Amyloid Precursor Protein-cleaving Enzyme Research Articles

Application of Dominant Gut Microbiota Promises to Replace Fecal Microbiota Transplantation as a New Treatment for Alzheimer's Disease.

Several studies have confirmed that the pathophysiological progression of Alzheimer's disease (AD) is closely related to changes in the intestinal microbiota; thus, modifying the intestinal microbiota has emerged as a new way to treat AD. Effective interventions for gut microbiota include the application of probiotics and other measures such as fecal microbiota transplantation (FMT). However, the application of probiotics ignores that the intestine is a complete microecosystem with competition among microorganisms. FMT also has issues when applied to patient treatment. In a previous study, we found that eight species of bacteria that are isolated with high frequency in the normal intestinal microbiota (i.e., intestinal dominant microbiota) have biological activities consistent with the effects of FMT. In this article, we confirmed that the treatment of intestinal dominant microbiota significantly restored intestinal microbiota abundance and composition to normal levels in APP/PS1 mice; downregulated brain tissue pro-inflammatory cytokines (IL-1β and IL-6) and amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1) expression levels; and reduced the area of Aβ plaque deposition in the brain hippocampus. Our study provides a new therapeutic concept for the treatment of AD, adjusting the intestinal microecological balance through dominant intestinal microbiota may be an alternative to FMT.

Antioxidant and anti-Alzheimer activities of Clivia miniata (Lindl) roots, bulbs, and aerial parts: In-vitro and in-silico studies

Clivia miniata (Lindl) is a member of the family Amaryllidaceae known for its chemically diverse alkaloids with a wide range of biological activities. Many reports revealed a direct role of oxidative stress in the early stage of Alzheimer’s disease (AD). Meanwhile, β-site amyloid precursor protein cleavage enzyme 1 (BACE-1) is a molecular target for the treatment of AD. We aimed to investigate C. miniata root, bulb, and aerial part chemical profiling, antioxidant, BACE-1, and AChE enzyme inhibitory activities. Results showed that the total root had the most potent radical scavenging activity as compared to the total bulb and aerial part, respectively. Ethanol root extract had the most potent BACE-1 inhibitory activity (IC50 = 0.02 ± 0.001 µg/mL) as compared to the bulb and aerial part (IC50 = 0.93 ± 0.13, 1.80 ± 0.24 µg/mL), respectively. Moreover, the total root extract mitigated AChE enzyme activity more than total bulb and aerial fractions with IC50 values of (0.06 ± 0.02, 0.58 ± 0.3, and 1.89 ± 0.42 µg/mL, respectively. Bioassay-guided acid-base fractionation confirmed superior BACE-1 inhibitory activity of the root fractions particularly, methylene chloride and ethyl acetate fractions with (IC50 values of 0.21 ± 0.60 and 0.01 ± 0.001 µg/mL), respectively. UPLC-MS analysis of ethyl acetate and methylene chloride fractions of C. miniata root led to the identification of eight phenolics and thirteen alkaloids, respectively. Molecular docking studies against BACE-1 protein revealed that lycorine di-hexoside, miniatine, and cliviaaline were the most promising hits. Further investigation of anti-AD potential of the aforementioned small molecules is required.

5-Methyltetrahydrofolate Alleviates Memory Impairment in a Rat Model of Alzheimer's Disease Induced by D-Galactose and Aluminum Chloride.

The effects of 5-methyltetrahydrofolate (5-MTHF) on a rat model of Alzheimer's disease (AD) induced by D-galactose (D-gal) and aluminum chloride (AlCl3) were investigated. Wistar rats were given an i.p. injection of 60 mg/kg D-gal and 10 mg/kg AlCl3 to induce AD and three doses of 1 mg/kg, 5 mg/kg or 10 mg/kg 5-MTHF by oral gavage. A positive control group was treated with 1 mg/kg donepezil by gavage. Morris water maze performance showed that 5 and 10 mg/kg 5-MTHF significantly decreased escape latency and increased the number of platform crossings and time spent in the target quadrant for AD rats. The administration of 10 mg/kg 5-MTHF decreased the brain content of amyloid β-protein 1-42 (Aβ1-42) and phosphorylated Tau protein (p-Tau) and decreased acetylcholinesterase and nitric oxide synthase activities. Superoxide dismutase activity, vascular endothelial growth factor level and glutamate concentration were increased, and malondialdehyde, endothelin-1, interleukin-6, tumor necrosis factor-alpha and nitric oxide decreased. The administration of 10 mg/kg 5-MTHF also increased the expression of disintegrin and metallopeptidase domain 10 mRNA and decreased the expression of β-site amyloid precursor protein cleavage enzyme 1 mRNA. In summary, 5-MTHF alleviates memory impairment in a D-gal- and AlCl3-exposed rat model of AD. The inhibition of Aβ1-42 and p-Tau release, reduced oxidative stress, the regulation of amyloid precursor protein processing and the release of excitatory amino acids and cytokines may be responsible.

Preventive effects of arctigenin from Arctium lappa L against LPS-induced neuroinflammation and cognitive impairments in mice.

Arctigenin (Arc) is a phenylpropanoid dibenzylbutyrolactone lignan in Arctium lappa L, which has been widely applied as a traditional Chinese herbal medicine for treating inflammation. In the present study, we explored the neuroprotective effect and the potential mechanisms of arctigenin against LPS-evoked neuroinflammation, neurodegeneration, and memory impairments in the mice hippocampus. Daily administration of arctigenin (50mg/kg per day, i.g.) for 28days revealed noticeable improvements in spatial learning and memory deficits after exposure to LPS treatment. Arctigenin prevented LPS-induced neuronal/synaptic injury and inhibited the increases in Abeta (Aβ) generation and the levels of amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1). Moreover, arctigenin treatment also suppressed glial activation and reduced the production of proinflammatory cytokines. In LPS-treated BV-2 microglial cells and mice, activation of the TLR4 mediated NF-κB signaling pathway was significantly suppressed by arctigenin administration. Mechanistically, arctigenin reduced the LPS-induced interaction of adiponectin receptor 1 (AdipoR1) with TLR4 and its coreceptor CD14 and inhibited the TLR4-mediated downstream inflammatory response. The outcomes of the current study indicate that arctigenin mitigates LPS-induced apoptotic neurodegeneration, amyloidogenesis and neuroinflammation as well as cognitive impairments, and suggest that arctigenin may be a potential therapeutic candidate for neuroinflammation/neurodegeneration-related diseases.

Extracellular-Signal-Regulated Kinase Inhibition Switches APP Processing from β- to α-Secretase under Oxidative Stress: Modulation of ADAM10 by SIRT1/NF-κB Signaling.

The sequential cleavage of full-length amyloid precursor protein (APP) by secretases has been at the center of efforts for understanding the onset of Alzheimer's disease (AD). A decrease in α-secretase activity was observed during the progression of AD; however, the precise molecular mechanism involved in the downregulation of α-secretase under oxidative stress is not fully understood. In the present study, we have demonstrated that pharmacological inhibition of mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) by mitogen-activated protein kinase kinase-1 (MEK-1) inhibitor (PD98059) restored the expression of a disintegrin and metalloproteinase 10 (ADAM10) with a concomitant decrease in β-site APP cleavage enzyme 1 (BACE1) under oxidative stress. Silent mating-type information regulation 2 homologue 1 (SIRT1) activation by resveratrol also mitigated alterations in secretase levels through MAPK/ERK signaling. Intracerebroventricular (ICV) administration of streptozotocin in rats showed amyloidogenic processing of APP and altered the SIRT1/ERK axis in the hippocampus. We also observed that the ADAM10 expression is controlled at the transcriptional level by oxidative stress. Using the luciferase reporter activity of ADAM10 promoter deletion constructs, we have identified the region 290 bp upstream of the transcription start site (TSS) possessing regulatory elements responsible for ADAM10 downregulation with hydrogen peroxide (H2O2) treatment. Further, bioinformatics analysis revealed the presence of putative nuclear factor kappa B (NF-κB) binding sites in the ADAM10 promoter region. Treatment of cortical neurons with the NF-κB inhibitor (Bay 11-7082) mitigated the transcriptional upregulation of ADAM10 by PD98059. Overall, our findings suggest that SIRT1/ERK/NF-κB axis contributes to the downregulation of ADAM10, resulting in the shift from nonamyloidogenic to amyloidogenic processing of APP under oxidative stress.

Vitamin D deficiency exacerbates Alzheimer-like pathologies by reducing antioxidant capacity

Vitamin D (VD) deficiency is prevalent among aging people and Alzheimer's disease (AD) patients. However, the roles of VD deficiency in the pathology of AD remain largely unexplored. In this study, APP/PS1 mice were fed a VD-deficient diet for 13 weeks to evaluate the effects of VD deficiency on the learning and memory functions and the neuropathological characteristics of the mice. Our study revealed that VD deficiency accelerated cognitive impairment in the APP/PS1 mice. Mechanistic studies revealed that VD deficiency promoted glial activation and increased inflammatory factor secretion. Furthermore, VD deficiency increased the production and deposition of Aβ by elevating the expression levels of amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1). In addition, VD deficiency increased the phosphorylation of Tau at Thr181, Thr205 and Ser396 by increasing the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3α/β (GSK3α/β) and promoted synaptic dystrophy and neuronal loss. All these effects of VD deficiency may be ascribed to enhanced oxidative stress via the downregulation of superoxide dismutase 1 (SOD1), glutathione peroxidase 4 (GPx4) and cystine/glutamate exchanger (xCT). Taken together, our data suggest that VD deficiency exacerbates Alzheimer-like pathologies via promoting inflammatory stress, increasing Aβ production and elevating Tau phosphorylation by decreasing antioxidant capacity in the brains of APP/PS1 mice. Hence, rescuing the VD status of AD patients should be taken into consideration during the treatment of AD.

Brain region\u2013specific lipid alterations in the PLB4 hBACE1 knock-in mouse model of Alzheimer\u2019s disease

BackgroundLipid dysregulation is associated with several key characteristics of Alzheimer’s disease (AD), including amyloid-β and tau neuropathology, neurodegeneration, glucose hypometabolism, as well as synaptic and mitochondrial dysfunction. The β-site amyloid precursor protein cleavage enzyme 1 (BACE1) is associated with increased amyloidogenesis, and has been affiliated with diabetes via its role in metabolic regulation.MethodsThe research presented herein investigates the role of hBACE1 in lipid metabolism and whether specific brain regions show increased vulnerability to lipid dysregulation. By utilising advanced mass spectrometry techniques, a comprehensive, quantitative lipidomics analysis was performed to investigate the phospholipid, sterol, and fatty acid profiles of the brain from the well-known PLB4 hBACE1 knock-in mouse model of AD, which also shows a diabetic phenotype, to provide insight into regional alterations in lipid metabolism.ResultsResults show extensive region – specific lipid alterations in the PLB4 brain compared to the wild-type, with decreases in the phosphatidylethanolamine content of the cortex and triacylglycerol content of the hippocampus and hypothalamus, but increases in the phosphatidylcholine, phosphatidylinositol, and diacylglycerol content of the hippocampus. Several sterol and fatty acids were also specifically decreased in the PLB4 hippocampus.ConclusionCollectively, the lipid alterations observed in the PLB4 hBACE1 knock-in AD mouse model highlights the regional vulnerability of the brain, in particular the hippocampus and hypothalamus, to lipid dysregulation, hence supports the premise that metabolic abnormalities have a central role in both AD and diabetes.

In Silico Study of Centella asiatica Active Compound as BACE1 Inhibitor in Alzheimer’s Disease

Alzheimer (AD) is a chronical neurodegenerative disease which is the 6 th leading cause of death worldwide. About 36 million cases in the world and may increase to 115 million in 2050. The pathological cause of AD is the presence of residual Aβ peptides . Aβ peptides is produced in the cleavage process of the amyloid precursor protein (APP) sequentially by Beta amyloid precursor protein cleavage enzyme 1 (BACE1) and γ-secretase. Flavonol, germacrene B, and sitosterol are compounds found in Centella asiatica which is has potential as BACE1 inhibitor. The aim of this study was to analyze the interaction between BACE1 with flavonol, germacrene B and sitosterol by molecular docking to predict the BACE1 inhibitor potent of those compound. We obtained BACE1 from RSCB database, flavonol, germacrene B and sitosterol from PubChem database. Molecular dockcing was done using Hex 8.0.0. The docking result were vizualized with Discovery Studio 3.5. Interaction of BACE1 resulted binding energy for sitosterol was -239,7 kcal/mol , flavonol was -188,1 kcal/mol, and germacrene B was -185,6 kcal/mol. Flavonol and sitosterol bound to the active site of BACE1 involving Thr232 and Ile110 on flavonol, while Tyr71 on sitosterol. All of the active compounds didn’t have the interaction at S1’ subsite, which is the center of BACE1 active site which has become the key of APP activation from BACE1 . This study has shown that flavonol and sitosterol had potential to reduce BACE1 activity but not directly inhibit BACE1 activity .

Geraniin Attenuates Lipopolysaccharide-Induced Cognitive Impairment in Mice by Inhibiting Toll-Like Receptor 4 Activation.

Geraniin has been reported to possess potent anti-inflammatory properties and to modulate the macrophage polarization. This study sought to evaluate the protective effects and underlying mechanisms of geraniin on lipopolysaccharide (LPS)-induced neuroinflammation and neurobiological alternations as well as cognitive impairment. Daily intragastrical administration with geraniin (20 mg kg-1 day-1) for 14 days significantly prolonged the duration in the target quadrant (26.53 ± 2.03 versus 37.09 ± 3.27%; p < 0.05) and increased crossing-target number (1.93 ± 0.22 versus 3.08 ± 0.17; p < 0.01) in the probe test of LPS-treated mice. Geraniin also ameliorated LPS-elicited neural/synaptic impairments and decreased levels of LPS-induced Aβ generation (p < 0.05), amyloid precursor protein (APP) (p < 0.05) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1) (p < 0.05). Furthermore, geraniin suppressed the production of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) (9.85 ± 0.58 versus 5.20 ± 0.52 pg/mg of protein; p < 0.01), interleukin (IL)-1β (16.31 ± 0.67 versus 8.62 ± 0.46 pg/mg of protein; p < 0.01), and IL-6 (12.12 ± 0.45 versus 7.43 ± 0.32 pg/mg of protein; p < 0.05), and inhibited glial cell activation. Moreover, geraniin effectively polarized the microglia toward an anti-inflammatory M2 phenotype. Further study revealed that geraniin targeted toll-like receptor 4 (TLR4)-mediated signaling and decreased the production of pro-inflammatory cytokines in BV-2 microglial cells. These results indicate that geraniin mitigates LPS-elicited neural/synaptic neurodegeneration, amyloidogenesis, neuroinflammation, and cognitive impairment and suggest geraniin as a therapeutic option for neuroinflammation-associated neurological disorders, such as Alzheimer's disease.

Pseudoginsenoside-F11 alleviates cognitive deficits and Alzheimer's disease-type pathologies in SAMP8 mice.

Alzheimer's disease (AD) is a common neurodegenerative disease which is characterized by aggregation of amyloid beta (Aβ) and hyperphosphorylated tau. We previously reported that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, improved cognitive function and reduced Aβ aggregation in APP/PS1 mice, a familial AD model. Here, we chose senescence-accelerated mouse prone 8 (SAMP8) mice, a widely used model of aging, to investigate the effect of PF11 on sporadic AD. PF11 was orally administered to male 6-month-old SAMP8 mice for 3 months. Consistent with previous studies, SAMP8 mice showed several AD-type pathologies including cognitive impairment, Aβ deposition and tau hyperphosphorylation. We found increased protein levels of cytoplasmic amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1) in the hippocampus and cortex of SAMP8 mice. The protein level of demethylated protein phosphatase 2A (PP2A) was elevated in SAMP8 animals and the protein level of leucine carboxyl methyltransferase 1 (LCMT-1) was reduced. PF11 attenuated learning and memory impairments in the novel object recognition test and Morris water maze. PF11 promoted the transport of APP from cytoplasm to plasma membrane and decreased the abnormally high expression of BACE1 in hippocampus and cortex of SAMP8 mice. The elevated protein level of demethylated PP2A and the reduced expression of LCMT-1 in hippocampus and cortex of SAMP8 were also attenuated by PF11. Together, our findings indicate that PF11 has beneficial effects on AD-like pathological changes in SAMP8 mice and may act by inhibiting amyloidogenic processing of APP and attenuating tau hyperphosphorylation.

Icariside II Ameliorates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Inhibiting the Amyloidogenic Pathway: Involvement of BDNF/TrkB/CREB Signaling and Up-Regulation of PPARα and PPARγ in Rats.

Chronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline of vascular dementia (VD) as it is conducive to induce beta-amyloid (Aβ) aggregation. Icariside II (ICS II), a plant-derived flavonoid compound, has showed neuroprotective effect on animal models of Alzheimer’s disease (AD) by decreasing Aβ levels. Here, we assessed the effect of ICS II on CCH-induced cognitive deficits and Aβ levels in rats, and the possible underlying mechanisms were also explored. It was disclosed that CCH induced by bilateral common carotid artery occlusion (BCCAO) caused cognitive deficits, neuronal injury and increase of Aβ1-40 and Aβ1-42 levels in the rat hippocampus, while oral administration of ICS II for 28 days abolished the above deficits in the hippocampus of BCCAO rats. Meanwhile, ICS II significantly decreased the expression of beta-amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1), as well as increased the expression of a disintegrin and metalloproteinase domain 10 (ADAM10) and insulin-degrading enzyme (IDE). ICS II also activated peroxisome proliferator-activated receptor (PPAR)α and PPARγ, enhanced the expression of brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), levels of Akt and cAMP response element binding protein (CREB) phosphorylation. Together, these findings suggested that ICS II attenuates CCH-induced cognitive deficits by inhibiting the amyloidogenic pathway via involvement of BDNF/TrkB/CREB signaling and up-regulation of PPARα and PPARγ in rats.

BACE1 gene silencing alleviates isoflurane anesthesia‑induced postoperative cognitive dysfunction in immature rats by activating the PI3K/Akt signaling pathway.

Postoperative cognitive dysfunction (POCD) is a severe complication characterized by cognitive dysfunction following anesthesia and surgery. The aim of the present study was to investigate the effects of β-site amyloid precursor protein cleavage enzyme 1 (BACE1) gene silencing on isoflurane anesthesia-induced POCD in immature rats via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Rat models were established and then transfected with BACE1 small interfering RNA and wortmannin (an inhibitor of PI3K). Blood gas analysis was performed, and a series of behavioral experiments were conducted to evaluate the cognitive function, learning ability and locomotor activity of rats. Reverse transcription quantitative polymerase chain reaction and western blot analysis were employed to determine the mRNA and protein expression of the associated genes. An ELISA was used to detect the inflammatory indicators and the content of amyloid precursor protein (APP) and amyloid-β (Aβ). Apoptosis of the hippocampal CA1 region was observed by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. Initially, it was revealed that the percentage of stagnation time in rats was increased by BACE1 gene silencing; the escape latency and swimming distance were markedly reduced from the 4th to the 6th day, the time the rats spent in first passing the target area was shortened, and the times of passing the target area were increased by BACE1 gene silencing, demonstrating that BACE1 gene silencing enhanced the spatial memory ability of rats. Additionally, it was determined that silencing BACE1 improved the pathological state induced by isoflurane anesthesia in immature rats, and attenuated the inflammatory response and the levels of APP and Aβ in hippocampal tissues. Furthermore, it was suggested that silencing BACE1 may have promoted the activation of the PI3K/Akt signaling pathway, thereby inhibiting the apoptosis of the hippocampal CA1 region. Taken together, these results indicated that BACE1 gene silencing may improve isoflurane anesthesia-induced POCD in immature rats by activating the PI3K/Akt signaling pathway and inhibiting the Aβ generated by APP.

Phloroglucinol ameliorates cognitive impairments by reducing the amyloid β peptide burden and pro-inflammatory cytokines in the hippocampus of 5XFAD mice

Among the various causative factors involved in the pathogenesis of Alzheimer's disease (AD), oxidative stress has emerged as an important factor. Phloroglucinol is a polyphenol component of phlorotannin, which is found at sufficient levels in Ecklonia cava (E. cava). Phloroglucinol has been reported to exert antioxidant activities in various tissues. Previously, we reported that the stereotaxic injection of phloroglucinol regulated synaptic plasticity in an AD mouse model. In this study, we aimed to investigate the effects of oral administration of phloroglucinol in AD. The oral administration of phloroglucinol for 2 months attenuated the impairments in cognitive function observed in 6-month-old 5X familial AD (5XFAD) mice, as assessed with the T-maze and Y-maze tests. The administration of phloroglucinol for 2 months in 5XFAD mice caused a reduction in the number of amyloid plaques and in the protein level of BACE1, a major amyloid precursor protein cleavage enzyme, together with γ-secretase. Phloroglucinol also restored the reduction in dendritic spine density and the number of mature spines in the hippocampi of 5XFAD mice. In addition, phloroglucinol-administered 5XFAD mice displayed lower protein levels of GFAP and Iba-1 and mRNA levels of TNF-α and IL-6 compared with vehicle-administered 5XFAD mice. These results demonstrated that phloroglucinol alleviated the neuropathological features and behavioral phenotypes in the 5XFAD mouse model. Taken together, our results suggest that phloroglucinol has therapeutic potential for AD treatment.

Honokiol Ameliorates Amyloidosis and Neuroinflammation and Improves Cognitive Impairment in Alzheimer's Disease Transgenic Mice.

The present study examined the effects of honokiol on amyloid-β (Aβ)-induced cognitive impairment and the underlying mechanisms in APPswe/PS1dE9 transgenic mice. The results showed that honokiol administration (20 mg/kg per day, intraperitoneally) for 6 weeks effectively improved spatial memory deficits in APPswe/PS1dE9 transgenic mice. Honokiol significantly lowered Aβ production and senile plaque deposition by downregulating β-site amyloid precursor protein cleavage enzyme 1 and enhancing Aβ phagocytosis by microglia. Honokiol reduced glial cell activation and the production of proinflammatory cytokines (TNF-α, IL-1β, and IL-6). Honokiol increased the transcriptional activity and protein levels of peroxisome proliferator-activated receptor-γ (PPARγ) However, all of the beneficial effects of honokiol on pathologic changes, including biochemistry and cognitive function, could be blocked by GW9662, a specific PPARγ inhibitor. These findings suggested that honokiol may be a natural PPARγ agonist, acting to attenuate Aβ generation and neuroinflammation. Therefore, honokiol may be a potential therapeutic approach for Alzheimer's disease.

An update on pathological implications of enzymatic dysregulation in Alzheimer's disease

Alzheimer’s Disease (AD) is the most prevalent non-reversible neurodegenerative disorder that affects the memory and cognitive centres of brain. It has been reported that, AD turns out to be prominent among the people aged~65 or above and is regarded as the most common cause of dementia. Moreover, AD stands among the leading causes of death in the first world nations, accounting more than 60% incidence of progressive cognitive impairment in elderly people. Amyloid beta and neurofibrillary tangles are two putative cytotoxic entities that have been identified, aggregation of which has been associated with the pathological signature of AD. Beta secretase-an amyloid precursor protein cleavage enzyme, plays a pivotal role in such pathogenic process of AD. Several other enzymatic dysregulations have also been linked with AD. Involvement of enzymatic dysregulation is the most discussed pathological implication in AD and therapeutic approaches have been postulated targeting such anomalies. Together, global consequences of enzymatic dysregulation and related therapeutic possibilities in AD remain the prime focus of present time. Therefore, research and study for the eloquent insight into the AD pathology from enzymatic perspective is essential and the same endeavour has been carried out in the present study.

Flavonoid-rich ethanol extract from the leaves of Diospyros kaki attenuates cognitive deficits, amyloid-beta production, oxidative stress, and neuroinflammation in APP/PS1 transgenic mice

Amyloid-β peptide (Aβ) initiates a cascade of pathological events, including activation of microglial cells, oxidative stress, and inflammation, leading to neuronal death and the typical pathological changes in Alzheimer’s disease (AD). Flavonoids have been reported to exert neuroprotective activities, not only through their generally accepted antioxidant effects, but also through their ability to protect against neurotoxin-induced injury. Flavonoids reduce Aβ production, inhibit neuroinflammation, increase cerebrovascular function, and improve cognitive performance. Here, we analyzed the effects of a flavonoid-rich ethanol extract from the leaves of Diospyros kaki (FLDK) in APP/PS1 transgenic mice. We found that oral treatment with FLDK reversed learning and memory impairment, reduced Aβ burden and expression of β-site amyloid precursor protein cleavage enzyme 1 (BACE1), and decreased microglial activation in senile plaques. FLDK restored antioxidant enzyme activities, as well as reduced the lipid peroxidation product, malondialdehyde, and inflammatory mediators. These results demonstrate that FLDK alleviates cognitive decline and reduces Aβ burden, microglial activation, oxidative stress, and inflammation responses. Thus, FLDK treatment may be a potential therapeutic strategy for preventing and treating AD, at least in part via its anti-oxidant and anti-inflammatory biological activities and its effect on the Aβ producing enzyme BACE1.

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

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.

F-box Only Protein 2 (Fbxo2) Regulates Amyloid Precursor Protein Levels and Processing

The amyloid precursor protein (APP) is an integral membrane glycoprotein whose cleavage products, particularly amyloid-β, accumulate in Alzheimer disease (AD). APP is present at synapses and is thought to play a role in both the formation and plasticity of these critical neuronal structures. Despite the central role suggested for APP in AD pathogenesis, the mechanisms regulating APP in neurons and its processing into cleavage products remain incompletely understood. F-box only protein 2 (Fbxo2), a neuron-enriched ubiquitin ligase substrate adaptor that preferentially binds high-mannose glycans on glycoproteins, was previously implicated in APP processing by facilitating the degradation of the APP-cleaving β-secretase, β-site APP-cleaving enzyme. Here, we sought to determine whether Fbxo2 plays a similar role for other glycoproteins in the amyloid processing pathway. We present in vitro and in vivo evidence that APP is itself a substrate for Fbxo2. APP levels were decreased in the presence of Fbxo2 in non-neuronal cells, and increased in both cultured hippocampal neurons and brain tissue from Fbxo2 knock-out mice. The processing of APP into its cleavage products was also increased in hippocampi and cultured hippocampal neurons lacking Fbxo2. In hippocampal slices, this increase in cleavage products was accompanied by a significant reduction in APP at the cell surface. Taken together, these results suggest that Fbxo2 regulates APP levels and processing in the brain and may play a role in modulating AD pathogenesis.

Arctigenin Effectively Ameliorates Memory Impairment in Alzheimer's Disease Model Mice Targeting Both -Amyloid Production and Clearance

Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

Modest reductions in BACE1 activity significantly reduce beta-amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease

Inhibiting the amyloidogenic processing of the amyloid precursor protein (APP) by blocking the activity of the β-site APP cleavage enzyme (BACE) has been extensively pursued as a therapeutic strategy for Alzheimer's disease (AD). Indeed, brief treatment with high doses of anti-BACE1 antibodies effectively reduced peripheral and central Aβ production in wild-type mice and nonhuman primates (Atwal et al., STM 2011), suggesting a potential therapeutic role for this antibody. However, it is still unclear what level of Aβ reduction could translate to a therapeutically meaningful impact on the progression of disease pathology if treatment were continued chronically. Therefore, to test the effectiveness of the anti-BACE1 antibodies for reducing/preventing A β plaque deposition and associated pathology, we treated transgenic mice expressing London mutant (V717I) human APP (hAPPlon) for four months starting at an age prior to the onset of plaque deposition. Female transgenic hAPPlon mice or non-transgenic littermate controls received either short-term treatment (3 IP injections, each separated by 4 days), with control antibody or anti-BACE1 antibodies (30mg/kg, 100mg/kg) starting at 2–3 months-of-age, or chronic treatment (weekly IP injections for 16 weeks) of a control antibody or anti-BACE1 antibody (100mg/kg), starting at 10.5 months-of-age. Serum, plasma and brain tissue was collected for PK/PD and pathology analysis. We found that short-term anti-BACE1 treatment (100mg/kg) modestly reduced guanidine-extracted total brain A β 40 and A β 42 levels by 17% and 31%, respectively, compared with control-treated hAPPlon mice when measured by ELISA. Chronic anti-BACE1 treatment significantly reduced A β plaques by ∼50% throughout the brain, compared with control-treated hAPPlon mice. This was associated with a reduction in total brain A β 40 and A β 42 levels by 73% and 55%, respectively. Plaque-associated neuroinflammation, as measured by microglia and astrocyte activation, was also significantly reduced. Modest but chronic inhibition of BACE1 activity with high affinity anti-BACE1 antibodies can significantly reduce A β plaque deposition and associated pathology in a mouse model of AD. This suggests that partial inhibition of BACE1 could be an effective therapeutic strategy in human AD patients as well.