Aβ Production Research Articles

QSAR Modeling for Predicting Beta-Secretase 1 Inhibitory Activity in Alzheimer's Disease with Support Vector Regression

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, with the accumulation of β-amyloid (Aβ) plaques playing a key role in its progression. Beta-Secretase 1 (BACE1) is a crucial enzyme in Aβ production, making it a prime therapeutic target for AD treatment. However, designing effective BACE1 inhibitors has been challenging due to poor selectivity and limited blood-brain barrier permeability. To address these challenges, we employed a machine learning approach using Support Vector Regression (SVR) in a Quantitative Structure-Activity Relationship (QSAR) model to predict the inhibitory activity of potential BACE1 inhibitors. Our model, trained on a dataset of 7,298 compounds from the ChEMBL database, accurately predicted pIC50 values using molecular descriptors, achieving an R² of 0.690 on the testing set. The model's performance demonstrates its utility in prioritizing drug candidates, potentially accelerating drug discovery. This study highlights the effectiveness of computational approaches in optimizing drug discovery and suggests that further refinement could enhance the model’s predictive power for AD therapeutics.

Investigation of amyloid‑β peptide production and clearance pathways in different stages of Alzheimer's disease.

Alzheimer's disease (AD) is an age‑related, progressive decline in cognitive ability. Accumulation and deposition of amyloid‑β (Aβ) is still the best‑known cause of AD that worsens over time. It is unclear whether the increase in Aβ production or the inefficiency of the degradation system causes the accumulation of β‑fibrils during AD development. This research investigated Aβ‑producing and clearance pathways in different stages of AD. For this purpose, patients were categorized into four experimental groups: patients with mild cognitive impairment, patients with moderate cognitive decline, patients with very severe cognitive decline, and healthy patients as control. Levels of Aβ‑40, soluble amyloid precursor protein beta (sAPPβ), matrix metalloproteinase‑9 (MMP‑9), matrix metalloproteinase‑3 (MMP‑3), neprilysin (NEP), angiotensin‑converting enzyme (ACE), and insulin‑degrading enzyme (IDE) were determined by ELISA kits and immunoblotting in serum samples. According to the results, the levels of Aβ‑40 and sAPPβ increased in AD patients from an early stage, and levels were maintained in progressive AD stages. MMP‑9 also increased in the early stage, but its content decreased with disease development. MMP‑3 was significantly higher in the three stages of AD compared to the control patients. However, IDE, NEP, and ACE enzymes as clearing systems decreased in all studied AD samples, with their reductions more remarkable in the middle and late stages. The results showed that multiple Aβ‑degrading enzymes such as NEP and IDE in AD patients decline as AD progresses, while Aβ‑40 and sAPPβ increased from the early stage of the disease. Therefore, it could be concluded that detection of the dementia phase is a critical step for therapeutic strategies.

Glutamate Transporter 1 as a Novel Negative Regulator of Amyloid β.

Glutamate transporter-1 (GLT-1) dynamics are implicated in excitotoxicity and Alzheimer's disease (AD) progression. Early stages of AD are often marked by hyperactivity and increased epileptiform activity preceding cognitive decline. Previously, we identified a direct interaction between GLT-1 and Presenilin 1 (PS1) in the brain, highlighting GLT-1 as a promising target in AD research. This study reports the significance of this interaction and uncovers a novel role of GLT-1 in modulating amyloid-beta (Aβ) production. Overexpression of GLT-1 in cells reduces the levels of Aβ40 and Aβ42 by decreasing γ-secretase activity pertinent to APP processing and induces a more "open" PS1 conformation, resulting in decreased Aβ42/40 ratio. Inhibition of the GLT-1/PS1 interaction using cell-permeable peptides produced an opposing effect on Aβ, highlighting the pivotal role of this interaction in regulating Aβ levels. These findings emphasize the potential of targeting the GLT-1/PS1 interaction as a novel therapeutic strategy for AD.

Novel insights into famotidine as a GSK-3β inhibitor: An explorative study in aluminium chloride-induced Alzheimer’s disease rat model

Alzheimer's disease (AD), a chronic neurodegenerative disease, presents a substantial global health challenge. This study explored the potential therapeutic role of famotidine, a histamine (H2) receptor antagonist, as a glycogen synthase kinase-3β (GSK-3β) inhibitor in the context of AD induced by aluminium chloride (AlCl3) in a rat model. The intricate relationship between GSK-3β dysregulation and AD pathogenesis, particularly in amyloid-β (Aβ) production, formed the basis for investigating famotidine's efficacy. Molecular modelling revealed famotidine's efficient binding to GSK-3β, suggesting inhibitory potential. In behavioural assessments, famotidine-treated groups exhibited dose-dependent improvements in Morris Water Maze, Novel Object Recognition, and Y-Maze tests, comparable to the standard Rivastigmine tartrate group. Biochemical analyses showed that famotidine inhibits acetylcholinesterase, decreases lipid peroxidation, increases antioxidant activity, and mitigates oxidative stress. Moreover, famotidine significantly lowered the levels of GSK-3β, IL-6, and Aβ(1−42). The neuroprotective effects of famotidine were further supported by histopathological analysis. This comprehensive investigation underscores famotidine's potential as a GSK-3β inhibitor, providing insights into its therapeutic impact on AD induced by AlCl3. The study offers a promising avenue for repurposing famotidine due to its established safety profile and widespread availability, highlighting its potential in addressing the formidable challenge of AD.

Lactate increases ADAM10 activity and reduces BACE1 activity in mouse brain.

The accumulation and aggregation of beta-amyloid (Aβ) peptides contributes to neuronal dysfunction and death. These Aβ peptides originate from a transmembrane protein known as amyloid precursor protein (APP), which can be processed via two competing pathways. Alpha-secretase (ADAM10) cleavage is thought to be neuroprotective while beta-secretase (BACE1) cleavage results in the production of Aβ. Aerobic exercise reduces BACE1 activity, but the mechanisms involved are unknown though several exercise-induced mediators such as lactate may be involved. The current study examined whether systemic lactate can alter APP processing and BACE1 and ADAM10 activity. Mice were randomly assigned to one of four groups (n=10 per group): (1) sedentary; (2) lactate-injection (1.0gkg-1 body mass); (3) exercise; and (4) exercise and oxamate (lactate dehydrogenase inhibitor; 750mgkg-1 body mass). Two hours following intervention, the hippocampus and prefrontal cortex (PFC) were collected. In the PFC lactate-injection and exercise resulted in higher ADAM10 activity compared to sedentary (exercise P=0.0215, lactate P=0.0038), in the hippocampus lactate-injection was higher compared to sedentary (lactate P=0.011), and this was absent in the presence of oxamate. Hippocampal BACE1 activity was lower in the lactate group compared to the exercise group (P=0.01). Oxamate resulted in higher BACE1 protein content compared to sedentary in the PFC (vs. sedentary P=0.048). These findings suggest that lactate is important for regulating ADAM10 activity and thereby shifts APP processing away from Aβ production. KEY POINTS: Exercise is known to alter the processing of amyloid precursor protein by reducing the activity of the rate-limiting enzyme BACE1 and increasing the activity of ADAM10. It is thought that exercise-induced factors are responsible for these enzymatic changes. This study examined if lactate accumulation plays a role in this process. Mice were assigned to one of four groups: sedentary, lactate, exercise and exercise + lactate. The findings demonstrate that lactate accumulation alters brain BACE1 and ADAM10 and shifts amyloid precursor protein processing away from beta-amyloid production.

Astrocyte-derived lactoferrin inhibits neuronal ferroptosis by reducing iron content and GPX4 degradation in APP/PS1 transgenic mice

Increased astrocytic lactoferrin (Lf) expression was observed in the brains of elderly individuals and Alzheimer's disease (AD) patients. Our previous study revealed that astrocytic Lf overexpression improved cognitive capacity by facilitating Lf secretion to neurons to inhibit β-amyloid protein (Aβ) production in APP/PS1 mice. Here, we further discovered that astrocytic Lf overexpression inhibited neuronal loss by decreasing iron accumulation and increasing glutathione peroxidase 4 (GPX4) expression in neurons within APP/PS1 mice. Furthermore, human Lf (hLf) treatment inhibited ammonium ferric citrate (FAC)-induced ferroptosis by chelating intracellular iron. Additionally, machine learning analysis uncovered a correlation between Lf and GPX4. hLf treatment boosted low-density lipoprotein receptor-related protein 1 (LRP1) internalization and facilitated its interaction with heat shock cognate 70 (HSC70), thereby inhibiting HSC70 binds to GPX4, and eventually attenuating GPX4 degradation and FAC-induced ferroptosis. Overall, astrocytic Lf overexpression inhibited neuronal ferroptosis through two pathways: reducing intracellular iron accumulation and promoting GPX4 expression via inhibiting chaperone-mediated autophagy (CMA)-mediated GPX4 degradation. Hence, upregulating astrocytic Lf expression is a promising strategy for combating AD.

Social isolation impairs cognition via Aβ-mediated synaptic dysfunction

Social isolation (SI) is a common phenomenon in the modern world, especially during the coronavirus disease 2019 pandemic, and causes lasting cognitive impairments and mental disorders. However, it is still unclear how SI alters molecules in the brain and induces behavioural dysfunctions. Here, we report that SI impairs cognitive function and induces depressive-like behaviours in C57BL/6 J mice, in addition to impairing synaptic plasticity and increasing the levels of APP cleavage-related enzymes, thereby promoting Aβ production. Moreover, we show that in APP/PS1 transgenic mice, SI accelerates pathological changes and behavioural deficits. Interestingly, downregulation of the expression of the BACE1 attenuates SI-induced Aβ toxicity and synaptic dysfunction. Furthermore, early intervention with BACE1 shRNA blocks SI-induced cognitive impairments. Together, our data strongly suggest that SI-induced upregulation of BACE1 expression mediates Aβ toxicity and induces behavioural deficits. Down-regulation of BACE1 may be a promising strategy for preventing SI-induced cognitive impairments.

ZiBu PiYin recipe regulates central and peripheral Aβ metabolism and improves diabetes-associated cognitive decline in ZDF rats

Ethnopharmacological relevanceCognitive impairment caused by central neuropathy in type 2 diabetes mellitus (T2DM), namely diabetes-associated cognitive decline (DACD), is one of the common complications in patients with T2DM. Studies have shown that brain β-amyloid (Aβ) deposition is a typical pathological change in patients with DACD, and that there is a close relationship between intestinal microorganisms and cognitive impairment. However, the specific mechanism(s) of alteration in Aβ metabolism in DACD, and of the correlation between Aβ metabolism and intestinal microorganisms remain unknown. Aim of the studyRevealing the mechanism of ZBPYR regulating Aβ metabolism and providing theoretical basis for clinical evaluation and diagnosis of DACD. Materials and methodsWe characterized Aβ metabolism in the central and peripheral tissues of Zucker diabetic fatty (ZDF) rats with DACD, and then explored the preventive and therapeutic effects of ZiBu PiYin Recipe (ZBPYR). Specifically, we assessed these animals for the formation, transport, and clearance of Aβ; the morphological structure of the blood-brain barrier (BBB); and the potential correlation between Aβ metabolism and intestinal microorganisms. ResultsZBPYR provided improvements in the structure of the BBB, attenuation of Aβ deposition in the central and peripheral tissues, and a delay in the development of DACD by improving the expression of Aβ production, transport, and clearance related protein in ZDF rats. In addition, ZBPYR improved the diversity and composition of intestinal microorganisms, decreased the abundance of Coprococcus, a bacterium closely related to Aβ production, and up regulate the abundance of Streptococcus, a bacterium closely related to Aβ clearance. ConclusionThe mechanism of ZBPYR ability to ameliorate DACD may be closely related to changes in the intestinal microbiome.

Alzheimer's Disease as a Membrane Dysfunction Tauopathy? New Insights into the Amyloid Cascade Hypothesis.

The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42.

Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production.

Missense mutations in the amyloid precursor protein (APP) and presenilin-1 (PSEN1) cause early-onset familial Alzheimer's disease (FAD) and alter proteolytic production of secreted 38-to-43-residue amyloid β-peptides (Aβ) by the PSEN1-containing γ-secretase complex, ostensibly supporting the amyloid hypothesis of pathogenesis. However, proteolysis of APP substrate by γ-secretase is processive, involving initial endoproteolysis to produce long Aβ peptides of 48 or 49 residues followed by carboxypeptidase trimming in mostly tripeptide increments. We recently reported evidence that FAD mutations in APP and PSEN1 cause deficiencies in early steps in processive proteolysis of APP substrate C99 and that this results from stalled γ-secretase enzyme-substrate and/or enzyme-intermediate complexes. These stalled complexes triggered synaptic degeneration in a C. elegans model of FAD independently of Aβ production. Here we conducted full quantitative analysis of all proteolytic events on APP substrate by γ-secretase with six additional PSEN1 FAD mutations and found that all six are deficient in multiple processing steps. However, only one of these (F386S) was deficient in certain trimming steps but not in endoproteolysis. Fluorescence lifetime imaging microscopy in intact cells revealed that all six PSEN1 FAD mutations lead to stalled γ-secretase enzyme-substrate/intermediate complexes. The F386S mutation, however, does so only in Aβ-rich regions of the cells, not in C99-rich regions, consistent with the deficiencies of this mutant enzyme only in trimming of Aβ intermediates. These findings provide further evidence that FAD mutations lead stalled and stabilized γ-secretase enzyme-substrate and/or enzyme-intermediate complexes and are consistent with the stalled process rather than the products of γ-secretase proteolysis as the pathogenic trigger.

It's good to know what to BACE the specificity of your inhibitors on.

Production, aggregation, and clearance of the amyloid β peptide (Aβ) are important processes governing the initial pathogenesis of Alzheimer's disease (AD). Inhibition of β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) (one of two key proteases responsible for Aβ production) as an AD-therapeutic approach so far has failed to yield a successful drug. BACE1 and its homologue BACE2 are frequently inhibited by the same inhibitors. Several genetic and cerebral organoid modeling studies suggest that BACE2 has dose-dependent AD-suppressing activity, which makes its unwanted inhibition potentially counterproductive for AD treatment. The in vivo effects of an unwanted cross inhibition of BACE2 have so far been impossible to monitor because of the lack of an easily accessible pharmacodynamic marker specific for BACE2 cleavage. In this issue of the JCI, work led by Stefan F. Lichtenthaler identifies soluble VEGFR3 (sVEGFR3) as a pharmacodynamic plasma marker for BACE2 activity not shared with BACE1.

Cortical neurodegeneration caused by Psen1 mutations is independent of Aβ

Mutations in the PSEN genes are the major cause of familial Alzheimer's disease, and presenilin (PS) is the catalytic subunit of γ-secretase, which cleaves type I transmembrane proteins, including the amyloid precursor protein (APP) to release Aβ peptides. While PS plays an essential role in the protection of neuronal survival, PSEN mutations also increase the ratio of Aβ42/Aβ40. Thus, it remains unresolved whether PSEN mutations cause AD via a loss of its essential function or increases of Aβ42/Aβ40. Here, we test whether the knockin (KI) allele of Psen1 L435F, the most severe FAD mutation located closest to the active site of γ-secretase, causes age-dependent cortical neurodegeneration independent of Aβ by crossing various Psen mutant mice to the App-null background. We report that removing Aβ completely through APP deficiency has no impact on the age-dependent neurodegeneration in Psen mutant mice, as shown by the absence of effects on the reduced cortical volume and decreases of cortical neurons at the ages of 12 and 18 mo. The L435F KI allele increases Aβ42/Aβ40 in the cerebral cortex while decreasing de novo production and steady-state levels of Aβ42 and Aβ40 in the presence of APP. Furthermore, APP deficiency does not alleviate elevated apoptotic cell death in the cerebral cortex of Psen mutant mice at the ages of 2, 12, and 18 mo, nor does it affect the progressive microgliosis in these mice. Our findings demonstrate that Psen1 mutations cause age-dependent neurodegeneration independent of Aβ, providing further support for a loss-of-function pathogenic mechanism underlying PSEN mutations.

Corilagin improves cognitive impairment in APP/PS1 mice by reducing Aβ generation and enhancing synaptic plasticity

Alzheimer's disease (AD) is closely associated with the neurotoxic effects of amyloid-β (Aβ), leading to synaptic damage, neuronal loss and cognitive dysfunction. Previous in vitro studies have demonstrated the potential of corilagin to counteract Aβ-induced oxidative stress, inflammatory injury, and β-site amyloid precursor protein cleaving enzyme-1 (BACE1) activity in Aβ production. However, the in vivo protective effects of corilagin on Alzheimer's disease remain unexplored. The purpose of this study was to investigate the protective effects of corilagin on APP/PS1 mice and the underlying mechanisms. The cognitive function of the mice was assessed by step-through passive avoidance and Morris water maze tests. Nissl staining was used to evaluate neuronal damage in the hippocampus. ELISA and Western blotting analyses were used to determine the associated protein expression. Transmission electron microscopy was utilized to observe the synaptic ultrastructure of hippocampal neurons. Golgi staining was applied to assess dendritic morphology and dendritic spine density in hippocampal pyramidal neurons. Immunohistochemistry and Western blotting were performed to examine the expression of synaptic-associated proteins. The results showed that corilagin improves learning and memory in APP/PS1 mice, reduces hippocampal neuron damage, inhibits BACE1 and reduces Aβ generation. It also improves synaptic plasticity and the expression of synaptic-associated proteins. Corilagin effectively reduces Aβ generation by inhibiting BACE1, ultimately reducing neuronal loss and enhancing synaptic plasticity to improve synaptic transmission. This study sheds light on the potential therapeutic role of corilagin in Alzheimer's disease.

Maresin1 restrains chronic inflammation and Aβ production to ameliorate Alzheimer's disease via modulating ADAM10/17 and its associated neuroprotective signal pathways: A pilot study

Chronic inflammation is an important pathogenetic factor that leads to the progression of Alzheimer's disease (AD), and specialized pro-resolving lipid mediators (SPMs) play critical role in regulating inflammatory responses during AD pathogenesis. Maresin1 (MaR1) is the latest discovered SPMs, and it is found that MaR1 improves AD cognitive impairment by regulating neurotrophic pathways to protect AD synapses and reduce Aβ production, which made MaR1 as candidate agent for AD treatment. Unfortunately, the underlying mechanisms are still largely known. In this study, the AD mice and cellular models were subjected to MaR1 treatment, and we found that MaR1 reduced Aβ production to ameliorate AD-related symptoms and increased the expression levels of ADAM10/17, sAPPα and sAPPβ to exert its anti-inflammatory role. In addition, as it was determined by Western Blot analysis, we observed that MaR1 could affected the neuroprotective signal pathways. Specifically, MaR1 downregulated p57NTR and upregulated TrkA to activate the p75NTR/TrkA signal pathway, and it could increase the expression levels of p-PI3K and p-Akt, and downregulated p-mTOR to activate the PI3K/AKT/ERK/mTOR pathway. Finally, we verified the role of ADAM10/17 in regulating AD progression, and we found that silencing of ADAM10/17 inactivated the above neuroprotective signal pathways to aggravate AD pathogenesis. In conclusion, MaR1 is verified as potential therapeutic agent for AD by eliminating Aβ production, upregulating ADAM10/17, sAPPα and sAPPβ, and activating the neuroprotective p75NTR/TrkA pathway and the PI3K/AKT/ERK/mTOR pathway.

Chronic administration of prebiotics and probiotics ameliorates pathophysiological hallmarks of Alzheimer's disease in a APP/PS1 transgenic mouse model.

Introduction: The gut microbiota (MB), although one of the main producers of Aβ in the body, in physiological conditions contributes to the maintainance of a healthy brain. Dysbiosis, the dysbalance between Gram-negative and Gram-positive bacteria in the MB increases Aβ production, contributing to the accumulation of Aβ plaques in the brain, the main histopathological hallmark of Alzheimer's disease (AD). Administration of prebiotics and probiotics, maintaining or recovering gut-MB composition, could represent a nutraceutical strategy to prevent or reduce AD sympthomathology. Aim of this research was to evaluate whether treatment with pre- and probiotics could modify the histopathological signs of neurodegeneration in hippocampal CA1 and CA3 areas of a transgenic mouse model of AD (APP/PS1 mice). The hippocampus is one of the brain regions involved in AD. Methods: Tg mice and Wt littermates (Wt-T and Tg-T) were fed daily for 6months from 2months of age with a diet supplemented with prebiotics (a multi-extract of fibers and plant complexes, containing inulin/fruit-oligosaccharides) and probiotics (a 50%-50% mixture of Lactobacillus rhamnosus and Lactobacillus paracasei). Controls were Wt and Tg mice fed with a standard diet. Brain sections were immunostained for Aβ plaques, neurons, astrocytes, microglia, and inflammatory proteins that were evaluated qualitatively and quantitatively by immunofluorescence, confocal microscopy and digital imaging with ImageJ software. Results: Quantitative analyses demonstrated that: 1) The treatment with pre- and probiotics significantly decreased Aβ plaques in CA3, while in CA1 the reduction was not significant; 2) Neuronal damage in CA1 Stratum Pyramidalis was significantly prevented in Tg-T mice; no damage was found in CA3; 3) In both CA1 and CA3 the treatment significantly increased astrocytes density, and GFAP and IBA1 expression, especially around plaques; 4) Microglia reacted differently in CA1 and CA3: in CA3 of Tg-T mice there was a significant increase of CD68+ phagocytic microglia (ball-and-chain phenomic) and of CX3CR1 compared with CA1. Discussion: The higher microglia reactivity could be responsible for their more efficient scavenging activity towards Aβ plaques in CA3 in comparison to CA1. Treatment with pre- and probiotics, modifying many of the physiopathological hallmarks of AD, could be considered an effective nutraceutical strategy against AD symptomatology.

Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease

Alzheimer's Disease (AD) is characterized by an accumulation of pathologic amyloid-beta (Aβ) and Tau proteins, neuroinflammation, metabolic changes and neuronal death. Reactive astrocytes participate in these pathophysiological processes by releasing pro-inflammatory molecules and recruiting the immune system, which further reinforces inflammation and contributes to neuronal death. Besides these neurotoxic effects, astrocytes can protect neurons by providing them with high amounts of lactate as energy fuel. Astrocytes rely on aerobic glycolysis to generate lactate by reducing pyruvate, the end product of glycolysis, through lactate dehydrogenase. Consequently, limited amounts of pyruvate enter astrocytic mitochondria through the Mitochondrial Pyruvate Carrier (MPC) to be oxidized. The MPC is a heterodimer composed of two subunits MPC1 and MPC2, the function of which in astrocytes has been poorly investigated. Here, we analyzed the role of the MPC in the pathogeny of AD, knowing that a reduction in overall glucose metabolism has been associated with a drop in cognitive performances and an accumulation of Aβ and Tau. We generated 3xTgAD mice in which MPC1 was knocked-out in astrocytes specifically and focused our study on the biochemical hallmarks of the disease, mainly Aβ and neurofibrillary tangle production. We show that inhibition of the MPC before the onset of the disease significantly reduces the quantity of Aβ and Tau aggregates in the brain of 3xTgAD mice, suggesting that acting on astrocytic glucose metabolism early on could hinder the progression of the disease.

Cerebrovascular Endothelial Dysfunction: Role of BACE1.

Dysfunctional endothelium is increasingly recognized as a mechanistic link between cardiovascular risk factors and dementia, including Alzheimer disease. BACE1 (β-site amyloid-β precursor protein-cleaving enzyme 1) is responsible for β-processing of APP (amyloid-β precursor protein), the first step in the production of Aβ (amyloid-β) peptides, major culprits in the pathogenesis of Alzheimer disease. Under pathological conditions, excessive activation of BACE1 exerts detrimental effects on endothelial function by Aβ-dependent and Aβ-independent mechanisms. High local concentration of Aβ in the brain blood vessels is responsible for the loss of key vascular protective functions of endothelial cells. More recent studies recognized significant contribution of Aβ-independent proteolytic activity of endothelial BACE1 to the pathogenesis of endothelial dysfunction. This review critically evaluates existing evidence supporting the concept that excessive activation of BACE1 expressed in the cerebrovascular endothelium impairs key homeostatic functions of the brain blood vessels. This concept has important therapeutic implications. Indeed, improved understanding of the mechanisms of endothelial dysfunction may help in efforts to develop new approaches to the protection and preservation of healthy cerebrovascular function.

Tetramethylpyrazine Nitrone (TBN) Reduces Amyloid β Deposition in Alzheimer's Disease Models by Modulating APP Expression, BACE1 Activity, and Autophagy Pathways.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with age. A wealth of evidence indicates that the amyloid β (Aβ) aggregates result from dyshomeostasis between Aβ production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aβ reduction represent a promising strategy for AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with potential for the treatment of AD. Previously, we demonstrated that TBN markedly enhanced cognitive functions and decreased the levels of Aβ, APP, BACE 1, and hyperphosphorylated tau in 3×Tg-AD mice. However, the mechanism by which TBN inhibits Aβ deposition is still unclear. In this study, we employed APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months, and N2a/APP695swe cells treated with TBN (300 μM) to explore the mechanism of TBN in Aβ reduction. Our results indicate that TBN significantly alleviated cognitive impairment and reduced Aβ deposition in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway, inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, and decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-β, and NF-κB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of miR-346 and increase the levels of miR-147 and miR-106a in the N2a/APP695swe cells. These findings indicate that TBN may reduce Aβ levels likely by reducing APP expression by regulating APP gene transcriptional factors and miRNAs, reducing BACE1 expression, and promoting autophagy activities.

Generation and Characterization of a Novel Knockin Mouse Model Expressing PSEN1 D385A: Implications for Investigating Herbal Drug Effects in γ-Secretase Activity.

Presenilin (PSEN, PS) is essential for γ-secretase function, and mutations can disrupt amyloid-β (Aβ) production in familial Alzheimer's disease. Targeting γ-secretase is complex due to its broad involvement in physiological processes. Our aim was to create a novel knockin (KI) mouse model expressing PSEN1 D385A mutation and investigate the efficacy of a Geniposide and Ginsenoside Rg1 combination (NeuroProtect modified formula, NP-2) in restoring γ-secretase activity. Using gene manipulation, we established the PS1 D385A KI mouse model and confirmed the mutation, mRNA, and protein levels using Southern blotting, northern blotting, and western blotting, respectively. In vitro γ-secretase assay was conducted to measure γ-secretase activity, while histological analyses examined neurogenesis effects. NP-2 administration evaluated its impact on γ-secretase activity. The PS1 D385A KI homozygotes displayed severe cerebral hemorrhage, postnatal lethality, developmental disorders, reduced proliferation of neural progenitor cells, and disrupted γ-secretase function. The mutation abolished PS1 protein self-shearing, leading to compromised γ-secretase activity. NP-2 intervention effectively restored γ-secretase activity in the heterozygous mice. PS1 D385A mutant disrupted PS1 protein self-cleaving, impairing γ-secretase activity in KI mice. NP-2 restored γ-secretase function, offering potential for novel AD treatment strategies despite the challenges posed by γ-secretase's complex role in physiological processes.

Antioxidant and Neuroprotective Effects of Seed Oils from Trichosanthes kirilowii and T. laceribractea in Caenorhabditis elegans: A Comparative Analysis and Mechanism Study.

Excess reactive oxygen species (ROS) can accelerate amyloid β (Aβ) aggregation and tau protein hyperphosphorylation in neuron cells, which further leads to neurodegenerative diseases such as Alzheimer's disease (AD). Therefore, there is an urgent need to find natural and safe antioxidants for preventing or treating such neurodegenerative diseases. The seeds of Trichosanthes kirilowii Maxim and T. laceribractea Hayata have long been used for medicinal and edible purposes in China. However, the antioxidant and neuroprotective activities and underlying mechanisms of their seed oils still remain unclear. Herein, we examine the antioxidant and neuroprotective effects of seed oils extracted from different germplasms, T. kirilowii (YNHH and SDJN) and T. laceribractea (ZJQT and SXHZ), on ROS levels and neuroprotective activities in C. elegans. The results demonstrated that the seed oils significantly reduced the ROS levels in C. elegans by 17.03-42.74%, with T. kirilowii (YNHH and SDJN) exhibiting significantly stronger ROS scavenging abilities than T. laceribractea (ZJQT and SXHZ). The seed oils from T. kirilowii (YNHH and SDJN) alleviated the production and aggregation of Aβ and the phosphorylation and polymerization of tau, suggesting a potential neuroprotective role. Conversely, seed oils from T. laceribractea (ZJQT and SXHZ) show minimal neuroprotective effects in C. elegans. These differential outcomes might stem from distinct mechanisms underlying antioxidant and neuroprotective effects, with the ctl-2 gene implicated as pivotal in mediating the significant neuroprotective effects of seed oils from T. kirilowii (YNHH and SDJN). Our findings have provided valuable insights into the antioxidant and neuroprotective properties of T. kirilowii seed oils, paving the way for further research aimed at elucidating the underlying mechanisms and exploring their potential therapeutic applications in combating neurodegenerative diseases.