cells which were induced by the conditioned medium from Aβ(1-42)-treated BV-2 cells. Moreover, LSP improved the cognitive function and inhibited the NLRP3 inflammasome in APP/PS1 mice. Taken together, LSP inhibited the NLRP3 inflammasome-mediated neuroinflammation in the in vitro and in vivo models of AD, which was closely associated with the LRP1/AMPK-mediated autophagy. Thus, the findings from this study further provide evidences for LSP serving as a potential drug for the treatment of AD in the future.

Alzheimer\'s disease (AD) is a dementing, neurodegenerative disorder characterized by increased accumulation of beta-amyloid peptides (Aβ), degeneration of hippocampal neurons and the gradual development of learning and memory deficits. Therapeutically, there are still no ideal medicines available and this represents an urgent need for the development of new strategies to treat AD. Emerging lines of evidence suggest that modulation of the cannabinoid system exhibits neuroprotective effects in various neurological diseases, including AD. However, a consensus is yet to emerge as to the impact of hippocampal cannabinoid receptor 2 (CB2R) in protection of hippocampal neurons against Aβ induced neuronal toxicity. Here, we report that chronic treatment of primary hippocampal neuronal cultures with 100 nM Aβ1-42 oligomers for 7 days results in neurotoxicity, which includes increases in lactate dehydrogenase (LDH) levels, suggesting an Aβ1-42 -induced neuron apoptosis. Further, chronic Aβ1-42 reduces the ratio of phosphorylated Akt (pAkt)/Akt, in turn decreases neuronal Bcl-2/Bax ratio, and leads to an increase of caspase-3, which likely underlines the signal pathway of chronic Aβ1-42-induced neuron apoptosis. Interestingly, pre-treatments of CB2R agonist (JWH133, 10 μM) with Aβ1-42 prevents Aβ1-42-induced the decrease of pAkt/Akt ratio, the decrease of Bcl-2/Bax ratio, and the increase of caspase-3, and protects hippocampal neurons against Aβ1-42-induced apoptosis. All neuroprotective effects of JWH133 are abolished by a selective CB2R antagonist, AM630. Taken together, the activation of hippocampal CB2Rs protects neurons against Aβ1-42 toxicity, and the CB2R-mediated enhancement of the pAkt signaling is likely involved in the protection of hippocampal neurons against Aβ1-42-induced neuronal toxicity.

Alzheimer\'s disease (AD) is characterized by the amyloid-beta peptide (Aβ) misfolding to form aberrant amyloid aggregates in the brain. Although recent evidence implicates that amyloid deposition in vivo is highly related to biomembranes, how the characteristic lipid components of neuronal membranes mediate this process remains to be fully elucidated. Herein, we established vesicle models to mimic exosomes and investigated their influence on the kinetics of Aβ(1-42) amyloidosis. By using ternary vesicles composed of three brain lipids monosialoganglioside GM1, cholesterol and sphingomyelin, we found that GM1 could regulate peptide fibrillation by facilitating the conformational transition of Aβ(1-42), and further quantitatively analyzed the influence of GM1-containing vesicles on the kinetics of Aβ(1-42) fibrillation. In addition, GM1-containing vesicles induced the formation of Aβ(1-42) fibrils at low concentrations, and these fibrils were toxic to PC12 cells. By analyzing the role of GM1 in this ternary mixture of membranes at the molecular level, we confirmed that GM1 clusters are presented as attachment sites for peptides, thus promoting the fibrillation of Aβ(1-42).

BACKGROUND: Rhodiola crenulata has been wildly used as a healthy food, antidepressant and antifatigue for many years in China. Recent studies suggested that Rhodiola crenulata extract (RCE) has cognitive protective effects in the treatment of Alzheimer\'s disease (AD).
OBJECTIVE: To assess the protective effects of RCE on cognitive deficits and clarify its therapeutic mechanisms in Aβ1-42 -induced rat models of AD.
METHODS: RCE was prepared by freeze-drying technology. Their protective effects on Aβ1-42-induced rat models of AD and the preliminary therapeutic mechanisms were studied.
METHODS: The Y maze test and Morris water maze (MWM) test were conducted to evaluate the learning and memory abilities of the rats. Subsequently, biochemical assays, hematoxylin-eosin staining, immunohistochemistry and Western blotting were performed to elucidate the mechanisms.
RESULTS: RCE significantly increased the spontaneous alternation (F (6, 111) = 8.165, p < 0.001), prolonged the swimming time (F (6, 111) = 20.143, p < 0.001) and decreased the escape latency in rat models of AD. In addition, RCE significantly increased the acetylcholine (Ach) level and the choline acetyl transferase (ChAT) activity (F (6, 34) = 6.033, p < 0.001; F (6, 34) = 6.958, p < 0.001, respectively), repaired the damage of hippocampus neurons and prevented Aβ formation in the hippocampus in Aβ1-42 injected rats. Moreover, RCE increased the superoxide dismutase (SOD) activity and decreased the malondialdehyde (MDA) level in cortex of Aβ1-42 injected rats (F (6, 34) = 5.097, p < 0.01; F (6, 34) = 2.907, p < 0.05, respectively), significantly reduced the expressions of p-tau (ser396) and induced the expressions of p-GSK3β (ser9) in hippocampus (F (6, 34) = 15.297, p < 0.001; F (6, 34) = 9.652, p < 0.001, respectively).
CONCLUSIONS: Our findings demonstrated that RCE significantly alleviated the learning and memory deficits in the Aβ1-42-induced rat models of AD. The mechanisms involved its protection effects against cholinergic system deficiency, oxidative stress damage and GSK3β activation. RCE may be a potential therapeutic medicine with multi-targets to prevent the progression of cognitive deterioration in AD.

Ginsenoside compound K (CK) is the main metabolite of protopanaxadiol-type ginsenosides and has been demonstrated to exert neuroprotective and cognition-enhancing effects. The effects of CK on cognitive function in vascular dementia (VD) has not been elucidated. Therefore, the present study aims to elucidate the effects of CK on memory function as well as its potential mechanism in VD rats. Sprague-Dawley rats were subjected to Chronic Cerebral Hypoperfusion (CCH) by permanent bilateral common carotid artery occlusion (2VO). CCH induced neuronal damage and aggravated the aggregation of Amyloid-β1-42 peptides (Aβ1-42), which plays a critical role in the neurotoxicity and cognitive impairment. CK treatment attenuated CCH-induced Aβ1-42 deposition and ameliorated cognition impairment. Furthermore, CK enhanced the activity of the pSer9-Glycogen synthase kinase 3β (pSer9-GSK3β) and the insulin degrading enzyme (IDE), which mainly involved the production and clearance of Aβ1-42. Moreover, CK treatment enhanced the activity of protein kinase B (PKB/Akt), a key kinase in phosphatidylinositol 3 kinase (PI3K)/Akt pathway that can regulate the activity of GSK-3β and IDE. In short, our findings provide the first evidence that CK might attenuate cognitive deficits and Aβ1-42 deposition in the hippocampus via enhancing the expression of pSer9-GSK-3β and IDE.

In our previous studies, an active fraction derived from lychee seed could inhibit β-amyloid-induced apoptosis of PC12 cells and neurons. The primarily microglia cells are recognized as the brain\'s resident macrophages and thought to remodel of the brain by removing presumably redundant, apoptotic neurons. In the current study, we aimed to investigate the anti-neuroinflammation effect of lychee seed fraction (LSF) in Aβ(1-42)-induced BV-2 cells and the underlying mechanism. The morphology results displayed that LSF could improve the status of Aβ(1-42)-induced BV-2 cells. The enzyme-linked immunosorbent assay, real-time PCR, and Western blotting results showed that LSF could significantly reduce the release, mRNA levels, and protein expressions of the pro-inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in Aβ(1-42)-induced BV-2 cells, which were downregulated through suppressing the NF-κB signaling pathway. Furthermore, LSF could upregulate Bcl-2 and downregulate Bax, Caspase-3, and cleaved-PARP protein expressions. Taken together, our results first demonstrated that LSF could suppress the inflammatory response via inhibiting NF-κB signaling pathway, and inhibit apoptosis in Aβ(1-42)-induced BV-2 cells. Our findings further prove that LSF as a potential drug may be used for treating AD in the future.

Alzheimer\'s disease (AD) is a multifactorial neurodegenerative disease and a growing health problem worldwide. Because the drugs currently used to treat AD have certain drawbacks such as single targeting, there is a need to develop novel multi-target compounds, among which oxoisoaporphine alkaloid derivatives are promising candidates. In this study, the possible anti-AD activities of 14 novel oxoisoaporphine alkaloid derivatives that we synthesized were screened and evaluated. We found that, in the 14 novel derivatives, compound 8-1 significantly reduced Aβ1-42 secretion in SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw). Next, we found that compound 8-1 could down-regulate the expression level of β-amyloid precursor protein (APP) in APPsw cells. Moreover, compound 8-1 significantly delayed paralysis in the Aβ1-42-transgenic Caenorhabditis elegans strain GMC101, which could be explained by the fact that compound 8-1 down-regulated acetylcholinesterase activity, protected against H2O2-induced acute oxidative stress and paraquat-induced chronic oxidative stress, and enhanced autophagy activity. Taken together, our data suggest that compound 8-1 could attenuate the onset and development of AD.