Aβ Production Research Articles

Gentidelasides A-G: loganin derivatives from Gentiana delavayi with reducing Aβ secretion via suppressing BACE1 expression.

Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute configurations were unambiguously elucidated by analysis of extensive NMR spectroscopy, ECD, and HRESIMS, as well as enzymatic hydrolysis. In vitro bioassay, compound 7 showed obvious inhibitory effects on the production of Aβ40 and Aβ42, with IC50 values of 0.052 ± 0.0023 nM and 1.52 ± 0.95 nM, respectively, which probably exert their prevention of Alzheimer's disease by inhibiting the expression of β-site amyloid precursor protein cleaving enzyme 1. The molecular docking simulation revealed that compound 7 inhibited BACE1 through hydrophilic and hydrophobic interactions in the active site cavities.

OATP1A2 mediates Aβ1-42 transport and may be a novel target for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease with an unknown cause. Many studies have suggested that the imbalance between the clearance and accumulation of β-amyloid protein (Aβ) in the brain of AD patients is the main cause of AD development of AD. Meanwhile, drug transporters play a key role in the transport of drugs and endogenous substances in vivo as well as in the development of many diseases. Could they be related to the imbalance between Aβ clearance and accumulation? OATP1A2 is the most abundant subfamily of organic anion transporting polypeptides (OATPs) that transport amphipathic substrates. Its high bilateral expression in brain endothelial cells suggests it plays a crucial role in delivering drugs and neuroactive peptides to brain tissue. Could it also be involved in mediating the production and accumulation of Aβ in the central system? This could lead to an imbalance between Aβ clearance and accumulation, ultimately resulting in AD development. This hypothesis would be bold and novel in the field of science. In this study, we successfully established the OATP1A2-HEK293T transgenic cell model, and found that the uptake of Aβ1-42 by OATP1A2-HEK293T cells was significantly higher than that of NC-HEK293T control cells and human astrocytes by adding different concentrations of Aβ1-42 to the cells of each group, suggesting that OATP1A2 expressed in the human brain is involved in Aβ amyloid protein transport.

GNG5 is a novel regulator of Aβ42 production in Alzheimer's disease.

The therapeutic options for Alzheimer's disease (AD) are limited, underscoring the critical need for finding an effective regulator of Aβ42 production. In this study, with 489 human postmortem brains, we revealed that homotrimer G protein subunit gamma 5 (GNG5) expression is upregulated in the hippocampal-entorhinal region of pathological AD compared with normal controls, and is positively correlated with Aβ pathology. In vivo and in vitro experiments confirm that increased GNG5 significantly promotes Aβ pathology and Aβ42 production. Mechanically, GNG5 regulates the cleavage preference of γ-secretase towards Aβ42 by directly interacting with the γ-secretase catalytic subunit presenilin 1 (PS1). Moreover, excessive GNG5 increases the protein levels and the activation of Rab5, leading to the increased number of early endosomes, the major cellular organelle for production of Aβ42. Furthermore, immunoprecipitation and immunofluorescence revealed co-interaction of Aβ42 with GPCR family CXCR2, which is known as the receptor for IL-8, thus facilitating the dissociation of G-proteins βγ from α subunits. Treatment of Aβ42 in neurons combined with structure prediction indicated Aβ42 oligomers as a new ligand of CXCR2, upregulating γ subunit GNG5 protein levels. The co-localizations of GNG5 and PS1, CXCR2 and Aβ42 were verified in eight human brain regions. Besides, GNG5 is significantly reduced in extracellular vesicles (EVs) derived from cerebral cortex or serum of AD patients compared with healthy cognition controls. In brief, GNG5 is a novel regulator of Aβ42 production, suggesting its clinical potential as a diagnosis biomarker and the therapeutic target for AD. The GNG5 content in EVs derived from serum and brain tissue of patients with AD significantly reduced. The GNG5 expression in the hippocampal-entorhinal neurons of donors with pathological AD significantly increased, and can exist in homotrimer subtypes. GNG5 expression positively correlates with Aβ pathology and Aβ42 production. Homotrimer-GNG5 binds to the γ-secretase catalytic subunit PS1 and preferentially generates Aβ42 in early endosome. GNG5 leads to enhanced Rab5 protein and activation levels, increased number of early endosome, promoting Aβ42 production. Further, Aβ42 binds to CXCR2 to upregulate GNG5 levels in a feedback loop.

Protective effects of a lactobacilli mixture against Alzheimer’s disease-like pathology triggered by Porphyromonas gingivalis

Porphyromonas gingivalis (P. gingivalis) is one of the pathogens involved in gingival inflammation, which may trigger neuroinflammatory diseases such as Alzheimer’s disease (AD). This study aimed to investigate the protective (preventive and treatment) effects of a lactobacilli mixture combining Lactobacillus reuteri PTCC1655, Lactobacillus brevis CD0817, Lacticaseibacillus rhamnosus PTCC1637, and Lactobacillus plantarum PTCC1058 against P. gingivalis-induced gingival inflammation and AD-like pathology in rats. These probiotic strains exhibited cognitive enhancement effects, but this study proposed to assess their activity in a mixture. To propose a probable mechanism for P. gingivalis cognitive impairments, the TEs balance were analyzed in hippocampus and cortex tissues. Animals were divided into five groups: the control, lactobacilli, P. gingivalis, lactobacilli + P. gingivalis (prevention), and P. gingivalis + lactobacilli group (treatment) groups. The behavioral and histopathological changes were compared among them. Finally, The Trace elements (TEs) levels in the hippocampus and cortex tissues were analyzed. The palatal tissue sections of the P. gingivalis infected rats showed moderate inflammation with dense infiltration of inflammatory cells, a limited area of tissue edema, and vascular congestion. Additionally, passive avoidance learning and spatial memory were impaired. Histopathological tests revealed the presence of Aβ-positive cells in the P. gingivalis group. While the Aβ-positive cells decreased in the treatment group, their formation was inhibited in the preventive group. Administration of a mixture of lactobacilli (orally) effectively mitigated the gingival inflammation, Aβ production, and improved learning and memory functions. Moreover, Zn, Cu, and Mn levels in the hippocampus were dramatically elevated by P. gingivalis infection, whereas lactobacilli mixture mitigated these disruptive effects. The lactobacilli mixture significantly prevented the disruptive effects of P. gingivalis on gingival and brain tissues in rats. Therefore, new formulated combination of lactobacilli may be a good candidate for inhibiting the P. gingivalis infection and its subsequent cognitive effects. The current study aimed to evaluate the effects of a lactobacilli mixture to manage the disruptive effects of P. gingivalis infection on memory.

Alzheimer's Disease-Derived Outer Membrane Vesicles Exacerbate Cognitive Dysfunction, Modulate the Gut Microbiome, and Increase Neuroinflammation and Amyloid-β Production.

Although our understanding of the molecular biology of Alzheimer's disease (AD) continues to improve, the etiology of the disease, particularly the involvement of gut microbiota disturbances, remains a challenge. Outer membrane vesicles (OMVs) play a key role in central nervous system diseases, but the impact of OMVs on AD progression remains unclear. In this study, we hypothesized that AD-derived OMVs (OMVsAD) were a risk factor in AD pathology. To test our hypothesis, young APP/PS1 mice (AD mice) were given OMVsAD by gavage. Young AD mice were euthanized 120days after gavage to assess the intestinal barrier, gut microbiota diversity, mediators of neuroinflammation, glial markers, amyloid burden, and short-chain fatty acid (SCFA) levels. Our results showed that OMVsAD accelerated cognitive dysfunction after 120days of intragastric administration. Morris water maze experiment and new object recognition test showed that OMVsAD caused significantly poorer spatial ability learning and memory of the AD mice. We observed the OMVsAD-treated APP/PS1 mice display OMVs disrupting the intestinal barrier compared with controls of normal human-derived OMVs. Compared with the OMVsHC group, claudin-5 and ZO-1 related to the intestinal barrier were significantly downregulated in the OMVsAD group. The OMVsAD activate microglia in the cerebral cortex and hippocampus of AD mice, and the levels of IL-1β, IL-6, TNF-α, and NF-Κb were upregulated. We also found that OMVsAD increased Aβ production. 16S rRNA sequencing showed that OMVsAD negatively regulated the α- and β-diversity index of intestinal flora and reduced the levels of SCFA. OMVsAD may change the intestinal flora of young AD, damage the intestinal mucosa and blood-brain barrier, and accelerate AD neuropathological damage.

The Icelandic mutation (APP-A673T) is protective against amyloid pathology in vivo.

A previous epidemiological study in Northern Europe showed that the A673T mutation (Icelandic mutation) in the amyloid precursor protein gene (APP) can protect against Alzheimer's disease (AD). While the effect of the A673T mutation on APP processing has been investigated primarily in vitro, its in vivo impact has not been evaluated. This is mainly because most existing AD mouse models carry the Swedish mutation. The Swedish and Icelandic mutations are both located near the β-cleavage site, and each mutation is presumed to have the opposite effect on β-cleavage. Therefore, in the AD mouse models with the Swedish mutation, its effects could compete with the effects of the Icelandic mutation. Here, we introduced the A673T mutation into App knock-in mice devoid of the Swedish mutation (AppG-F mice) to avoid potential deleterious effects of the Swedish mutation and generated AppG-F-A673T mice. APP-A673T significantly downregulated β-cleavage and attenuated the production of Aβ and amyloid pathology in the brains of these animals. The Icelandic mutation also reduced neuroinflammation and neuritic alterations. Both sexes were studied. This is the first successful demonstration of the protective effect of the Icelandic mutation on amyloid pathology in vivo. Our findings indicate that specific inhibition of the APP-BACE1 interaction could be a promising therapeutic approach. Alternatively, introduction of the disease-protective mutation such as APP-A673T using in vivo genome editing technology could be a novel treatment for individuals at high risk for AD, such as familial AD gene mutation carriers and APOE ε4 carriers.Significance statement The A673T mutation (Icelandic mutation) in the APP gene can protect against AD. The effect of the A673T mutation on amyloid pathology has not been evaluated in vivo. Utilizing a new AD mouse model that we have recently developed, we show that the APP-A673T attenuates amyloid pathology in vivo. We demonstrate that its protective effects are exerted by inhibiting β-cleavage and reducing the production of Aβ in the brain. Furthermore, we reveal that the Icelandic mutation also reduced neuroinflammation and neuritic alterations. Our findings indicate that specific inhibition of the APP-BACE1 interaction or introduction of protective variants via in vivo genome editing could be a promising therapeutic approach.

Epigenetic Mechanisms of Aluminum-Induced Neurotoxicity and Alzheimer's Disease: A Focus on Non-Coding RNAs.

Aluminum (Al) is known to induce neurotoxic effects, potentially contributing to Alzheimer's disease (AD) pathogenesis. Recent studies suggest that epigenetic modification may contribute to Al neurotoxicity, although the mechanisms are still debatable. Therefore, the objective of the present study was to summarize existing data on the involvement of epigenetic mechanisms in Al-induced neurotoxicity, especially AD-type pathology. Existing data demonstrate that Al exposure induces disruption in DNA methylation, histone modifications, and non-coding RNA expression in brains. Alterations in DNA methylation following Al exposure were shown to be mediated by changes in expression and activity of DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs). Al exposure was shown to reduce histone acetylation by up-regulating expression of histone deacetylases (HDACs) and impair histone methylation, ultimately contributing to down-regulation of brain-derived neurotrophic factor (BDNF) expression and activation of nuclear factor κB (NF-κB) signaling. Neurotoxic effects of Al exposure were also associated with aberrant expression of non-coding RNAs, especially microRNAs (miR). Al-induced patterns of miR expression were involved in development of AD-type pathology by increasing amyloid β (Aβ) production through up-regulation of Aβ precursor protein (APP) and β secretase (BACE1) expression (down-regulation of miR-29a/b, miR-101, miR-124, and Let-7c expression), increasing in neuroinflammation through NF-κB signaling (up-regulation of miR-9, miR-125b, miR-128, and 146a), as well as modulating other signaling pathways. Furthermore, reduced global DNA methylation, altered histone modification, and aberrant miRNA expression were associated with cognitive decline in Al-exposed subjects. However, further studies are required to evaluate the contribution of epigenetic mechanisms to Al-induced neurotoxicity and/or AD development.

Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease

Brain signaling of calcineurin (CN) and nuclear factor of activated T-cells (NFAT) transcription factor increases in Alzheimer disease (AD) and is associated with synaptic loss, neurodegeneration, neuroinflammation, amyloid-β (Aβ) production, and cognitive decline. CN/NFAT inhibitors ameliorate these neuropathologies in mouse models of AD. Further, chronic use of tacrolimus in transplant patients reduces risk of AD. Beagles naturally develop Aβ plaques and cognitive dysfunction. We evaluated the impact of FDA-approved CN inhibitor, tacrolimus, and experimental NFAT inhibitor, Q134R, on cognitive outcomes during a three-year prevention study in 37 middle-aged beagles. While beagles treated with CN/NFAT inhibitors showed differences in the pattern of cognitive maintenance and duration of their effect, there was improvement in spatial learning, as well as maintenance of memory, attention, and working memory relative to placebo dogs. CN/NFAT inhibition is a promising target for prevention of cognitive decline that may be rapidly implemented in human clinical trials.

Epileptic seizures induced by pentylenetetrazole kindling accelerate Alzheimer-like neuropathology in 5×FAD mice.

Clinical studies have shown that epileptic seizures worsen Alzheimer's disease (AD) pathology and related cognitive deficits; however, the underlying mechanism is unclear. To assess the effects of seizures on the progression of AD, chronic temporal lobe epilepsy was induced in five familial AD mutation (5×FAD) mice by kindling with the chemoconvulsant pentylenetetrazole (PTZ) at 3-3.5 months of age. The amyloidogenic pathway, tauopathy, synaptic damage, neuronal death, neurological inflammatory response and associated kinase signaling pathway dysregulation were examined at 9 months of age. We found that APP, p-APP, BACE1, Aβ and kinase-associated p-tau levels were elevated after PTZ kindling in 5×FAD mice. In addition, PTZ kindling exacerbated hippocampal synaptic damage and neuronal cell death, as determined by scanning electron microscopy and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, respectively. Finally, the levels of the neuroinflammation markers GFAP and Iba1, as well as the inflammatory cytokine IL-1β, were increased after PTZ insult. PTZ kindling profoundly exacerbated extracellular regulated kinase (ERK)-death-associated protein kinase (DAPK) signaling pathway overactivation, and acute ERK inhibitor treatment downregulated Aβ production and p-APP and p-tau levels in epileptic 5×FAD mice. In addition, long-term use of the antiseizure drug carbamazepine (CBZ) alleviated seizure-induced accelerated amyloid and tau pathology and ERK-DAPK overactivation in 5×FAD mice. Collectively, these results demonstrate that seizure-induced increases in AD-like neuropathology in 5×FAD mice are partially regulated by the ERK-DAPK pathway, suggesting that the ERK-DAPK axis could be a new therapeutic target for the treatment of AD patients with comorbid seizures.

A Lipid-Raft Theory of Alzheimer's Disease.

I present a theory of Alzheimer's disease (AD) that explains its symptoms, pathology, and risk factors. To do this, I introduce a new theory of brain plasticity that elucidates the physiological roles of AD-related agents. New events generate synaptic and branching candidates competing for long-term enhancement. Competition resolution crucially depends on the formation of membrane lipid rafts, which requires astrocyte-produced cholesterol. Sporadic AD is caused by impaired formation of plasma-membrane lipid rafts, preventing the conversion of short- to long-term memory and yielding excessive tau phosphorylation, intracellular cholesterol accumulation, synaptic dysfunction, and neurodegeneration. Amyloid β (Aβ) production is promoted by cholesterol during the switch to competition resolution, and cholesterol accumulation stimulates chronic Aβ production, secretion, and aggregation. The theory addresses all of the major established facts known about the disease and is supported by strong evidence.

The Role of circRNAs in the Pathological Mechanisms of Alzheimer's Disease and May Serve as Potential Biomarkers.

Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia in the elderly, and the mechanisms of AD have not been fully defined. Circular RNAs (circRNAs), covalently closed RNAs produced by reverse splicing, have critical effects in the pathogenesis of AD. CircRNAs participate in production and clearance of Aβ and tau, regulate neuroinflammation, synaptic plasticity and the process of apoptosis and autophagy, indicating that circRNAs may be alternative biomarkers and therapeutic targets. Our review summarizes the functions of circRNAs in the progression and development of AD, which provide insights into the prospect of circRNAs in the diagnosis and treatment of AD.

Autoantibodies to BACE1 promote Aβ accumulation and neurodegeneration in Alzheimer's disease.

The profile of autoantibodies is dysregulated in patients with Alzheimer's disease (AD). Autoantibodies to beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) are present in human blood. This study aims to investigate the clinical relevance and pathophysiological roles of autoantibodies to BACE1 in AD. Clinical investigations were conducted in two independent cohorts, the Chongqing cohort, and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort. The Chongqing cohort included 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects (CN). The AIBL cohort included 162 Aβ-PET- CN, 169 Aβ-PET+ cognitively normal subjects (preclinical AD), and 31 Aβ-PET+ cognitively impaired subjects (ClinicalAD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. Autoantibodies to BACE1 exacerbated brain amyloid deposition and subsequent AD-type pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration in APP/PS1 mice. Autoantibodies to BACE1 increased Aβ production by promoting BACE1 expression through inhibiting PPARγ signaling. These findings suggest that autoantibodies to BACE1 are pathogenic in AD and the upregulation of these autoantibodies may promote the development of the disease. This study offers new insights into the mechanism of AD from an autoimmune perspective.

BACE1 Inhibitors for Alzheimer's Disease: Current Challenges and Future Perspectives.

Disease-modifying therapies (DMT) for Alzheimer's disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human genetic and biomarker studies, suggests the accumulation of Aβ as a driver of AD pathogenesis and progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is the initiator for Aβ production. Underpinning a critical role for BACE1 in AD pathophysiology are the elevated BACE1 concentration and activity observed in the brain and body fluids of AD patients. Therefore, BACE1 is a prime drug target for reducing Aβ levels in early AD. Small-molecule BACE1 inhibitors have been extensively developed for the last 20 years. However, clinical trials with these molecules have been discontinued for futility or safety reasons. Most of the observed adverse side effects were due to other aspartic proteases cross-inhibition, including the homologue BACE2, and to mechanism-based toxicity since BACE1 has substrates with important roles for synaptic plasticity and synaptic homeostasis besides amyloid-β protein precursor (AβPP). Despite these setbacks, BACE1 persists as a well-validated therapeutic target for which a specific inhibitor with high substrate selectivity may yet to be found. In this review we provide an overview of the evolution in BACE1 inhibitors design pinpointing the molecules that reached advanced phases of clinical trials and the liabilities that precluded adequate trial effects. Finally, we ponder on the challenges that anti-amyloid therapies must overcome to achieve clinical success.

WuYou decoction effectively reduces neuronal damage, synaptic dysfunction, and Aβ production in rats exposed to chronic sleep deprivation by modulating the Aβ-related enzymes and SIRT1/Nrf2/NF-κB pathway

Ethnopharmacological relevanceChronic sleep deprivation (CSD) can result in neuronal damage, synaptic dysfunction, Aβ production, neuroinflammation, and ultimately cognitive deterioration. WuYou Decoction (WYD), a contemporary prescription, has shown promise in enhancing sleep quality and cognitive performance in individuals with insomnia. However, the specific molecular mechanisms responsible for the neuroprotective effects of WYD on CSD remain incompletely understood. Aim of the studyThis study aimed to investigate the neuroprotective effects of WYD on the CSD model and its molecular mechanism. Materials and methodsUHPLC-MS/MS analysis was utilized to analyze the active ingredients of WYD extract. The study employed the multi-platform water environment method to establish the CSD model in rats. Subsequent to treatment with varying doses of WYD in CSD rats, cognitive function and pathological alterations in hippocampus and cortex, including neuronal damage, synaptic dysfunction, Aβ production, and neuroinflammation, were evaluated through a combination of Morris Water Maze test, HE staining, Nissl staining, Golgi-Cox staining, Transmission electron microscope, ELISA, Immunohistochemistry staining, Immunofluorescence staining and Western blot. ResultsUHPLC-MS/MS analysis revealed a total of 99 active ingredients were identified from the WYD extract. The administration of WYD exhibited a mitigation of cognitive decline in the model of CSD, as evidenced by increased neuron count in the hippocampus and cortex, and improved density and length of dendritic spines in these brain regions. Furthermore, WYD was found to suppress the Aβ production, and inhibit the expression of BACE1, PS1, GFAP, IBA1, IL-1β, IL-6, TNF-α, phosphorylated IκBα (Ser32) and phosphorylated NF-κB p65 (Ser536) in the hippocampus and cortex, while also increasing the levels of PSD95, SYN1, ADAM10, IDE, SIRT1 and Nrf2. ConclusionsWYD exhibits neuroprotective properties in CSD, potentially through modulation of the Aβ-related enzymes and SIRT1/Nrf2/NF-κB pathway.

Exploring the Benzazoles Derivatives as Pharmacophores for AChE, BACE1, and as Anti-Aβ Aggregation to Find Multitarget Compounds against Alzheimer’s Disease

Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer’s disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and benzothiazole, employed as pharmacophores, could act as multitarget drugs. AD is a multifactorial disease in which several pharmacological targets have been identified—some are involved with amyloid beta (Aβ) production, such as beta secretase (BACE1) and beta amyloid aggregation, while others are involved with the cholinergic system as acetylcholinesterase (AChE) and butirylcholinesterase (BChE) and nicotinic and muscarinic receptors, as well as the hyperphosphorylation of microtubule-associated protein (tau). In this review, we describe the in silico and in vitro evaluation of benzazoles on three important targets in AD: AChE, BACE1, and Aβ. Benzothiazoles and benzimidazoles could be the best benzazoles to act as multitarget drugs for AD because they have been widely evaluated as AChE inhibitors, forming π–π interactions with W286, W86, Y72, and F338, as well as in the AChE gorge and catalytic site. In addition, the sulfur atom from benzothiazol interacts with S286 and the aromatic ring from W84, with these compounds having an IC50 value in the μM range. Also, benzimidazoles and benzothiazoles can inhibit Aβ aggregation. However, even though benzazoles have not been widely evaluated on BACE1, benzimidazoles evaluated in vitro showed an IC50 value in the nM range. Therefore, important chemical modifications could be considered to improve multitarget benzazoles’ activity, such as substitutions in the aromatic ring with electron withdrawal at position five, or a linker 3 or 4 carbons in length, which would allow for better interaction with targets.

The Dual Role of Amyloid Beta-Peptide in Oxidative Stress and Inflammation: Unveiling Their Connections in Alzheimer's Disease Etiopathology.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and it is currently the seventh leading cause of death worldwide. It is characterized by the extracellular aggregation of the amyloid β-peptide (Aβ) into oligomers and fibrils that cause synaptotoxicity and neuronal death. Aβ exhibits a dual role in promoting oxidative stress and inflammation. This review aims to unravel the intricate connection between these processes and their contribution to AD progression. The review delves into oxidative stress in AD, focusing on the involvement of metals, mitochondrial dysfunction, and biomolecule oxidation. The distinct yet overlapping concept of nitro-oxidative stress is also discussed, detailing the roles of nitric oxide, mitochondrial perturbations, and their cumulative impact on Aβ production and neurotoxicity. Inflammation is examined through astroglia and microglia function, elucidating their response to Aβ and their contribution to oxidative stress within the AD brain. The blood-brain barrier and oligodendrocytes are also considered in the context of AD pathophysiology. We also review current diagnostic methodologies and emerging therapeutic strategies aimed at mitigating oxidative stress and inflammation, thereby offering potential treatments for halting or slowing AD progression. This comprehensive synthesis underscores the pivotal role of Aβ in bridging oxidative stress and inflammation, advancing our understanding of AD and informing future research and treatment paradigms.

Cheminformatics-driven prediction of BACE-1 inhibitors: Affinity and molecular mechanism exploration

The β-secretase, sometimes referred to as BACE1 or Asp2, is the enzyme responsible for initiating the production of Aβ by breaking down the amyloid precursor protein. Hence, BACE is a pivotal target for pharmacological intervention aimed at diminishing the production of Aβ in Alzheimer's disease (AD). We did a quantitative structure-activity relationship (QSAR) study on 1235 compounds that had been experimentally reported as BACE-1 inhibitors (Ki) to find the target molecule and structural patterns linked to blocking the BACE-1 receptor. The OECD-recommended genetic algorithm-multiple linear regression (GA-MLR) QSAR model strikes a good balance between being able to make accurate predictions and understanding how things work. It achieves high values for many evaluation metrics, including R2tr = 0.8047, Q2LMO = 0.802, R2ex = 0.805, CCCex = 0.891, Q2-F1=0.801, Q2-F2=0.799, and Q2-F3=0.815. The mechanistic interpretation of QSAR has identified some nitrogen atoms that are required to block beta-secretase and make it less effective at doing its job. A positively charged aromatic carbon atom has a more significant impact on beta-secretase-1 inhibition. The docking study showed that the catalytic dye residues Asp32 and Asp228 become protonated when compound 27 is present, but they stay unprotonated when compound 27 is not present. These rings of pyrazine and pyridine interact hydrophobically with Tyr71 and Ile118 residues, confirming the pharmacophoric features seen in the QSAR data. We examined the stability of both the protein-ligand complex and the apo-protein. The apoprotein had an average gyration radius of 22.13, whereas the protein-ligand complex had an average gyration radius of 22.91. No changes were made to the results from the molecular docking, molecular dynamics (MD) simulation, MMGBSA (Molecular Mechanics Generalized Born Surface Area), or DFT analyses. Therefore, the current work could effectively contribute to the future development of BACE inhibitors in medication design.

Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial Alzheimer's disease mutations.

The production of neurotoxic amyloid-β peptides (Aβ) is central to the initiation and progression of Alzheimer's disease (AD) and involves sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. APP and the secretases are transmembrane proteins and their co-localisation in the same membrane-bound sub-compartment is necessary for APP cleavage. The intracellular trafficking of APP and the β-secretase, BACE1, is critical in regulating APP processing and Aβ production and has been studied in several cellular systems. Here, we summarise the intracellular distribution and transport of APP and its secretases, and the intracellular location for APP cleavage in non-polarised cells and neuronal models. In addition, we review recent advances on the potential impact of familial AD mutations on APP trafficking and processing. This is critical information in understanding the molecular mechanisms of AD progression and in supporting the development of novel strategies for clinical treatment.

Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aβ production in COS cells transfected with wild-type or mutant PSEN1. The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aβ42 in PSEN1 G266S-transfected cells significantly increased. Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

PFOS sub-chronic exposure selectively activates Aβ clearance pathway to improve the cognitive ability of AD mice

Perfluorooctane sulfonate (PFOS), an emerging persistent organic pollutant, has been controversial in its impact on cognitive functions. Our previous research has confirmed that the sub-chronic PFOS exposure leads to neuronal apoptosis in the cerebral cortex, impairing cognitive functions in normal mice. However, our current study presents a surprising finding: sub-chronic exposure to PFOS effectively reduces cognitive impairments in Alzheimer's disease (AD) mice and significantly retards the disease's progression. Our results indicate that PFOS exposure upregulates the expression level of insulin-degrading enzyme (IDE) in the prefrontal cortex (PFC) of AD mice, thereby selectively enhancing the amyloid-beta (Aβ) clearance pathway without affecting the Aβ production. Moreover, PFOS exposure inhibits microglial proliferation and reduces inflammatory cytokines levels in the PFC of AD mice, providing further supporting for the pivotal role of IDE in attenuating AD progression under PFOS exposure. Collectively, our study is the first to demonstrate that sub-chronic PFOS exposure can alleviates cognitive impairments in AD pathology, with the IDE-mediated Aβ clearance pathway potentially playing a critical role.