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Alzheimer's disease (AD) accounts for approximately 60% of dementia cases worldwide. Advanced age is the most significant risk factor for AD and approximately two-thirds of cases relate to women. While the previous meta-analysis suggests that estrogen receptor (ESR) genetic polymorphisms are closely associated with dementia, the implications of this observation on a molecular level are not entirely understood. Our study explores this intricate molecular puzzle through the use of a variety of bioinformatics tools. Initially, we attempted to elucidate mechanisms underlying breast cancer development by identifying the high-throughput dataset of Show less

Saponins are triterpenoid or steroidal glycosides and are an important group of naturally occurring compounds of plant origin. They exhibit diverse pharmacological potentials including radical scavenging, as well as neuroprotective, anti-diabetic and anti-inflammatory activities, owing to their diverse chemical scaffolds. Saponins consist of an aglycone part (non-sugar) and a glycone part (sugar) and have at least one glycosidic (C-O sugar bond) linkage present between the glycone and aglycone mostly at C-3. On the basis of the aglycone part, saponins are classified into triterpenoid glycosides, steroid glycosides and alkaloid glycosides. Saponins exhibit neuroprotective activities against various disorders of the central nervous system (CNS) including stroke, Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD). They mediate their therapeutic effects by modulation of various pathological targets. This study highlights various neuroprotective mechanisms of saponins including free radical scavenging, modulation of neuroprotective signaling pathways, activation of neurotrophic factors, modulation of neurotransmitters, inhibition of BACE1 enzyme and tau hyper-phosphorylation. The study concludes that saponins have considerable efficacy against various pathological targets of neurological disorders, especially AD, and might be an important source of leads against neurodegenerative disorders. Show less

There is compelling evidence that head injury is a significant environmental risk factor for Alzheimer's disease (AD) and that a history of traumatic brain injury (TBI) accelerates the onset of AD. Amyloid-β plaques and tau aggregates have been observed in the post-mortem brains of TBI patients; however, the mechanisms leading to AD neuropathology in TBI are still unknown. In this study, we hypothesized that focal TBI induces changes in miRNA expression in and around affected areas, resulting in the altered expression of genes involved in neurodegeneration and AD pathology. For this purpose, we performed a miRNA array in extracts from rats subjected to experimental TBI, using the controlled cortical impact (CCI) model. In and around the contusion, we observed alterations of miRNAs associated with dementia/AD, compared to the contralateral side. Specifically, the expression of miR-9 was significantly upregulated, while miR-29b, miR-34a, miR-106b, miR-181a and miR-107 were downregulated. Via qPCR, we confirmed these results in an additional group of injured rats when compared to naïve animals. Interestingly, the changes in those miRNAs were concomitant with alterations in the gene expression of mRNAs involved in amyloid generation and tau pathology, such as β-APP cleaving enzyme (BACE1) and Glycogen synthase-3-β (GSK3β). In addition increased levels of neuroinflammatory markers (TNF-α), glial activation, neuronal loss, and tau phosphorylation were observed in pericontusional areas. Therefore, our results suggest that the secondary injury cascade in TBI affects miRNAs regulating the expression of genes involved in AD dementia. Show less

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with unmet medical need. This investigation consisted of testing a range of ethanolic ethnomedicinal plant extracts (n = 18) traditionally used in the treatment of disorders such as anxiety, delirium, and memory loss. They were then screened for in vitro inhibitory activity against acetylcholinesterase (AChE), butylcholinesterase (BuChE), beta-secretase 1/beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), and antioxidant activities. Plants with potent activities were further characterised using a recently developed in vivo model of AD, Globodera pallida. The ability of phytoextracts to protect this organism against amyloid-beta Aβ (1-42) exposure was assessed by measuring chemosensing, survival rate, production of reactive oxygen species (ROS), and antioxidant responses. Extracts (n = 5) from Juglans regia (leaves), Ellettaria cardamomum (seeds), Cinnamomum zeylanicum (bark), Salvia officinalis (leaves/flowers), and Hypericum perforatum (flowers) exerted concentration-dependent inhibitory activities against AChE and BuChE. Three of these plant extracts (i.e., J. regia, E. cardamomum, and S. officinalis) possessed strong concentration-dependent inhibitory activity against BACE1. Furthermore, the five selected medicinal plant extracts not only enhanced significantly (p < 0.05) the nematode’s chemosensing, survival rate, and antioxidant responses (i.e., anti-ROS production, mitochondrial reductase activity, oxidized glutathione (GSSG) to reduced glutathione (GSH) ratio), but also greatly restored (p < 0.05) in a concentration-dependent manner the Aβ (1-42)-induced deleterious changes in these same parameters. In brief, this investigation highlights plant extracts with strong anti-AD activities which could be trialled as novel therapeutic supplements or undergo further biodiscovery research. Show less

Increasing evidence indicates that β-secretase 1 (BACE1) activity and concentration in blood are candidate biomarkers for Alzheimer's disease (AD). Investigating potential demographic, biological, and clinical determinants of BACE1 in the blood matrix is the critical step to validate and qualify BACE1 bio-indicators for different contexts-of-use (CoU), such as risk assessment, early detection, diagnosis, prognosis, management of AD, and outcome of amyloid pathway targeted drugs. To evaluate the influence of age, sex, HDL-cholesterol and comorbidities (cardiovascular diseases, hypertension, diabetes) on circulating BACE-1 activity. prospective analysis of serum samples, clinical, biological, and demographic variables. Three cohorts: 1) Memory Clinic of the Department of Internal Medicine, S. Anna University Hospital, Ferrara (Italy); 2) outpatients attending the Menopause and Osteoporosis Centre (MOC) of the University of Ferrara (Ferrara, Italy); 3) Prevention Center of the University of Ferrara. 504 cognitively healthy individuals (median age: 62 years, interquartile range: 51-73) and 175 patients with AD (78 years, 74-82). serum BACE1 (sBACE1), age, sex, HDL-cholesterol, major comorbidities. Age was the strongest independent predictor of sBACE1 variance (β=0.425, p<0.0001), followed by sex (β=0.180, p<0.0001), high density lipoprotein-cholesterol (HDL-C) (β=-0.168, p<0.0001) and hypertension (β=0.111, p<0.05) (overall model, R2: 0.232). The probability of having elevated sBACE1 activity increased after 70 years of age, with women being more susceptible to higher sBACE1 activity than men. We provide evidence about potential clinical and biological determinants of sBACE1 activity with a strong association among biomarker, female sex, and older age. Show less

Alzheimer's disease (AD) is an irreversible, progressive neurological disorder characterized by amyloid plaques, hyperphosphorylated tau protein (hyper p-tau), neuronal damage, memory loss, etc. Various factors, such as age, lifestyle, family history, environmental factors, and gene mutation, cause AD. BACE-1 is an interesting target to prevent or reverse AD progression. BACE-1 cleaves amyloid precursor protein (APP) into soluble amyloid precursor protein β (sAPPβ) and membrane-bound C-terminal fragment called C99, a rate-limiting step, and C99 is further cleaved by gamma-secretase to generate neurotoxic amyloid β (Aβ). Discovery and development of selective β amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibitors have a great potential for the treatment and maintenance of Alzheimer's disease. In this review, we have compiled literature pertaining to guanidine-based novel BACE-1 inhibitors for the treatment and maintenance of AD. We have also discussed role of BACE-1 substrates, and its crystal structure, BACE-1 inhibitors in the clinical trial, and essential points to overcome challenges associated with selective development of BACE-1 inhibitors. This paper provides valuable information for the design and discovery of selective new BACE-1 inhibitors against other aspartyl protease enzymes to treat AD. Show less

Cerebrospinal fluid (CSF) β-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer's disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer's disease cases ( Show less

Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as β-secretase, is an aspartic protease. The sorting of this enzyme into Rab11-positive recycling endosomes regulates the BACE1-mediated cleavage of its substrates, however, the mechanisms underlying this targeting remain poorly understood. The neural cell adhesion molecule 2 (NCAM2) is a substrate of BACE1. We show that BACE1 cleaves NCAM2 in cultured hippocampal neurons and NCAM2-transfected CHO cells. The C-terminal fragment of NCAM2 that comprises the intracellular domain and a small portion of NCAM2's extracellular domain, associates with BACE1. This association is not affected in cells with inhibited endocytosis, indicating that the interaction of NCAM2 and BACE1 precedes the targeting of BACE1 from the cell surface to endosomes. In neurons and CHO cells, this fragment and BACE1 co-localize in Rab11-positive endosomes. Overexpression of full-length NCAM2 or a recombinant NCAM2 fragment containing the transmembrane and intracellular domains but lacking the extracellular domain leads to an increase in BACE1 levels in these organelles. In NCAM2-deficient neurons, the levels of BACE1 are increased at the cell surface and reduced in intracellular organelles. These effects are correlated with increased levels of the soluble extracellular domain of BACE1 in the brains of NCAM2-deficient mice, suggesting increased shedding of BACE1 from the cell surface. Of note, shedding of the extracellular domain of Sez6, a protein cleaved exclusively by BACE1, is reduced in NCAM2-deficient animals. These results indicate that the BACE1-generated fragment of NCAM2 regulates BACE1 activity by promoting the targeting of BACE1 to Rab11-positive endosomes. Show less

Insufficiencies of the micronutrient thiamine (Vitamin B1) have been associated with inducing Alzheimer's disease (AD)-like neuropathology. The hypometabolic state associated with chronic thiamine insufficiency (TI) has been demonstrated to be a contributor towards the development of amyloid plaque deposition and neurotoxicity. However, the molecular mechanism underlying TI induced AD pathology is still unresolved. Previously, we have established that TI stabilizes the metabolic stress transcriptional factor, Hypoxia Inducible Factor-1α (HIF1α). Utilizing neuronal hippocampal cells (HT22), TI-induced HIF1α activation triggered the amyloidogenic cascade through transcriptional expression and increased activity of β-secretase (BACE1). Knockdown and pharmacological inhibition of HIF1α during TI significantly reduced BACE1 and C-terminal Fragment of 99 amino acids (C99) formation. TI also increased the expression of the HIF1α regulated pro-apoptotic protein, BCL2/adenovirus E1B 19 kDa protein-interacting protein (BNIP3). Correspondingly, cell toxicity during TI conditions was significantly reduced with HIF1α and BNIP3 knockdown. The role of BNIP3 in TI-mediated toxicity was further highlighted by localization of dimeric BNIP3 into the mitochondria and nuclear accumulation of Endonuclease G. Subsequently, TI decreased mitochondrial membrane potential and enhanced chromatin fragmentation. However, cell toxicity via the HIF1α/BNIP3 cascade required TI induced oxidative stress. HIF1α, BACE1 and BNIP3 expression was induced in 3xTg-AD mice after TI and administration with the HIF1α inhibitor YC1 significantly attenuated HIF1α and target genes levels in vivo. Overall, these findings demonstrate a critical stress response during TI involving the induction of HIF1α transcriptional activity that directly promotes neurotoxicity and AD-like pathology. Show less

The physiological or dietary advantages of germinated grains have been the subject of numerous discussions over the past decade. Around 23 million tons of oats are consumed globally, making up a sizeable portion of the global grain market. Oat seedlings contain more protein, beta-glucan, free amino acids, and phenolic compounds than seeds. The progressive neurodegenerative disorder of Alzheimer's is accompanied by worsening memory and cognitive function. A key indicator of this disorder is the unusual buildup of amyloid-beta protein (or Aβ) in human brains. In this context, oat seedling extract (OSE) has been identified as a new therapeutic candidate for AD, due to its antioxidant activity and AD-specific mechanism of action. This study directly investigated how OSE affected AD and its impacts by examining the cognitive function and exploring the inflammatory response mechanism. The dried oat seedlings were grounded finely with a grinder, inserted with 50% fermented ethanol 10 times ( Show less

Neurologic deficits associated with human immunodeficiency virus (HIV) infection impact about 50% of persons with HIV (PWH). These disorders, termed HIV-associated neurocognitive disorders (HAND), possess neuropathologic similarities to Alzheimer's disease (AD), including intra- and extracellular amyloid-beta (Aβ) peptide aggregates. Aβ peptide is produced through cleavage of the amyloid precursor protein (APP) by the beta secretase BACE1. However, this is precluded by cleavage of APP by the non-amyloidogenic alpha secretase, ADAM10. Previous studies have found that BACE1 expression was increased in the CNS of PWH with HAND as well as animal models of HAND. Further, BACE1 contributed to neurotoxicity. Yet in in vitro models, the role of ADAM10 and its potential regulatory mechanisms had not been examined. To address this, primary rat cortical neurons were treated with supernatants from HIV-infected human macrophages (HIV/MDMs). We found that HIV/MDMs decreased levels of both ADAM10 and Sirtuin1 (SIRT1), a regulator of ADAM10 that is implicated in aging and in AD. Both decreases were blocked with NMDA receptor antagonists, and treatment with NMDA was sufficient to induce reduction in ADAM10 and SIRT1 protein levels. Furthermore, decreases in SIRT1 protein levels were observed at an earlier time point than the decreases in ADAM10 protein levels, and the reduction in SIRT1 was reversed by proteasome inhibitor MG132. This study indicates that HIV-associated insults, particularly excitotoxicity, contribute to changes of APP secretases by downregulating levels of ADAM10 and its regulator. Show less

Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been applied to ameliorate cognitive impairment in mild-to-moderate AD patients. However, the overall molecular mechanism of SQYG in treating AD has not been clarified. This study aimed to investigate the molecular mechanism of SQYG on AD using an integration strategy of network pharmacology and molecular docking. The active compounds of SQYG and common targets between SQYG and AD were screened from databases. The herb-compound network, compound-target network, and protein-protein interaction network were constructed. The enrichment analysis of common targets and molecular docking were performed. 816 compounds and 307 common targets between SQYG and AD were screened. KEGG analysis revealed that common targets were mainly enriched in lipid metabolism, metal ion metabolism, IL-17 signaling pathway, GABA receptor signaling, and neuroactive ligand-receptor interaction. Molecular docking analysis showed high binding affinity between ginsenoside Rg1 and A The therapeutic mechanisms of SQYG on AD were associated with regulating lipid metabolism, metal ion metabolism, IL-17 signaling pathway, and GABA receptor signaling. Ginsenoside Rg1, tanshinone IIA, baicalin, astragaloside IV, and folic acid may play an important role in AD treatment. Show less

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular compound 2JY-OBZ4 is one of structural analogue of Huperzine A (Hup-A), an anti-AD drug in China. In our previous work, 2JY-OBZ4 exhibited potent effects on tau hyperphosphorylation, Aβ production and acetylcholinesterase (AChE) activity. However, 2JY-OBZ4's anti-AD effects and the underlying molecular mechanisms remain unclear. We here reported that 2JY-OBZ4 resisted tau hyperphosphorylation at Thr181 and Ser396 sites in HEK293-hTau cells transfected with GSK-3β, decreased tau phosphorylation via upregulating the activity of PP2A in HEK293-hTau cells and reduced Aβ production through regulating protein levels of APP cleavage enzymes in N2a-hAPP cells. Meanwhile, we found that 2JY-OBZ4 had no adverse effects on cell viability of mice primary neuron even at high concentration, and ameliorated synaptic loss induced by human oligomeric Aβ42. 2JY-OBZ4 had moderate AChE inhibitory activity with the half maximal inhibitory concentration (IC50) to be 39.48 μg/ml Show less

Moderate physical exercise is conducive to the brains of healthy humans and AD patients. Previous reports have suggested that treadmill exercise plays an anti-AD role and improves cognitive ability by promoting amyloid clearance, inhibiting neuronal apoptosis, reducing oxidative stress level, alleviating brain inflammation, and promoting autophagy-lysosome pathway in AD mice. However, few studies have explored the relationships between the ubiquitin-proteasome system and proper exercise in AD. The current study was intended to investigate the mechanism by which the exercise-regulated E3 ubiquitin ligase improves AD. Both wild type and APP/PS1 transgenic mice were divided into sedentary (WTC and ADC) and exercise (WTE and ADE) groups (n = 12 for each group). WTE and ADE mice were subjected to treadmill exercise of 12 weeks in order to assess the effect of treadmill running on learning and memory ability, Aβ plaque burden, hyperphosphorylated Tau protein and E3 ubiquitin ligase. The results indicated that exercise restored learning and memory ability, reduced Aβ plaque areas, inhibited the hyperphosphorylation of Tau protein activated PI3K/Akt/Hsp70 signaling pathway, and improved the function of the ubiquitin-proteasome system (increased UCHL-1 and CHIP levels, decreased BACE1 levels) in APP/PS1 transgenic mice. These findings suggest that exercise may promote the E3 ubiquitin ligase to clear β-amyloid and hyperphosphorylated Tau by activating the PI3K/Akt signaling pathway in the hippocampus of AD mice, which is efficient in ameliorating pathological phenotypes and improving learning and memory ability. Show less

Growing pieces of evidence suggest that Alzheimer's disease (AD) is interlinked with Type 2 diabetes mellitus (DM), which has been described as "type 3 DM". In this study, we investigate the neuronal insult attributable to advanced glycation end products (AGEs) as the models of DM-related AD to understand the effects exerted by calycosin on neurodegenerative changes both in vivo and in vitro studies and also studied the associated molecular mechanisms. The results reported herein revealed that the viability of the PC12 cells induced by AGEs increased when treated with calycosin. It was also observed that the learning and memory abilities of AGE-induced DM-related AD rats improved under these conditions. Analysis of the reported results indicates that calycosin can effectively down-regulate the activity of GSK-3β to result in the reversal of the process of tau hyperphosphorylation, inhibit the expression of RAGE and BACE-1 proteins, resulting in a decrease in the production of β-amyloid and regulate the PGC-1α/TFAM signaling pathway to repair mitochondrial dysfunction. It can be inferred that calycosin can potentially exhibit important therapeutic properties that can be exploited during the treatment of AD, especially DM-related AD. Show less

The blood brain barrier (BBB) limits the therapeutic perspective for central nervous system (CNS) disorders. Previously we found an anti-mouse transferrin receptor (TfR) VHH (Nb62) that was able to deliver a biologically active neuropeptide into the CNS in mice. Here, we aimed to test its potential to shuttle a therapeutic relevant cargo. Since this VHH could not recognize the human TfR and hence its translational potential is limited, we also aimed to find and validate an anti-human transferrin VHH to deliver a therapeutic cargo into the CNS. Alpaca immunizations with human TfR, and subsequent phage selection and screening for human TfR binding VHHs was performed to find a human TfR specific VHH (Nb188). Its ability to cross the BBB was determined by fusing it to neurotensin, a neuropeptide that reduces body temperature when present in the CNS but is not able to cross the BBB on its own. Next, the anti-β-secretase 1 (BACE1) 1A11 Fab and Nb62 or Nb188 were fused to an Fc domain to generate heterodimeric antibodies (1A11AM-Nb62 and 1A11AM-Nb188). These were then administered intravenously in wild-type mice and in mice in which the murine apical domain of the TfR was replaced by the human apical domain (hAPI KI). Pharmacokinetic and pharmacodynamic (PK/PD) studies were performed to assess the concentration of the heterodimeric antibodies in the brain over time and the ability to inhibit brain-specific BACE1 by analysing the brain levels of Aβ Selections and screening of a phage library resulted in the discovery of an anti-human TfR VHH (Nb188). Fusion of Nb188 to neurotensin induced hypothermia after intravenous injections in hAPI KI mice. In addition, systemic administration 1A11AM-Nb62 and 1A11AM-Nb188 fusions were able to reduce Aβ We have discovered an anti-human TfR specific VHH that is able to reach the CNS when administered systemically. In addition, both the currently discovered anti-human TfR VHH and the previously identified mouse-specific anti-TfR VHH, are both able to shuttle a therapeutically relevant cargo into the CNS. We suggest the mouse-specific VHH as a valuable research tool in mice and the human-specific VHH as a moiety to enhance the delivery efficiency of therapeutics into the CNS in human patients. Show less

As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer's disease (AD) for decades in China. However, Hup-A causes some side effects. To search for new analogs or derivatives of Hup-A, we produced five Lycopodium alkaloids and two analogues by chemical synthesis: Lyconadins A-E, H-R-NOB, and 2JY-OBZ4. To systematically evaluate the therapeutic effects of the seven compounds on AD cell models. We assessed the effects of the seven compounds on cell viability via CCK-8 kit and used HEK293-hTau cells and N2a-hAPP cells as AD cell models to evaluate their potential therapeutic effects. We examined their effects on cholinesterase activity by employing the mice primary neuron. All compounds did not affect cell viability; in addition, Lyconadin A and 2JY-OBZ4 particularly increased cell viability. Lyconadin D and Lyconadin E restored tau phosphorylation at Thr231, and H-R-NOB and 2JY-OBZ4 restored tau phosphorylation at Thr231 and Ser396 in GSK-3β-transfected HEK293-hTau cells. 2JY-OBZ4 decreased the level of PP2Ac-pY307 and increased the level of PP2Ac-mL309, supporting that 2JY-OBZ4 may activate PP2A. Lyconadin B, Lyconadin D, Lyconadin E, H-R-NOB, and 2JY-OBZ4 increased sAβPPα level in N2a-hAPP cells. 2JY-OBZ4 decreased the levels of BACE1 and sAβPPβ, thereby reduced Aβ production. Seven compounds exhibited weaker AChE activity inhibition efficiency than Hup-A. Among them, 2JY-OBZ4 showed the strongest AChE inhibition activity with an inhibition rate of 17% at 10μM. Among the seven Lycopodium compounds, 2JY-OBZ4 showed the most expected effects on promoting cell viability, downregulating tau hyperphosphorylation, and Aβ production and inhibiting AChE in AD. Show less

Natural products have significantly contributed to drug discovery for neurodegenerative diseases. Caffeine is one of the well-known central nervous system(CNS)-active natural products. Besides its CNS stimulant properties, it is a mild inhibitor of acetylcholinesterase (AChE) and possesses memory-enhancing properties. The present work aimed to improve the AChE inhibition activity of the caffeine. The rationally designed caffeine-based triazoles were synthesized and evaluated in vitro for cholinesterase and β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitory activities. The attachment of triazole to the caffeine enhances its AChE inhibition activity from half-maximal inhibitory concentration (IC Show less

Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive loss of cognitive functions like thinking, memory, reasoning, behavioral abilities, and social skills thus affecting the ability of a person to perform normal daily functions independently. There is no definitive cure for this disease, and treatment options available for the management of the disease are not very effective as well. Based on histopathology, AD is characterized by the accumulation of insoluble deposits of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although several molecular events contribute to the formation of these insoluble deposits, the aberrant post-translational modifications (PTMs) of AD-related proteins (like APP, Aβ, tau, and BACE1) are also known to be involved in the onset and progression of this disease. However, early diagnosis of the disease as well as the development of effective therapeutic approaches is impeded by lack of proper clinical biomarkers. In this review, we summarized the current status and clinical relevance of biomarkers from cerebrospinal fluid (CSF), blood and extracellular vesicles involved in onset and progression of AD. Moreover, we highlight the effects of several PTMs on the AD-related proteins, and provide an insight how these modifications impact the structure and function of proteins leading to AD pathology. Finally, for disease-modifying therapeutics, novel approaches, and targets are discussed for the successful treatment and management of AD. Show less

The amyloid cascade is the most frequently accepted hypothesis of Alzheimer's Disease (AD). According to this hypothesis, the formation of plaques precedes the appearance of fibrillary tangles. Therapeutic agents able to inhibit the formation of plaques are therefore considered as potential disease-modifying treatments (DMT) that could prevent or limit the progression of AD. Plaques are deposits formed by aggregates of amyloid-β (Aβ)-peptides. These peptides are metabolites of amyloid precursor protein (APP) first mediated by two enzymes: β-secretase 1 (BACE1) and γ-secretase. Molecular identification of these two enzymes has stimulated the development of their inhibitors. The clinical testing of these two classes of molecules has not been successful to date. The oligomerization of Aβ-peptides into plaques is now targeted by immunological approaches such as antibodies and vaccines. Structural consideration of the Aβ-peptide sequence led to the launch of the antibody Aducanumab. Several other antibodies are in late clinical phases. Progress in the understanding of the effects of N-truncated Aβ-peptides such as pE3-42, formed by the action of recently well characterized enzymes (aminopeptidase A, dipeptidylpeptidase-4 and glutaminyl cyclase) suggests that oligomerization can be limited either by enzyme inhibitors or antibody approaches. This strategy associating two structurally interconnected mechanisms is focused in this review. Show less

Stroke is ranked as the fifth leading cause of death and the leading cause of adult disability in the USA. The progression of neuronal damage after stroke is recognized to be a complex integration of glia, neurons, and the surrounding extracellular matrix, therefore potential treatments must target the detrimental effects created by these interactions. In this study, we examined the spatial cellular and neuroinflammatory mechanisms occurring early after ischemic stroke utilizing Nanostring Digital Spatial Profiling (DSP) technology. Male C57bl/6 mice were subjected to photothrombotic middle cerebral artery occlusion (MCAO) and sacrificed at 3 days post-ischemia. Spatial distinction of the ipsilateral hemisphere was studied according to the regions of interest: the ischemic core, peri-infarct tissues, and peri-infarct normal tissue (PiNT) in comparison to the contralateral hemisphere. We demonstrated that the ipsilateral hemisphere initiates distinct spatial regulatory proteomic profiles with DSP technology that can be identified consistently with the immunohistochemical markers, FJB, GFAP, and Iba-1. The core border profile demonstrated an induction of neuronal death, apoptosis, autophagy, immunoreactivity, and early degenerative proteins. Most notably, the core border resulted in a decrease of the neuronal proteins Map2 and NeuN; an increase in the autophagy proteins BAG3 and CTSD; an increase in the microglial and peripheral immune invasion proteins Iba1, CD45, CD11b, and CD39; and an increase in the neurodegenerative proteins BACE1, APP, amyloid β 1-42, ApoE, and hyperphosphorylated tau protein S-199. The peri-infarct region demonstrated increased astrocytic, immunoreactivity, apoptotic, and neurodegenerative proteomic profiles, with an increase in BAG3, GFAP, and hyperphosphorylated tau protein S-199. The PiNT region displayed minimal changes compared to the contralateral cortex with only an increase in GFAP. In this study, we showed that mechanisms known to be associated with stroke, such as apoptosis and inflammation, occur in distinct spatial domains of the injured brain following ischemia. We also demonstrated the dysregulation of specific autophagic pathways that may lead to neurodegeneration in peri-infarct brain tissues. Taken together, these data suggest that identifying post-ischemic mechanisms occurring in a spatiotemporal manner may lead to more precise targets for successful therapeutic interventions to treat stroke. Show less

Alzheimer's disease is a neurodegenerative disease caused by excessive amyloid β protein-induced neurotoxicity. However, drugs targeting amyloid β protein production face many problems, such as the low utilization rate of drugs by cells and the difficulty of drugs in penetrating the blood-brain barrier. A tetrahedral framework nucleic acid is a new type of nanonucleic acid structure that functions as a therapy and drug carrier. Here, we synthesized a BACE1 aptamer-modified tetrahedral framework nucleic acid and tested its therapeutic effect on Alzheimer's disease Show less

Alzheimer's disease (AD), as a progressive and irreversible brain disorder, remains the most universal neurodegenerative disease. No effective therapeutic methods are established yet due to the hindrance of the blood-brain barrier (BBB) and the complex pathological condition of AD.  Therefore, a multifunctional nanocarrier (Rapa@DAK/siRNA) for AD treatment is constructed to achieve small interfering RNA of β-site precursor protein (APP) cleaving enzyme-1 (BACE1 siRNA) and rapamycin co-delivery into the brain, based on Aleuria aurantia lectin (AAL) and β-amyploid (Aβ)-binding peptides (KLVFF) modified PEGylated dendrigraft poly-l-lysines (DGLs) via intranasal administration. Nasal administration provides an effective way to deliver drugs directly into the brain through the nose-to-brain pathway. AAL, specifically binding to L-fucose located in the olfactory epithelium, endows Rapa@DAK/siRNA with high brain entry efficiency through intranasal administration. KLVFF peptide as an Aβ targeting ligand and aggregation inhibitor enables nanoparticles to bind with Aβ, inhibit Aβ aggregation, and reduce toxicity. Meanwhile, the release of BACE1 siRNA and rapamycin is confirmed to reduce BACE1 expression, promote autophagy, and reduce Aβ deposition. Rapa@DAK/siRNA is verified to improve the cognition of transgenic AD mice after intranasal administration. Collectively, the multifunctional nanocarrier provides an effective and potential intranasal avenue for combination therapy of AD. Show less

The pathogenesis of Alzheimer's disease (AD) is very complex, and there are many hypotheses. Therefore, the development of a multi-target-directed-ligand may be an effective therapeutic strategy. Our previous study showed that notopterol (a natural product from Show less

Alzheimer's disease (AD) is a progressive neurological illness with few effective treatments. Thus, ameliorating the effects of AD using natural products has attracted global attention with promising efficacy and safety. In this study, ten tropical fruits including Show less

Cholesterol metabolism seems dysregulated and linked to amyloid-β (Aβ) formation in neurodegeneration, but the underlying mechanisms are poorly known. Resveratrol (RSV) is a polyphenol with antioxidant activity and neuroprotective properties. Here, we analyzed the effect of age and RSV supplementation on cholesterol metabolism in the brain and blood serum, and its potential link to Aβ processing, in SAMP8 mice-an animal model of aging and Alzheimer's disease. In the brain, our results revealed an age-related increase in ApoE and unesterified cholesterol in the plasma membrane whereas LDL receptor, HMG-CoA reductase, HMG-CoA-C1 synthase, and ABCA1 transporter remained unaltered. Furthermore, BACE-1 and APP gene expression was decreased. This dysregulation could be involved in the amyloidogenic processing pathway of APP towards Aβ formation. In turn, RSV exhibited an age-dependent effect. While levels of unesterified cholesterol in the plasma membrane were not affected by RSV, several participants in cholesterol uptake, release, and de novo synthesis differed, depending on age. Thus, RSV supplementation exhibited a different neuroprotective effect acting on Aβ processing or cholesterol metabolism in the brain at earlier or later ages, respectively. In blood serum, HDL lipoprotein and free cholesterol were increased by age, whereas VLDL and LDL lipoproteins remained unaltered. Again, the protective effect of RSV by decreasing the LDL or increasing the HDL levels also seems to depend on the intervention's moment. In conclusion, age is a prominent factor for cholesterol metabolism dysregulation in the brain of SAMP8 mice and influences the protective effects of RSV through cholesterol metabolism and Aβ processing. Show less

Pomegranate (Punica granatum L.) extract has been reported to inhibit cholinesterase and the β-site amyloid precursor protein cleaving enzyme 1 (BACE1); however, most of its constituents' potential inhibition of these enzymes remains unknown. Thus, we investigated the anti-Alzheimer's disease (anti-AD) potential of 16 ellagitannin and gallotannin, and nine anthocyanin derivatives' inhibition of BACE1, AChE, and BChE, and gallagic acid inhibited both the best. Further, a kinetic study identified different modes of inhibition, and a molecular docking simulation revealed that active compounds inhibited these three enzymes with low binding energy through hydrophilic and hydrophobic interactions in the active site cavities. Gallagic acid and castalagin decreased Aβ peptides secretion from neuroblastoma cells that overexpressed human β-amyloid precursor protein significantly by 10 μM. Further, treatment with gallagic acid and castalagin reduced BACE1 and APPsβ expression levels significantly without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Co-incubation of Aβ42 with gallagic acid reduced Aβ42-induced intracellular reactive oxygen species (ROS) production significantly. Our results suggest that pomegranate constituents, specifically gallagic acid, may be useful in developing therapeutic treatment modalities for AD. Show less

Biochanin-A (5,7 dihydroxy 4 methoxy isoflavone) is a phytochemical phytoestrogen that is highly effective against various diseases. Biochanin-A is a nutritional and dietary isoflavonoid naturally present in red clover, chickpea, soybeans and other herbs. Biochanin- A possesses numerous biological activities. The study focused on collective data of therapeutic activities of Biochanin-A. According to the literature, biochanin-A revealed a range of activities starting from chemoprevention, by hindering cell growth, activation of tumor cell death, hampering metastasis, angiogenic action, cell cycle regulation, neuroprotection, by controlling microglial activation, balancing antioxidants, elevating the neurochemicals, suppressing BACE-1, NADPH oxidase hindrance to inflammation, by mitigating the MAPK and NF- κB, discharge of inflammatory markers, upregulating the PPAR-γ, improving the function of heme oxygenase-1, erythroid 2 nuclear factors, detoxifying the oxygen radicals and stimulating the superoxide dismutase action, and controlling its production of transcription factors. Against pathogens, biochanin-A acts by dephosphorylating tyrosine kinase proteins, obstructing gram-negative bacteria, suppressing the development of cytokines from viruses, and improving the action of a neuraminidase cleavage of caspase-3, and acts as an efflux pump inhibitor. In metabolic disorders, biochanin-A acts by encouraging transcriptional initiation and inhibition, activating estrogen receptors, and increasing the activity of differentiation, autophagy, inflammation, and blood glucose metabolism. Therefore, biochanin-A could be used as a therapeutic drug for various pathological conditions and treatments in human beings. Show less