Search Results (98)

Background/Objectives: Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM). Methods: T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain. Computational studies supported the in vivo findings. Results: SITG significantly reduced the brain enzyme levels of acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, and glycogen synthase kinase-3β (GSK-3β) in T2DM-induced rats. It also reduced inflammation by lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). Additionally, SITG improved oxidative stress markers by reducing malondialdehyde (MDA) and enhancing glutathione (GSH). It increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while reducing pro-apoptotic markers such as Bcl-2-associated X (BAX) and Caspace-3. SITG also lowered blood glucose levels and improved plasma insulin levels. To explore potential molecular level mechanisms, docking was performed on AChE, COX-2, GSK-3β, BACE-1, and Caspace-3. The potential binding affinity of SITG for the above-mentioned target enzymes were 10.8, 8.0, 9.7, 7.7, and 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further binding mode analysis of the lowest energy conformation revealed interactions with the critical residues. Conclusions: These findings highlight SITG’s neuroprotective molecular targets in T2DM-associated neurodegeneration and its potential as a therapeutic approach for AD, warranting further clinical investigations. Full article

The major pathological characteristics of Alzheimer’s disease (AD) include senile plaques and neurofibrillary tangles (NFTs), which are mainly composed of aggregated amyloid-beta (Aβ) peptide and hyperphosphorylated tau protein, respectively. The excessive production of reactive oxygen species (ROS) and neuroinflammation are crucial contributing factors to the pathological mechanisms of AD. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor critical for tissue adaption to low-oxygen tension. Growing evidence has suggested HIF-1 as a potential therapeutic target for AD; conversely, other experimental findings indicate that HIF-1 induction contributes to AD pathogenesis. These previous findings thus point to the complex, even contradictory, roles of HIF-1 in AD. In this review, we first introduce the general pathogenic mechanisms of AD as well as the potential pathophysiological roles of HIF-1 in cancer, immunity, and oxidative stress. Based on current experimental evidence in the literature, we then discuss the possible beneficial as well as detrimental mechanisms of HIF-1 in AD; these sections also include the summaries of multiple chemical reagents and proteins that have been shown to exert beneficial effects in AD via either the induction or inhibition of HIF-1. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative disorder influenced by various genetic factors. In addition to the well-established amyloid precursor protein (APP), Presenilin-1 (PSEN1), Presenilin-2 (PSEN2), and apolipoprotein E (APOE), several other genes such as Sortilin-related receptor 1 (SORL1), Phospholipid-transporting ATPase ABCA7 (ABCA7), Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), Phosphatidylinositol-binding clathrin assembly protein (PICALM), and clusterin (CLU) were implicated. These genes contribute to neurodegeneration through both gain-of-function and loss-of-function mechanisms. While it was traditionally thought that heterozygosity in autosomal recessive mutations does not lead to disease, haploinsufficiency was linked to several conditions, including cancer, autism, and intellectual disabilities, indicating that a single functional gene copy may be insufficient for normal cellular functions. In AD, the haploinsufficiency of genes such as ABCA7 and SORL1 may play significant yet under-explored roles. Paradoxically, heterozygous knockouts of PSEN1 or PSEN2 can impair synaptic plasticity and alter the expression of genes involved in oxidative phosphorylation and cell adhesion. Animal studies examining haploinsufficient AD risk genes, such as vacuolar protein sorting-associated protein 35 (VPS35), sirtuin-3 (SIRT3), and PICALM, have shown that their knockout can exacerbate neurodegenerative processes by promoting amyloid production, accumulation, and inflammation. Conversely, haploinsufficiency in APOE, beta-secretase 1 (BACE1), and transmembrane protein 59 (TMEM59) was reported to confer neuroprotection by potentially slowing amyloid deposition and reducing microglial activation. Given its implications for other neurodegenerative diseases, the role of haploinsufficiency in AD requires further exploration. Modeling the mechanisms of gene knockout and monitoring their expression patterns is a promising approach to uncover AD-related pathways. However, challenges such as identifying susceptible genes, gene–environment interactions, phenotypic variability, and biomarker analysis must be addressed. Enhancing model systems through humanized animal or cell models, utilizing advanced research technologies, and integrating multi-omics data will be crucial for understanding disease pathways and developing new therapeutic strategies. Full article

Background: The goal of the current study was to investigate the inhibitory activity of six phenolic compounds, i.e., rosmarinic acid, gallic acid, oleuropein, epigallocatechin gallate (EGCG), 3-hydroxytyrosol, and quercetin, against β-site amyloid precursor protein cleaving enzyme-1 (BACE1), also known as β-secretase or memapsin 2, which is implicated in the pathogenesis of Alzheimer’s disease (AD). Methods and Results: The inhibitory potential against BACE1, molecular docking simulations, as well as neurotoxicity and the effect on the AD-related gene expression of the selected phenolics were tested. BACE1 inhibitory activity was carried out using the ELISA microplate assay via fluorescence resonance energy transfer (FRET) technology. Molecular docking experiments were performed in the human BACE1 active site (PDB code: 2WJO). Neurotoxicity of the compounds was carried out in SH-SY5Y, a human neuroblastoma cell line, by the Alamar Blue method. A gene expression analysis of the compounds on fourteen genes linked to AD was conducted using the real-time polymerase chain reaction (RT-PCR) method. Rosmarinic acid, EGCG, oleuropein, and quercetin (also used as the reference) were able to inhibit BACE1 with their respective IC₅₀ values 4.06 ± 0.68, 1.62 ± 0.12, 9.87 ± 1.01, and 3.16 ± 0.30 mM. The inhibitory compounds were observed to occupy the non-catalytic site of the BACE1. However, hydrogen bonds were found to be present between rosmarinic acid and EGCG and aspartic amino acid D228 in the catalytic site. Oleuropein and quercetin effectively suppressed the expression of PSEN, APOE, and CLU, which are recognized to be linked to the pathogenesis of AD. Conclusions: The outcomes of the work bring quercetin, EGCG, and rosmarinic acid to the forefront as promising BACE1 inhibitors. Full article

Petunidin-3-O-(trans-p-coumaroylrutinoside)-5-O-glucoside (PtCG), the primary anthocyanin ingredient in Lycium ruthenicum Murr., possesses a range of biological activities, including antioxidative properties and melanin inhibition. This study aimed to investigate the protective effect of PtCG on D-galactose (D-gal)-induced aging in female mice and elucidate the underlying molecular pathways. Behavioral experiments, including the MWW and Y-maze tests, revealed that PtCG significantly ameliorated cognitive decline and enhanced learning and memory abilities in aging mice. Regarding biochemical indicators, PtCG considerably improved superoxide dismutase (SOD) and glutathione (GSH) activity while reducing malondialdehyde (MDA) and acetylcholinesterase (AChE) levels in the hippocampus and serum. Furthermore, PtCG ingestion alleviated liver injury by decreasing alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (AKP) levels, and attenuated renal damage by reducing blood urea nitrogen (BUN) and uric acid (UA) levels. Transmission electron microscopy (TEM) results demonstrated that PtCG restored the function and quantity of synapses in the hippocampus. Hematoxylin and eosin (H&E), Masson’s trichrome, and Nissl staining revealed that PtCG significantly improved the relevant pathological characteristics of liver and hippocampal tissues in aging mice. The molecular mechanism investigation showed that PtCG downregulated the protein expression of microglial marker ionized calcium-binding adapter molecule 1 (Iba1), astrocytic marker glial fibrillary acidic protein (GFAP), β-secretase 1 (BACE-1), and amyloid-beta_1–42 (Aβ_1–42) in the hippocampus of aging mice. The protein expression of inflammatory pathway components, including nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), and interleukin-1 beta (IL-1β), was also suppressed. These findings suggest that PtCG may possess anti-aging properties, with its mechanism of action potentially linked to the attenuation of neuroinflammation, oxidative stress, and liver and kidney damage. PtCG may have future applications as a functional food for the treatment of aging-related disorders. Full article

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. Full article

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. Full article

In this manuscript, a novel presenilin-2 (PSEN2) mutation, Val226Ala, was found in a 59-year-old Korean patient who exhibited rapid progressive memory dysfunction and hallucinations six months prior to her first visit to the hospital. Her Magnetic Resonance Imaging (MRI) showed brain atrophy, and both amyloid positron emission tomography (PET) and multimer detection system-oligomeric amyloid-beta (Aβ) results were positive. The patient was diagnosed with early onset Alzheimer’s disease. The whole-exome analysis revealed a new PSEN2 Val226Ala mutation with heterozygosity in the 5th transmembrane domain of the PSEN2 protein near the lumen region. Analyses of the structural prediction suggested structural changes in the helix, specifically a loss of a hydrogen bond between Val226 and Gln229, which may lead to elevated helix motion. Multiple PSEN2 mutations were reported in PSEN2 transmembrane-5 (TM5), such as Tyr231Cys, Ile235Phe, Ala237Val, Leu238Phe, Leu238Pro, and Met239Thr, highlighting the dynamic importance of the 5th transmembrane domain of PSEN2. Mutations in TM5 may alter the access tunnel of the Aβ substrate in the membrane to the gamma-secretase active site, indicating a possible influence on enzyme function that increases Aβ production. Interestingly, the current patient with the Val226Ala mutation presented with a combination of hallucinations and memory dysfunction. Although the causal mechanisms of hallucinations in AD remain unclear, it is possible that PSEN2 interacts with other disease risk factors, including Notch Receptor 3 (NOTCH3) or Glucosylceramidase Beta-1 (GBA) variants, enhancing the occurrence of hallucinations. In conclusion, the direct or indirect role of PSEN2 Val226Ala in AD onset cannot be ruled out. Full article

This study aimed to provide scientific data on the anti-Alzheimer’s disease (AD) effects of phenolic compounds from Drynariae Rhizoma (DR) extract using a multi-component approach. Screening of DR extracts, fractions, and the ten phenolic compounds isolated from DR against the key AD-related enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and monoamine oxidase-B (MAO-B) confirmed their significant inhibitory activities. The DR extract was confirmed to have BACE1-inhibitory activity, and the ethyl acetate and butanol fractions were found to inhibit all AD-related enzymes, including BACE1, AChE, BChE, and MAO-B. Among the isolated phenolic compounds, compounds (2) caffeic acid 4-O-β-D-glucopyranoside, (6) kaempferol 3-O-rhamnoside 7-O-glucoside, (7) kaempferol 3-o-b-d-glucopyranoside-7-o-a-L-arabinofuranoside, (8) neoeriocitrin, (9) naringin, and (10) hesperidin significantly suppressed AD-related enzymes. Notably, compounds 2 and 8 reduced soluble Amyloid Precursor Protein β (sAPPβ) and β-secretase expression by over 45% at a concentration of 1.0 μM. In the thioflavin T assay, compounds 6 and 7 decreased Aβ aggregation by approximately 40% and 80%, respectively, and degraded preformed Aβ aggregates. This study provides robust evidence regarding the potential of DR as a natural therapeutic agent for AD, highlighting specific compounds that may contribute to its efficacy. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative condition characterized by memory and cognitive decline in older individuals. Beta-amyloid (Aβ), a significant component of senile plaques, is recognized as a primary contributor to AD pathology. Hence, substances that can inhibit Aβ production and/or accumulation are crucial for AD prevention and treatment. Agrimonia pilosa LEDEB. (A. pilosa) (Rosaceae), specifically its aerial parts, was identified in our previous screening study as a promising candidate with inhibitory effects on Aβ production. Therefore, in this study, A. pilosa extract was investigated for its anti-amyloidogenic effects, and its bioactive principles were isolated and identified. The ethanol extract of A. pilosa reduced the levels of sAPPβ and β-secretase by approximately 3% and 40%, respectively, compared to the DMSO-treated control group in APP-CHO cells (a cell line expressing amyloid precursor protein), which were similar to those in the positive control group. In addition, the ethanol extract of A. pilosa also hindered Aβ’s aggregation into fibrils and facilitated the disaggregation of Aβ aggregates, as confirmed by a Thioflavin T (Th T) assay. Subsequently, the active constituents were isolated using a bioassay-guided isolation method involving diverse column chromatography. Eleven compounds were identified—epi-catechin (1), catechin (2), (2S, 3S)-dihydrokaempferol 3-O-β-D-glucopyranoside (3), (-)-epiafzelechin 5-O-β-D-glucopyranoside (4), kaempferol 3-O-β-D-glucopyranoside (5), apigenin 7-O-β-D-glucopyranoside (6), dihydrokaempferol 7-O-β-D-glucopyranoside (7), quercetin 3-O-β-D-glucopyranoside (8), (2S, 3S)-taxifolin 3-O-β-D-glucopyranoside (9), luteolin 7-O-β-D-glucopyranoside (10), and apigenin 7-O-β-D-methylglucuronate (11)—identified through 1D and 2D NMR analysis and comparison with data from the literature. These compounds significantly decreased Aβ production by reducing β- and γ-secretase levels. Moreover, none of the compounds affected the expression levels of sAPPα or α-secretase. Further, compounds 1, 2, 4, 8, and 10 demonstrated a dose-dependent reduction in Aβ aggregation and promoted the disaggregation of pre-formed Aβ aggregates. Notably, compound 8 inhibited the aggregation of Aβ into fibrils by about 43% and facilitated the disassembly of Aβ aggregates by 41% compared to the control group containing only Aβ. These findings underscore the potential of A. pilosa extract and its constituents to mitigate a crucial pathological aspect of AD. Therefore, A. pilosa extract and its active constituents hold promise for development as therapeutics and preventatives of AD. Full article

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-β (Aβ) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes a sequence of cleavages, referred as trimming, performed by γ-secretase. Here, we investigated conformational changes in a series of β-amyloid substrates (from less and more amyloidogenic pathways) in the active site of presenilin-1, the catalytic subunit of γ-secretase. The substrates are trimmed every three residues, finally leading to Aβ₄₀ and Aβ₄₂, which are the major components of amyloid plaques. To study conformational changes, we employed all-atom molecular dynamics simulations, while for unfolding, we used steered molecular dynamics simulations in an implicit membrane-water environment to accelerate changes. We have found substantial differences in the flexibility of extended C-terminal parts between more and less amyloidogenic pathway substrates. We also propose that the positively charged residues of presenilin-1 may facilitate the stretching and unfolding of substrates. The calculated forces and work/energy of pulling were exceptionally high for Aβ₄₀, indicating why trimming of this substrate is so infrequent. Full article

A pathogenic mutation in presenilin-1 (PSEN1), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal aunt, and paternal grandmother without genetic testing. He was diagnosed with early onset Alzheimer’s disease (EOAD). PSEN1 His214Asn was initially reported in an Italian family, where the patient developed phenotypes similar to the current proband patient. Magnetic resonance imaging (MRI) scans revealed a mild hippocampal atrophy. The amyloid positron emission tomography (amyloid-PET) was positive, along with the positive test results of the increased amyloid ß (Aβ) oligomerization tendency with blood. The PSEN1 His214 amino acid position plays a significant role in the gamma–secretase function, especially from three additional reported mutations in this residue: His214Asp, His214Tyr, and His214Arg. The structure prediction model revealed that PSEN1 protein His214 may interact with Trp215 of His-Trp cation-π interaction, and the mutations of His214 would destroy this interaction. The His-Trp cation-π interaction between His214 and Trp215 would play a crucial structural role in stabilizing the 4th transmembrane domain of PSEN1 protein, especially when aromatic residues were often reported in the membrane interface of the lipid–extracellular region of alpha helices or beta sheets. The His214Asn would alter the cleavage dynamics of gamma–secretase from the disappeared interactions between His214 and Trp215 inside of the helix, resulting in elevated amyloid production. Hence, the increased Aβ was reflected in the increased Aβ oligomerization tendency and the accumulations of Aβ in the brain from amyloid-PET, leading to EOAD. Full article

Alzheimer’s disease (AD), is a progressive neurodegenerative disorder that involves the deposition of β-amyloid plaques and the clinical symptoms of confusion, memory loss, and cognitive dysfunction. Despite enormous progress in the field, no curative treatment is available. Therefore, the current study was designed to determine the neuroprotective effects of N-methyl-(2S, 4R)-Trans-4-hydroxy-L-proline (NMP) obtained from Sideroxylon obtusifolium, a Brazilian folk medicine with anti-inflammatory and anti-oxidative properties. Here, for the first time, we explored the neuroprotective role of NMP in the Aβ_1–42-injected mouse model of AD. After acclimatization, a single intracerebroventricular injection of Aβ_1–42 (5 µL/5 min/mouse) in C57BL/6N mice induced significant amyloidogenesis, reactive gliosis, oxidative stress, neuroinflammation, and synaptic and memory deficits. However, an intraperitoneal injection of NMP at a dose of (50 mg/kg/day) for three consecutive weeks remarkably decreased beta secretase1 (BACE-1) and Aβ, activated the astrocyte and microglia expression level as well as downstream inflammatory mediators such as pNF-ĸB, TNF-α, and IL-1β. NPM also strongly attenuated oxidative stress, as evaluated by the expression level of NRF2/HO-1, and synaptic failure, by improving the level of both the presynaptic (SNAP-25 and SYN) and postsynaptic (PSD-95 and SNAP-23) regions of the synapses in the cortexes and hippocampi of the Aβ_1–42-injected mice, contributing to cognitive improvement in AD and improving the behavioral deficits displayed in the Morris water maze and Y-maze. Overall, our data suggest that NMP provides potent multifactorial effects, including the inhibition of amyloid plaques, oxidative stress, neuroinflammation, and cognitive deficits. Full article

Alzheimer’s disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping rates with the pharmacophore were subjected to molecular docking against the three enzymes and those with an adequate docking score (n = 12) were evaluated for physicochemical and toxicological parameters and commercial availability. The structure exhibiting the greatest inhibitory potential against all three enzymes was subjected to molecular dynamics simulations (100 ns) to assess the stability of the inhibitor-enzyme systems. The results of this in silico approach indicate ZINC1733 can be a potential multi-target inhibitor of AChE, BuChE, and BACE-1, and future enzymatic assays are planned to validate those results. Full article