Strategy For Treatment Of Alzheimer's Disease Research Articles

Ketone body metabolism and the NLRP3 inflammasome in Alzheimer's disease.

Alzheimer's disease (AD) is a degenerative brain disorder and the most common form of dementia. AD pathology is characterized by senile plaques and neurofibrillary tangles (NFTs) composed of amyloid-β (Aβ) and hyperphosphorylated tau, respectively. Neuroinflammation has been shown to drive Aβ and tau pathology, with evidence suggesting the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome as a key pathway in AD pathogenesis. NLRP3 inflammasome activation in microglia, the primary immune effector cells of the brain, results in caspase-1 activation and secretion of IL-1β and IL-18. Recent studies have demonstrated a dramatic interplay between the metabolic state and effector functions of immune cells. Microglial metabolism in AD is of particular interest, as ketone bodies (acetone, acetoacetate (AcAc), and β-hydroxybutyrate (BHB)) serve as an alternative energy source when glucose utilization is compromised in the brain of patients with AD. Furthermore, reduced cerebral glucose metabolism concomitant with increased BHB levels has been demonstrated to inhibit NLRP3 inflammasome activation. Here, we review the role of the NLRP3 inflammasome and microglial ketone body metabolism in AD pathogenesis. We also highlight NLRP3 inflammasome inhibition by several ketone body therapies as a promising new treatment strategy for AD.

Autoencoder to Identify Sex-Specific Sub-phenotypes in Alzheimer's Disease Progression Using Longitudinal Electronic Health Records.

Alzheimer's Disease (AD) is a complex neurodegenerative disorder significantly influenced by sex differences, with approximately two-thirds of AD patients being women. Characterizing the sex-specific AD progression and identifying its progression trajectory is a crucial step to developing effective risk stratification and prevention strategies. In this study, we developed an autoencoder to uncover sex-specific sub-phenotypes in AD progression leveraging longitudinal electronic health record (EHR) data from OneFlorida+ Clinical Research Consortium. Specifically, we first constructed temporal patient representation using longitudinal EHRs from a sex-stratified AD cohort. We used a long short-term memory (LSTM)-based autoencoder to extract and generate latent representation embeddings from sequential clinical records of patients. We then applied hierarchical agglomerative clustering to the learned representations, grouping patients based on their progression sub-phenotypes. The experimental results show we successfully identified five primary sex-based AD sub-phenotypes with corresponding progression pathways with high confidence. These sex-specific sub-phenotypes not only illustrated distinct AD progression patterns but also revealed differences in clinical characteristics and comorbidities between females and males in AD development. These findings could provide valuable insights for advancing personalized AD intervention and treatment strategies.

Tirzepatide shows neuroprotective effects via regulating brain glucose metabolism in APP/PS1 mice

Tirzepatide (LY3298176), a GLP-1 and GIP receptor agonist, is fatty-acid-modified and 39-amino acid linear peptide, which ameliorates learning and memory impairment in diabetic rats. However, the specific molecular mechanism remains unknown. In the present study, we investigated the role of tirzepatide in the neuroprotective effects in Alzheimer's disease (AD) model mice. Tirzepatide was administrated intraperitoneal (i.p.) APP/PS1 mice for 8 weeks with at 10 nmol/kg once-weekly, it significantly decreased the levels of GLP-1R, and GFAP protein expression and amyloid plaques in the cortex, it also lowered neuronal apoptosis induced by amyloid-β (Aβ), but did not affect the anxiety and cognitive function in APP/PS1 mice. Moreover, tirzepatide reduced the blood glucose levels and increased the mRNA expression of GLP-1R, SACF1, ATF4, Glu2A, and Glu2B in the hypothalamus of APP/PS1 mice. Tirzepatide increased the mRNA expression of glucose transporter 1, hexokinase, glucose-6-phosphate dehydrogenase, and phosphofructokinase in the cortex. Lastly, tirzepatide improved the energetic metabolism by regulated reactive oxygen species production and mitochondrial membrane potential caused by Aβ, thereby decreasing mitochondrial function and ATP levels in astrocytes through GLP-1R. These results provide valuable insights into the mechanism of brain glucose metabolism and mitochondrial function of tirzepatide, presenting potential strategies for AD treatment.

Alzheimer's Disease Knowledge Graph Enhances Knowledge Discovery and Disease Prediction.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, continues to increase in prevalence without any effective treatments to date. In this context, knowledge graphs (KGs) have emerged as a pivotal tool in biomedical research, offering new perspectives on drug repurposing and biomarker discovery by analyzing intricate network structures. Our study seeks to build an AD-specific knowledge graph, highlighting interactions among AD, genes, variants, chemicals, drugs, and other diseases. The goal is to shed light on existing treatments, potential targets, and diagnostic methods for AD, thereby aiding in drug repurposing and the identification of biomarkers. We annotated 800 PubMed abstracts and leveraged GPT-4 for text augmentation to enrich our training data for named entity recognition (NER) and relation classification. A comprehensive data mining model, integrating NER and relationship classification, was trained on the annotated corpus. This model was subsequently applied to extract relation triplets from unannotated abstracts. To enhance entity linking, we utilized a suite of reference biomedical databases and refine the linking accuracy through abbreviation resolution. As a result, we successfully identified 3,199,276 entity mentions and 633,733 triplets, elucidating connections between 5,000 unique entities. These connections were pivotal in constructing a comprehensive Alzheimer's Disease Knowledge Graph (ADKG). We also integrated the ADKG constructed after entity linking with other biomedical databases. The ADKG served as a training ground for Knowledge Graph Embedding models with the high-ranking predicted triplets supported by evidence, underscoring the utility of ADKG in generating testable scientific hypotheses. Further application of ADKG in predictive modeling using the UK Biobank data revealed models based on ADKG outperforming others, as evidenced by higher values in the areas under the receiver operating characteristic (ROC) curves. The ADKG is a valuable resource for generating hypotheses and enhancing predictive models, highlighting its potential to advance AD's disease research and treatment strategies.

Norboldine improves cognitive impairment and pathological features in Alzheimer's disease by activating AMPK/GSK3β/Nrf2 signaling pathway

Ethnopharmacological relevanceLindera aggregata (Sims) Kosterm is a common traditional herb that has multiple bioactivities. Radix Linderae (LR), the dry roots of Lindera aggregata (Sims) Kosterm, is a traditional Chinese herbal medicine with antioxidant, anti-inflammatory and immunomodulatory properties, first found in Kaibao Era. Norboldine (Nor) is an alkaloid extracted from LR and is one of the primary active ingredients of LR. However, the pharmacological functions and mechanism of Nor in Alzheimer's disease (AD) are still unknown. Aim of the studyThis study aims to investigate the effect and mechanism of Nor therapy in improving the cognitive impairment and pathological features of 3 × Tg mice. Materials and methods3 × Tg mice were treated with two concentrations of Nor for one month and then the memory and cognitive abilities of mice were assessed by novel object recognition experiment and Morris water maze. The impact of Nor on the pathology of ADwere examined in PC12 cells and animal tissues using western blotting and immunofluorescence. Finally, western blotting was used to verify the anti-apoptotic effect of Nor by activating AMPK/GSK3β/Nrf2 signaling pathway at animal and cellular levels. ResultsIn this study, we showed that Nor treatment improved the capacity of the learning and memory of 3 × Tg mice and alleviated AD pathology such as Aβ deposition. In addition, Nor restored the abnormalities of mitochondrial membrane potential, significantly reduced the production of intracellular ROS and neuronal cell apoptosis. Mechanistically, we combined network pharmacology and experimental verification to show that Nor may exert antioxidant stress and anti-apoptotic through the AMPK/GSK3β/Nrf2 signaling pathway. ConclusionOur data provide some evidence that Nor exerts a neuroprotective effect through the AMPK/GSK3β/Nrf2 pathway, thereby improving cognitive impairment in AD model mice. Natural products derived from traditional Chinese medicines are becoming increasingly popular in the process of new drug development and discovery, and our findings provide new perspectives for the discovery of improved treatment strategies for AD.

The alteration and role of glycoconjugates in Alzheimer’s disease

The alteration and role of glycoconjugates in Alzheimer’s disease

Serum neurofilament light chain and inflammatory cytokines as biomarkers for early detection of mild cognitive impairment

To investigate the association between serum neurofilament light chain (NfL) levels, inflammatory cytokines, and cognitive function to assess their utility in the early detection of mild cognitive impairment (MCI). We conducted a cross-sectional study involving 157 community-dwelling individuals aged 55 years and above, categorized into healthy controls, MCI, and probable Alzheimer's disease (AD). Serum levels of NfL, inflammatory cytokines, and AD pathology markers were measured using enzyme-linked immunosorbent assay (ELISA). Correlations between these biomarkers and cognitive function were analyzed, and the diagnostic performance of the cognitive assessment scales and serum biomarker concentrations was evaluated using receiver operating characteristic (ROC) curve analysis. Serum NfL levels were significantly elevated in MCI and probable AD groups compared to healthy controls. Positive correlations were found between serum NfL and inflammatory cytokines IL-1β, IL-6, and Aβ40. Combining serum NfL with p-tau217 and the Boston Naming Test significantly enhanced the predictive accuracy for MCI. However, combining serum NfL with inflammatory markers did not improve MCI prediction accuracy. Elevated serum NfL is associated with cognitive impairment and inflammatory markers, suggesting its potential as a peripheral serum biomarker for MCI detection. The combination of serum NfL with p-tau217 and cognitive tests could offer a more accurate prediction of MCI, providing new insights for AD treatment strategies.

Association of genetically predicted 486 blood metabolites on the risk of Alzheimer's disease: a Mendelian randomization study.

Studies have reported that metabolic disturbance exhibits in patients with Alzheimer's disease (AD). Still, the presence of definitive evidence concerning the genetic effect of metabolites on AD risk remains insufficient. A systematic exploration of the genetic association between blood metabolites and AD would contribute to the identification of new targets for AD screening and prevention. We conducted an exploratory two-sample Mendelian randomization (MR) study aiming to preliminarily identify the potential metabolites involved in AD development. A genome-wide association study (GWAS) involving 7,824 participants provided information on 486 human blood metabolites. Outcome information was obtained from a large-scale GWAS meta-analysis of AD, encompassing 21,982 cases and 41,944 controls of Europeans. The primary two-sample MR analysis utilized the inverse variance weighted (IVW) model while supplementary analyses used Weighted median (WM), MR Egger, Simple mode, and Weighted mode, followed by sensitivity analyses such as the heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. For the further identification of metabolites, replication and meta-analysis with FinnGen data, steiger test, linkage disequilibrium score regression, confounding analysis, and were conducted for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on AD. Besides, an extra replication analysis with EADB data was conducted for final evaluation of the most promising findings. After rigorous genetic variant selection, IVW, complementary analysis, sensitivity analysis, replication and meta-analysis with the FinnGen data, five metabolites (epiandrosterone sulfate, X-12680, pyruvate, docosapentaenoate, and 1-stearoylglycerophosphocholine) were identified as being genetically associated with AD. MVMR analysis disclosed that genetically predicted these four known metabolites can directly influence AD independently of other metabolites. Only epiandrosterone sulfate and X-12680 remained suggestive significant associations with AD after replication analysis with the EADB data. By integrating genomics with metabonomics, this study furnishes evidence substantiating the genetic association of epiandrosterone sulfate and X-12680 with AD. These findings hold significance for the screening, prevention, and treatment strategies for AD.

Exploring Acori Tatarinowii Rhizoma and Polygalae Radix in Alzheimer's: Network pharmacology and molecular docking analysis.

Explore Acori Tatarinowii Rhizoma (ATR) and Polygalae Radix (PR) mechanisms in Alzheimer's disease (AD) treatment through network pharmacology. ATR-PR was investigated in the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, Batman, and Traditional Chinese Medicines Integrated Database (TCMID) to gather information on its chemical components and target proteins. Target genes associated with AD were retrieved from the GeneCards and National Center for Biotechnology Information (NCBI) databases. The integration of these datasets with potential targets facilitated the construction of an AD and ATR-PR protein-protein interaction (PPI) network using the STRING database. The resulting network identified the core active ingredients and main targets of ATR-PR in AD treatment. Cluster analysis of the PPI network was performed using Cytoscape 3.7.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the Metascape database. Molecular docking simulations revealed potential interactions between the main active ingredients and core targets. Our analysis identified 8 putative components and 455 targets of ATR-PR. We systematically searched for 1306 genes associated with AD, conducted Venn diagram analysis resulting in 156 common targets, and constructed a PPI network with 57 key targets. GO functional analysis highlighted the primary biological processes associated with oxidative stress. KEGG pathway enrichment analysis revealed the involvement of 64 signaling pathways, with the PI3K/Akt signaling pathway playing a key role. Molecular docking analysis indicated a high affinity between the potential targets of ATR-PR and the main compounds of AD. This study sheds light on the complex network of interactions involving ATR-PR in the context of AD. The identified targets, pathways, and interactions provide a foundation for understanding the potential therapeutic mechanisms. The involvement of oxidative stress-related processes and the crucial role of the PI3K/Akt signaling pathway suggest avenues for targeted therapeutic interventions in Alzheimer's disease treatment. Our proposition of the combined use of ATR-PR has emerged as a potential treatment strategy for AD, supported by a network pharmacology approach. This framework provides a robust foundation for future clinical applications and experimental research in the pursuit of effective Alzheimer's disease treatments.

The protective effect of Astaxanthin on scopolamine - induced Alzheimer's model in mice.

To investigate the fundamental mechanisms of the neuroprotective impact of Astaxanthin (AST) in a mouse model of Alzheimer's disease (AD) induced by scopolamine. This research constituted an in vivo animal study encompassing 36 adult male mice, divided into 6 groups: Control, 100mg/kg AST, 2mg/kg scopolamine (AD group), 100mg/kg AST+2mg/kg scopolamine, 3mg/kg galantamine+2mg/kg scopolamine, and 100mg/kg AST+3mg/kg galantamine+2mg/kg scopolamine. After 14 days, the mice's short-term memory, hippocampus tissue, oxidative and inflammatory markers were evaluated. The AST demonstrated a beneficial influence on short-term memory and a reduction in acetylcholinesterase activity in the brain. It exhibited neuroprotective and anti-amyloidogenic properties, significantly decreased pro-inflammatory markers and oxidative stress, and reversed the decline of the Akt-1 and phosphorylated Akt pathway, a crucial regulator of abnormal tau. Furthermore, AST enhanced the effect of galantamine in reducing inflammation and oxidative stress. The findings indicate that AST may offer therapeutic benefits against cognitive dysfunction in AD. This is attributed to its ability to reduce oxidative stress, control neuroinflammation, and enhance Akt-1 and pAkt levels, thereby underscoring its potential in AD treatment strategies.

Dendrobium officinale phenolic extract maintains proteostasis by regulating autophagy in a Caenorhabditis elegans model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and accumulating evidence suggested that proteostatic imbalance is a key feature of the disease. Traditional Chinese medicine exhibits a multi-target therapeutic effect, making it highly suitable for addressing protein homeostasis imbalance in AD. Dendrobium officinale is a traditional Chinese herbs commonly used as tonic agent in China. In this study, we investigated protection effects of D. officinale phenolic extract (SH-F) and examined its underlying mechanisms by using transgenic Caenorhabditis elegans models. We found that treatment with SH-F (50 μg/mL) alleviated Aβ and tau protein toxicity in worms, and also reduced aggregation of polyglutamine proteins to help maintain proteostasis. RNA sequencing results showed that SH-F treatment significantly affected the proteolytic process and autophagy–lysosomal pathway. Furthermore, we confirmed that SH-F showing maintainance of proteostasis was dependent on bec-1 by qRT-PCR analysis and RNAi methods. Finally, we identified active components of SH-F by LC-MS method, and found the five major compounds including koaburaside, tyramine dihydroferulate, N-p-trans-coumaroyltyramine, naringenin and isolariciresinol are the main bioactive components responsible for the anti-AD activity of SH-F. Our findings provide new insights to develop a treatment strategy for AD by targeting proteostasis, and SH-F could be an alternative drug for the treatment of AD.

Black phosphorus nanosheets as therapeutic “garbage trucks” for the selective clearance of peripheral phosphorylated Tau proteins in Alzheimer’s disease

The onset of Alzheimer's disease (AD) is closely related to the accumulation of phosphorylated Tau proteins (P-Tau). However, due to the hindrance posed by the blood–brain barrier (BBB), current therapies targeting brain-derived P-Tau are largely ineffective. Interestingly, the clearance of peripheral P-Tau can eliminate P-Tau from the brain, enabling AD treatment and overcoming the challenges created by the BBB. Here, we prepared polyethylene glycol (PEG)-modified black phosphorus nanosheets (BP-PEG), which showed extended systemic circulation and acted as efficient “garbage trucks” for the removal of peripheral P-Tau. BP-PEG exhibited an exceptional capacity to bind to P-Tau in vitro. Further, in vivo biodistribution analysis demonstrated that BP-PEG accumulated in the liver and kidneys, which are the same organs that metabolize P-Tau. In vivo studies revealed that in okadaic acid (OA)-induced mouse models of AD, BP-PEG significantly reduced the levels of P-Tau in both the peripheral blood and the brain. Moreover, by promoting the clearance of peripheral P-Tau, BP-PEG improved several health indicators in mice, including cognitive function, glucose metabolism in the brain, inflammatory markers in the plasma and hippocampus, oxidative stress, and mitochondrial and myelin morphology. In conclusion, this study provides a new strategy for AD treatment, demonstrating the therapeutic value of removing P-Tau from the peripheral blood, and it also represents a novel attempt for the application of BP-PEG in AD therapy.

Significant downregulation of Alzheimer's amyloid-β levels enabled by engineered DNA nanomaterials

Although there are no effective therapies to block or reverse Alzheimer's disease (AD) progression at present, a promising therapeutic strategy is to reduce levels of amyloid-β (Aβ) proteins, which drive the formation of amyloid plaque, a primary hallmark in AD brains. Herein, we report that amphiphilic lipid-DNA molecules (LD) were designed by incorporating a long alkyl chain into the nucleotide base. It significantly down-regulated Alzheimer's Aβ levels in vivo and in vitro. In contrast to small-molecule chemical drugs and antibody therapies, the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier (BBB) and accumulate in the brain, increasing the therapeutic effects. Notably, lipid-DNA downregulated the levels of Aβ peptides significantly in vitro. AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement, which was associated with brain engagement of LD and reduced Aβ levels. Thus, the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides. This work might provide a promising DNA engineering strategy for AD treatment.

Non-coding RNAs in Regulation of Protein Aggregation and Clearance Pathways: Current Perspectives Towards Alzheimer's Research and Therapy.

Alzheimer's disease (AD) is the leading cause of dementia, affecting approximately 45.0 million people worldwide and ranking as the fifth leading cause of mortality. AD is identified by neurofibrillary tangles (NFTs), which include abnormally phosphorylated tau-protein and amyloid protein (amyloid plaques). Peptide dysregulation is caused by an imbalance between the production and clearance of the amyloid-beta (Aβ) and NFT. AD begins to develop when these peptides are not cleared from the body. As a result, understanding the processes that control both normal and pathological protein recycling in neuronal cells is critical. Insufficient Aβ and NFT clearance are important factors in the development of AD. Autophagy, lysosomal dysfunction, and ubiquitin-proteasome dysfunction have potential roles in the pathogenesis of many neurodegenerative disorders, particularly in AD. Modulation of these pathways may provide a novel treatment strategy for AD. Non-coding RNAs (ncRNAs) have recently emerged as important biological regulators, with particular relevance to the emergence and development of neurodegenerative disorders such as AD. ncRNAs can be used as potential therapeutic targets and diagnostic biomarkers due to their critical regulatory functions in several biological processes involved in disease development, such as the aggregation and accumulation of Aβ and NFT. It is evident that ncRNAs play a role in the pathophysiology of AD. In this communication, we explored the link between ncRNAs and AD and their regulatory mechanisms that may help in finding new therapeutic targets and AD medications.

Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer's disease pathology.

Evidence suggests that beta-amyloid (Aβ)-induced phosphorylation/aggregation of tau protein plays a critical role in the degeneration of neurons and development of Alzheimer's disease (AD), the most common cause of dementia affecting the elderly population. Many studies have pursued a variety of small molecules, including nanoparticles conjugated with drugs to interfere with Aβ and/or tau aggregation/toxicity as an effective strategy for AD treatment. We reported earlier that FDA approved PLGA nanoparticles without any drug can attenuate Aβ aggregation/toxicity in cellular/animal models of AD. In this study, we evaluated the effects of native PLGA on Aβ seed-induced aggregation of tau protein using a variety of biophysical, structural and spectroscopic approaches. Our results show that Aβ1-42 seeds enhanced aggregation of tau protein in the presence and absence of heparin and the effect was attenuated by native PLGA nanoparticles. Interestingly, PLGA inhibited aggregation of both 4R and 3R tau isoforms involved in the formation of neurofibrillary tangles in AD brains. Furthermore, Aβ seed-induced tau aggregation in the presence of arachidonic acid was suppressed by native PLGA. Collectively, our results suggest that native PLGA nanoparticles can inhibit the Aβ seed-induced aggregation of different tau protein isoforms highlighting their therapeutic implication in the treatment of AD.

Interaction Between a High-Fat Diet and Tau Pathology in Mice: Implications for Alzheimer's Disease.

Obesity is a modifiable risk factor for Alzheimer's disease (AD). However, its relation with tau pathology (i.e., aberrant tau protein behavior in tauopathies such as AD) has been inconclusive. This study investigated the interaction between a high-fat diet (HFD) and tau pathology in adult male mice. Transgenic mice overexpressing human P301S Tau (those with the pathology) and wild-type (WT) littermates were subjected to behavioral tests, functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and western blotting analysis to investigate the effects of prolonged HFD versus regular diet during adulthood. HFD increased body weight in both WT and P301S mice but had minimal effect on blood glucose levels. The brain response to HFD was tau genotype-specific. WT mice exhibited decreased recognition memory and enhanced network connectivity in fMRI, while P301S mice exhibited white matter tract disorganization in DTI as the sole significant finding. The reduction of insulin receptor β, insulin downstream signaling, neuronal nuclear protein, CD68-positive phagocytic activity, and myelin basic protein level were confined to the cortex of WT mice. In contrast to P301S mice, WT mice showed significant changes in the tau protein and its phosphorylation levels along with increased soluble neurofilament light levels in the hippocampus. HFD-induced brain dysfunction and pathological changes were blunted in mice with the pathology and more profound in healthy mice. Our findings highlight the need to consider this interaction between obesity and tau pathology when tailoring treatment strategies for AD and other tauopathies.

Intranasal Drug Delivery by Nanotechnology: Advances in and Challenges for Alzheimer's Disease Management.

Alzheimer's disease, a progressive neurodegenerative condition, is characterized by a gradual decline in cognitive functions. Current treatment approaches primarily involve the administration of medications through oral, parenteral, and transdermal routes, aiming to improve cognitive function and alleviate symptoms. However, these treatments face limitations, such as low bioavailability and inadequate permeation. Alternative invasive methods, while explored, often entail discomfort and require specialized assistance. Therefore, the development of a non-invasive and efficient delivery system is crucial. Intranasal delivery has emerged as a potential solution, although it is constrained by the unique conditions of the nasal cavity. An innovative approach involves the use of nano-carriers based on nanotechnology for intranasal delivery. This strategy has the potential to overcome current limitations by providing enhanced bioavailability, improved permeation, effective traversal of the blood-brain barrier, extended retention within the body, and precise targeting of the brain. The comprehensive review focuses on the advancements in designing various types of nano-carriers, including polymeric nanoparticles, metal nanoparticles, lipid nanoparticles, liposomes, nanoemulsions, Quantum dots, and dendrimers. These nano-carriers are specifically tailored for the intranasal delivery of therapeutic agents aimed at combatting Alzheimer's disease. In summary, the development and utilization of intranasal delivery systems based on nanotechnology show significant potential in surmounting the constraints of current Alzheimer's disease treatment strategies. Nevertheless, it is essential to acknowledge regulatory as well as toxicity concerns associated with this route; meticulous consideration is required when engineering a carrier. This comprehensive review underscores the potential to revolutionize Alzheimer's disease management and highlights the importance of addressing regulatory considerations for safe and effective implementations. Embracing this strategy could lead to substantial advancements in the field of Alzheimer's disease treatment.

Combining Multifunctional Delivery System with Blood-Brain Barrier Reversible Opening Strategy for the Enhanced Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative illness characterized by intracellular tau-phosphorylation, β-amyloid (Aβ) plaques accumulation, neuroinflammation, and impaired behavioral ability. Owing to the lack of effective brain delivery approaches and the presence of the blood-brain barrier (BBB), current AD therapeutic endeavors are severely limited. Herein, a multifunctional delivery system (RVG-DDQ/PDP@siBACE1) is elaborately combined with a protein kinase B(AKT) agonist (SC79) for facilitating RVG-DDQ/PDP@siBACE1 to target and penetrate BBB, enter brain parenchyma, and further accumulate in AD brain lesion. Moreover, compared with the unitary dose of RVG-DDQ/PDP@siBACE1, this collaborative therapy strategy exhibits a distinctive synergistic function including scavenging reactive oxygen species (ROS), decreasing of Aβ production, alleviating neuroinflammation by promoting the polarized microglia into the anti-inflammatory M2-like phenotype and significantly enhancing the cognitive functions of AD mice. More strikingly, according to these results, an innovative signaling pathway "lncRNA MALAT1/miR-181c/BCL2L11" is found that can mediate the neuronal apoptosis of AD. Taken together, combining the brain targeted delivery system with noninvasive BBB opening can provide a promising strategy and platform for targeting treatment of AD and other neurodegenerative diseases.

Real-time monitoring of the amyloid β1-42 monomer-to-oligomer channel transition using a lipid bilayer system.

This study describes the observation of the transformation of monomeric amyloid β1-42 (Aβ42) into oligomers in a lipid membrane utilizing a lipid bilayer system for electrophysiological measurement. The relevance of oligomers and protofibrils in Alzheimer's disease (AD) is underscored given their significant neurotoxicity. By closely monitoring the shift of Aβ42 from its monomeric state to forming oligomeric channels in phospholipid membranes, we noted that this transformation transpired within a 2-h frame. We manipulated the lipid membrane's constitution with components such as glycerophospholipid, porcine brain total lipid extract, sphingomyelin (SM), and cholesterol (Chol.) to effectively imitate nerve cell membranes. Interesting findings showcased Chol.'s ability to foster stable oligomeric channel formation in the lipid membrane, with SM and GM1 lipids potentially enhancing channel formation as well. Additionally, the study identified the potential of a catechin derivative, epigallocatechin gallate (EGCG), in obstructing oligomerization. With EGCG present in the outer solution of the Aβ42-infused membrane, a noteworthy reduction in channel current was observed, suggesting the successful inhibition of oligomerization. This conclusion held true in both, prior and subsequent, stages of oligomerization. Our findings shed light on the toxicity of oligomers, promising invaluable information for future advancements in AD treatment strategies.

Changes in the Glutamate/GABA System in the Hippocampus of Rats with Age and during Alzheimer's Disease Signs Development.

GABA and glutamate are the most abundant neurotransmitters in the CNS and play a pivotal part in synaptic stability/plasticity. Glutamate and GABA homeostasis is important for healthy aging and reducing the risk of various neurological diseases, while long-term imbalance can contribute to the development of neurodegenerative disorders, including Alzheimer's disease (AD). Normalization of the homeostasis has been discussed as a promising strategy for prevention and/or treatment of AD, however, data on the changes in the GABAergic and glutamatergic systems with age, as well as on the dynamics of AD development, are limited. It is not clear whether imbalance of the excitatory/inhibitory systems is the cause or the consequence of the disease development. Here we analyzed the age-related alterations of the levels of glutamate, GABA, as well as enzymes that synthesize them (glutaminase, glutamine synthetase, GABA-T, and GAD67), transporters (GLAST, GLT-1, and GAT1), and relevant receptors (GluA1, NMDAR1, NMDA2B, and GABAAr1) in the whole hippocampus of the Wistar rats and of the senescence-accelerated OXYS rats, a model of the most common (> 95%) sporadic AD. Our results suggest that there is a decline in glutamate and GABA signaling with age in hippocampus of the both rat strains. However, we have not identified significant changes or compensatory enhancements in this system in the hippocampus of OXYS rats during the development of neurodegenerative processes that are characteristic of AD.