Alzheimer's Disease Therapy Research Articles

Conditioned Media Therapy in Alzheimer's Disease: Current Findings and Future Challenges.

Alzheimer's disease (AD) is a neurodegenerative disorder accompanied by a reduction in cognition and memory. Till now, there is no definite cure for AD, although, there are treatments available that may improve some symptoms. Currently, in regenerative medicine stem cells are widely used, mainly for treating neurodegenerative diseases. There are numerous forms of stem cells to treat AD aiming at the expansion of the treatment methods for this particular disease. Since 10 years ago, science has gained abundant knowledge to treat AD by understanding the sorts of stem cells, methods, and phasing of injection. Besides, due to the side effects of stem cell therapy like the potentiation for cancer, and as it is hard to follow the cells through the matrix of the brain, researchers have presented a new therapy for AD. They prefer to use conditioned media (CM) that are full of different growth factors, cytokines, chemokines, enzymes, etc. without tumorigenicity or immunogenicity such as stem cells. Another benefit of CM is that CM could be kept in the freezer, easily packaged, and transported, and doesn't need to fit with the donor. Due to the beneficial effects of CM, in this paper, we intend to evaluate the effects of various types of CM of stem cells on AD.

Deep learning-based drug screening for the discovery of potential therapeutic agents for Alzheimer's disease

Alzheimer's disease (AD) is gradually increasing in prevalence and the complexity of its pathogenesis has led to a lengthy process of developing therapeutic drugs with limited success. Faced with this challenge, we proposed using a state-of-the-art drug screening algorithm to identify potential therapeutic compounds for AD from traditional Chinese medicine formulas with strong empirical support. We developed four deep neural network (DNN) models for AD drugs screening at the disease and target levels. The AD model was trained with compounds labeled for AD activity to predict active compounds at the disease level, while the acetylcholinesterase (AChE), monoamine oxidase-A (MAO-A), and 5-hydroxytryptamine 6 (5-HT6) models were trained for specific AD targets. All four models performed excellently and were used to identify potential AD agents in the Kaixinsan (KXS) formula. High-scoring compounds underwent experimental validation at the enzyme, cellular, and animal levels. Compounds like 2,4-di-tert-butylphenol and elemicin showed significant binding and inhibitory effects on AChE and MAO-A. Additionally, 13 compounds, including α-asarone, penetrated the blood-brain barrier (BBB), indicating potential brain target binding, and eight compounds enhanced microglial β-amyloid phagocytosis, aiding in clearing AD pathological substances. Our results demonstrate the effectiveness of deep learning models in developing AD therapies and provide a strong platform for AD drug discovery.

Hederagenin reduces Aβ-induced oxidative damage, decreases Aβ deposition and promotes cell survival by the P13 K/Akt signaling pathway.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive impairment. β-amyloid (Aβ) is one of the typical pathological features of AD, and its accumulation leads to neuronal death from oxidative stress. Here, we found that hederagenin (HG), a natural product, exhibits anti-tumor, anti-inflammatory, anti-depressant, anti-neurodegenerative biological activities. However, whether HG has anti-Aβ activity remains unclear. Based on the characteristics of HG, it is hypothesized that HG has biological activity against Aβ injury. Therefore, Aβ-injured SH-SY5Y cells were constructed, and the protective effect of HG against Aβ injury was further evaluated using C. elegans. The results showed that HG increased superoxide dismutase activity, effectively reduced Aβ-induced oxidative damage, and reduced apoptosis via the PI3 K/Akt signaling pathway. HG inhibited Aβ deposition and delayed senescence and paralysis in the C. elegans strain, CL4176. HG showed inhibitory effects on Aβ; therefore, more natural active products are expected to be applied in AD therapy.

Recent Advances in Targeting Transition Metals (Copper, Iron, and Zinc) in Alzheimer's Disease.

Changes in the transition metal homeostasis in the brain are closely linked with Alzheimer's disease (AD), including intraneuronal iron accumulation and extracellular copper and zinc pooling in the amyloid plague. The brain copper, zinc, and iron surplus are commonly acknowledged characteristics of AD, despite disagreements among some. This has led to the theory that oxidative stress resulting from abnormal homeostasis of these transition metals may be a causative explanation behind AD. In the nervous system, the interaction of metals with proteins appears to be an essential variable in the development or suppression of neurodegeneration. Chelation treatment may be an option for treating neurodegeneration induced by transition metal ion dyshomeostasis. Some clinicians even recommend using chelating agents as an adjunct therapy for AD. The current review also looks at the therapeutic strategies that have been attempted, primarily with metal-chelating drugs. Metal buildup in the nervous system, as reported in the AD, could be the result of compensatory mechanisms designed to improve metal availability for physiological functions.

Regulation of mitochondrial dysfunction by estrogens and estrogen receptors in Alzheimer's disease: A focused review.

Alzheimer's disease (AD) is a neurodegenerative disorder that primarily manifests itself by progressive memory loss and cognitive decline, thus significantly affecting memory functions and quality of life. In this review, we proceed from the understanding that the canonical amyloid-β hypothesis, while significant, has faced setbacks, highlighting the need to adopt a broader perspective considering the intricate interplay of diverse pathological pathways for effective AD treatments. Sex differences in AD offer valuable insights into a better understanding of its pathophysiology. Fluctuation of the levels of ovarian sex hormones during perimenopause is associated with changes in glucose metabolism, as a possible window of opportunity to further understand the roles of sex steroid hormones and their associated receptors in the pathophysiology of AD. We review these dimensions, emphasizing the potential of estrogen receptors (ERs) to reveal mitochondrial functions in the search for further research and therapeutic strategies for AD pharmacotherapy. Understanding and addressing the intricate interactions of mitochondrial dysfunction and ERs potentially pave the way for more effective approaches to AD therapy.

Drug Development for Alzheimer's and Parkinson's Disease: Where Do We Go Now?

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases' progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop new, disease-modifying drugs to treat AD and PD, describing as representative examples some advances in the development of drug candidates targeting oxidative stress and adenosine A2A receptors.

Novel drug discovery: Advancing Alzheimer's therapy through machine learning and network pharmacology

Alzheimer's disease (AD), marked by tau tangles and amyloid-beta plaques, leads to cognitive decline. Despite extensive research, its complex etiology remains elusive, necessitating new treatments. This study utilized machine learning (ML) to analyze compounds with neuroprotective potential. This approach exposed the disease's complexity and identified important proteins, namely MTOR and BCL2, as central to the pathogenic network of AD. MTOR regulates neuronal autophagy and survival, whereas BCL2 regulates apoptosis, both of which are disrupted in AD. The identified compounds, including Armepavine, Oprea1_264702,1-cyclopropyl-7-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid,(2S)-4′-Hydroxy-5,7,3′-trimethoxyflavan,Oprea1_130514,Sativanone,5-hydroxy-7,8-dimethoxyflavanone,7,4′-Dihydroxy-8,3′-dimethoxyflavanone,N,1-dicyclopropyl-6,Difluoro-Methoxy-Gatifloxacin,6,8-difluoro-1-(2-fluoroethyl),1-ethyl-6-fluoro-7-(4-methylpiperidin-1-yl),Avicenol C, demonstrated potential modulatory effects on these proteins. The potential for synergistic effects of these drugs in treating AD has been revealed via network pharmacology. By targeting numerous proteins at once, these chemicals may provide a more comprehensive therapeutic approach, addressing many aspects of AD's complex pathophysiology. A Molecular docking, dynamic simulation, and Principle Component Analysis have confirmed these drugs' efficacy by establishing substantial binding affinities and interactions with important proteins such as MTOR and BCL2. This evidence implies that various compounds may interact within the AD pathological framework, providing a sophisticated and multifaceted therapy strategy. In conclusion, our study establishes a solid foundation for the use of these drugs in AD therapy. Thus current study highlights the possibility of multi-targeted, synergistic therapeutic approaches in addressing the complex pathophysiology of AD by integrating machine learning, network pharmacology, and molecular docking simulations. This holistic technique not only advances drug development but also opens up new avenues for developing more effective treatments for this difficult and widespread disease.

Plasma pTau181 and pTau217 predict asymptomatic amyloid accumulation equally well as amyloid PET.

The dynamic phase of preclinical Alzheimer's disease, as characterized by accumulating cortical amyloid-β, is a window of opportunity for amyloid-β-lowering therapies to have greater efficacy. Biomarkers that accurately predict amyloid-β accumulation may be of critical importance for participant inclusion in secondary prevention trials and thus enhance development of early Alzheimer's disease therapies. We compared the abilities of baseline plasma pTau181, pTau217 and amyloid-β PET load to predict future amyloid-β accumulation in asymptomatic elderly. In this longitudinal cohort study, baseline plasma pTau181 and pTau217 were quantified using single molecule array assays in cognitively unimpaired elderly selected from the community-recruited F-PACK cohort based on the availability of baseline plasma samples and longitudinal amyloid-β PET data (median time interval = 5 years, range 2-10 years). The predictive abilities of pTau181, pTau217 and PET-based amyloid-β measures for PET-based amyloid-β accumulation were investigated using receiver operating characteristic analyses, correlations and stepwise regression analyses. We included 75 F-PACK subjects (mean age = 70 years, 48% female), of which 16 were classified as amyloid-β accumulators [median (interquartile range) Centiloid rate of change = 3.42 (1.60) Centiloids/year). Plasma pTau181 [area under the curve (95% confidence interval) = 0.72 (0.59-0.86)] distinguished amyloid-β accumulators from non-accumulators with similar accuracy as pTau217 [area under the curve (95% confidence interval) = 0.75 (0.62-0.88) and amyloid-β PET [area under the curve (95% confidence interval) = 0.72 (0.56-0.87)]. Plasma pTau181 and pTau217 strongly correlated with each other (r = 0.93, Pfalse discovery rate < 0.001) and, together with amyloid-β PET, similarly correlated with amyloid-β rate of change (r pTau181 = 0.33, r pTau217 = 0.36, r amyloid-β PET = 0.35, all Pfalse discovery rate ≤ 0.01). Addition of plasma pTau181, plasma pTau217 or amyloid-β PET to a linear demographic model including age, sex and APOE-ε4 carriership similarly improved the prediction of amyloid-β accumulation (ΔAkaike information criterion ≤ 4.1). In a multimodal biomarker model including all three biomarkers, each biomarker lost their individual predictive ability. These findings indicate that plasma pTau181, plasma pTau217 and amyloid-β PET convey overlapping information and therefore predict the dynamic phase of asymptomatic amyloid-β accumulation with comparable performances. In clinical trial recruitment, confirmatory PET scans following blood-based prescreening might thus not provide additional value for detecting participants in these early disease stages who are destined to accumulate cortical amyloid-β. Given the moderate performances, future studies should investigate whether integrating plasma pTau species with other factors can improve performance and thus enhance clinical and research utility.

In Vitro and Molecular Docking Evaluation of the Anticholinesterase and Antidiabetic Effects of Compounds from Terminalia macroptera Guill. & Perr. (Combretaceae).

Alzheimer's disease (AD) and diabetes are non-communicable diseases with global impacts. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are suitable therapies for AD, while α-amylase and α-glucosidase inhibitors are employed as antidiabetic agents. Compounds were isolated from the medicinal plant Terminalia macroptera and evaluated for their AChE, BChE, α-amylase, and α-glucosidase inhibitions. From 1H and 13C NMR data, the compounds were identified as 3,3'-di-O-methyl ellagic acid (1), 3,3',4'-tri-O-methyl ellagic acid-4-O-β-D-xylopyranoside (2), 3,3',4'-tri-O-methyl ellagic acid-4-O-β-D-glucopyranoside (3), 3,3'-di-O-methyl ellagic acid-4-O-β-D-glucopyranoside (4), myricetin-3-O-rhamnoside (5), shikimic acid (6), arjungenin (7), terminolic acid (8), 24-deoxysericoside (9), arjunglucoside I (10), and chebuloside II (11). The derivatives of ellagic acid (1-4) showed moderate to good inhibition of cholinesterases, with the most potent being 3,3'-di-O-methyl ellagic acid, with IC50 values of 46.77 ± 0.90 µg/mL and 50.48 ± 1.10 µg/mL against AChE and BChE, respectively. The compounds exhibited potential inhibition of α-amylase and α-glucosidase, especially the phenolic compounds (1-5). Myricetin-3-O-rhamnoside had the highest α-amylase inhibition with an IC50 value of 65.17 ± 0.43 µg/mL compared to acarbose with an IC50 value of 32.25 ± 0.36 µg/mL. Two compounds, 3,3'-di-O-methyl ellagic acid (IC50 = 74.18 ± 0.29 µg/mL) and myricetin-3-O-rhamnoside (IC50 = 69.02 ± 0.65 µg/mL), were more active than the standard acarbose (IC50 = 87.70 ± 0.68 µg/mL) in the α-glucosidase assay. For α-glucosidase and α-amylase, the molecular docking results for 1-11 reveal that these compounds may fit well into the binding sites of the target enzymes, establishing stable complexes with negative binding energies in the range of -4.03 to -10.20 kcalmol-1. Though not all the compounds showed binding affinities with cholinesterases, some had negative binding energies, indicating that the inhibition was thermodynamically favorable.

Integrated bioinformatics, network pharmacology, molecular docking, and molecular dynamics simulation to explore the potential pharmacological mechanism of Erigeron breviscapus (Vant.) Hand-Mazz regulating ferroptosis for the treatment of Alzheimer's disease

Ferroptosis plays a role in Alzheimer's disease (AD) development. Erigeron breviscapus (Vant.) Hand-Mazz (EBHM) shows promising effects in treating cognitive impairment-related diseases. However, the mechanisms by which EBHM regulates ferroptosis in AD treatment are not fully understood. This study used bioinformatics, network pharmacology, molecular docking, and molecular dynamics simulation to explore how EBHM regulates ferroptosis in AD treatment. The results identified four key genes—HSPA8, GSK3B, CTSB, and YWHAG—that are involved in this regulation, and constructed a multigene diagnostic model for AD. The model demonstrated moderate accuracy (area under the curve [AUC] = 0.636) in distinguishing AD from non-demented (ND) and was further validated with external datasets showing good diagnostic capabilities (AUC values of 0.898, 0.889, 0.746, and 0.712). Additionally, CIBERSORT analysis revealed a significant correlation between immune cell infiltration and these four genes, highlighting their potential role in AD immunity. Molecular docking studies indicated that 3,4,5-tricaffeoylquinic acid (TCQA) had the highest binding affinity to HSPA8, suggesting that TCQA and HSPA8 are key components and core targets in EBHM's regulation of ferroptosis in AD therapy. Molecular dynamics simulations confirmed the stability and strong binding affinity of the TCQA-HSPA8 complex. These findings enhance our understanding of the molecular mechanisms underlying ferroptosis regulation by EBHM for the treatment of AD and may offer new avenues for developing effective AD treatments.

Exploring Curcumin-Loaded Lipid-Based Nanomedicine as Efficient Targeted Therapy for Alzheimer's Diseases.

Alzheimer's disease (AD) is a neurological condition currently with 47 million people suffering from it globally. AD might have many reasons such as genetic issues, environmental factors, and Aβ accumulation, which is the biomarker of the disease. Since the primary reason is unknown, there is no targeted treatment at the moment, but ongoing research aims to slow its progression by managing amyloid-beta peptide production rather than symptomatic improvement. Since phytochemicals have been demonstrated to possess antioxidant, anti-inflammatory, and neuroprotective properties, they may target multiple pathological factors and can reduce the risk of the disease. Curcumin, as a phytochemical found in turmeric known for its antioxidant, free radical scavenging properties, and as an antiamyloid in treating AD, has come under investigation. Although its low bioavailability limits its efficacy, a prominent drug delivery system (DDS) is desired to overcome it. Hence, the potency of lipid-based nanoparticles encapsulating curcumin (LNPs-CUR) is considered in this study as a promising DDS. In vivo studies in animal models indicate LNPs-CUR effectively slow amyloid plaque formation, leading to cognitive enhancement and reduced toxicity compared to free CUR. However, a deeper understanding of CUR's pharmacokinetics and safety profile is crucial before LNPs-CUR can be considered as a medicine. Future investigations may explore the combination of NPs with other therapeutic agents to increase their efficacy in AD cases. This review provides the current position of CUR in the AD therapy paradigm, the DDS suggestions for CUR, and the previous research from the point of analytical view focused on the advantages and challenges.

Identifying potential Alzheimer's disease therapeutics through GSK-3β inhibition: A molecular docking and dynamics approach

Emerging as a promising drug target for Alzheimer's disease (AD) therapy, glycogen synthase kinase 3β (GSK-3β) has garnered attention. This study sought to rigorously scrutinize a compendium of natural compounds retrieved from the ZINC database through pharmacodynamic experiments, employing a 1 H-indazole-3-carboxamide (INDZ) scaffold, to identify compounds capable of inhibiting the GSK-3β protein. Utilizing a multi-step approach, the study involved pharmacophore analysis, followed by molecular docking to select five promising ligands for further investigation. Subsequently, ESMACS simulations were employed to assess the stability of the ligand-protein interactions. Evaluation of the binding modes and free energy of the ligands revealed that five compounds (2a-6a) exhibited crucial interactions with the active site residues. Furthermore, various methodologies, including hydrogen bond and clustering analyses, were utilized to ascertain their inhibitory potential and elucidate the factors contributing to ligand binding in the protein's active site. The findings from MMPBSA/GBSA analysis indicated that these five selected small molecules closely approached the IC50 value of the reference ligand (OH8), yielding energy values of −34.85, −32.58, −31.71, and −30.39 kcal/mol, respectively. Additionally, an assessment of the interactions using hydrogen bond and dynamic analyses delineated the effective binding of the ligands with the binding pockets in the protein. Through computational analysis, we obtained valuable insights into the molecular mechanisms of GSK-3β, aiding in the development of more potent inhibitors.

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough.

In females, Alzheimer's disease (AD) incidences increases as compared to males due to estrogen deficiency after menopause. Estrogen therapy is the mainstay therapy for menopause and associated complications. Estrogen, a hormone with multifaceted physiological functions, has been implicated in AD pathophysiology. Estrogen plays a crucial role in amyloid precursor protein (APP) processing and overall neuronal health by regulating various factors such as brain-derived neurotrophic factor (BDNF), intracellular calcium signalling, death domain-associated protein (Daxx) translocation, glutamatergic excitotoxicity, Voltage-Dependent Anion Channel, Insulin-Like Growth Factor 1 Receptor, estrogen-metabolising enzymes and apolipoprotein E (ApoE) protein polymorphisms. All these factors impact the physiology of postmenopausal women. Estrogen replacement therapies play an important treatment strategy to prevent AD after menopause. However, use of these therapies may lead to increased risks of breast cancer, venous thromboembolism and cardiovascular disease. Various therapeutic approaches have been used to mitigate the effects of estrogen on AD. These include hormone replacement therapy, Selective Estrogen Receptor Modulators (SERMs), Estrogen Receptor Beta (ERβ)-Selective Agonists, Transdermal Estrogen Delivery, Localised Estrogen Delivery, Combination Therapies, Estrogen Metabolism Modulation and Alternative Estrogenic Compounds like genistein from soy, a notable phytoestrogen from plant sources. However, mechanism via which these approaches modulate AD in postmenopausal women has not been explained earlier thoroughly. Present review will enlighten all the molecular mechanisms of estrogen and estrogen replacement therapies in AD. Along-with this, the association between estrogen, estrogen-metabolising enzymes and ApoE protein polymorphisms will also be discussed in postmenopausal AD.

Advances in Therapeutics to Alleviate Cognitive Decline and Neuropsychiatric Symptoms of Alzheimer's Disease.

Dementia exists as a 'progressive clinical syndrome of deteriorating mental function significant enough to interfere with activities of daily living', with the most prevalent type of dementia being Alzheimer's disease (AD), accounting for about 80% of diagnosed cases. AD is associated with an increased risk of comorbidity with other clinical conditions such as hypertension, diabetes, and neuropsychiatric symptoms (NPS) including, agitation, anxiety, and depression as well as increased mortality in late life. For example, up to 70% of patients diagnosed with AD are affected by anxiety. As aging is the major risk factor for AD, this represents a huge global burden in ageing populations. Over the last 10 years, significant efforts have been made to recognize the complexity of AD and understand the aetiology and pathophysiology of the disease as well as biomarkers for early detection. Yet, earlier treatment options, including acetylcholinesterase inhibitors and glutamate receptor regulators, have been limited as they work by targeting the symptoms, with only the more recent FDA-approved drugs being designed to target amyloid-β protein with the aim of slowing down the progression of the disease. However, these drugs may only help temporarily, cannot stop or reverse the disease, and do not act by reducing NPS associated with AD. The first-line treatment options for the management of NPS are selective serotonin reuptake inhibitors/selective noradrenaline reuptake inhibitors (SSRIs/SNRIs) targeting the monoaminergic system; however, they are not rational drug choices for the management of anxiety disorders since the GABAergic system has a prominent role in their development. Considering the overall treatment failures and side effects of currently available medication, there is an unmet clinical need for rationally designed therapies for anxiety disorders associated with AD. In this review, we summarize the current status of the therapy of AD and aim to highlight novel angles for future drug therapy in our ongoing efforts to alleviate the cognitive deficits and NPS associated with this devastating disease.

Brain-targeted Tet-1 peptide-PLGA nanoparticles for berberine delivery against STZ-induced Alzheimer’s disease in a rat model: Alleviation of hippocampal synaptic dysfunction, Tau pathology, and amyloidogenesis

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that causes severe dementia and memory loss. Surface functionalized poly(lactic-co-glycolic acid) nanoparticles have been reported for better transport through the blood–brain barrier for AD therapy. This study investigated the improved therapeutic potential of berberine-loaded poly(lactic-co-glycolic acid)/Tet-1 peptide nanoparticles (BBR/PLGA-Tet NPs) in a rat model of sporadic AD. BBR was loaded into the PLGA-Tet conjugate. BBR/PLGA-Tet NPs were physicochemically and morphologically characterized. AD was achieved by bilateral intracerebroventricular (ICV) injection of streptozotocin (STZ). Cognitively impaired rats were divided into STZ, STZ + BBR, STZ + BBR/PLGA-Tet NPs, and STZ + PLGA-Tet NPs groups. Cognitive improvement was assessed using the Morris Water Maze. Brain acetylcholinesterase and monoamine oxidase activities, amyloid β42 (Aβ42), and brain glycemic markers were estimated. Further, hippocampal neuroplasticity (BDNF, pCREB, and pERK/ERK), Tau pathogenesis (pGSK3β/GSK3β, Cdk5, and pTau), inflammatory, and apoptotic markers were evaluated. Finally, histopathological changes were monitored. ICV-STZ injection produces AD-like pathologies evidenced by Aβ42 deposition, Tau hyperphosphorylation, impaired insulin signaling and neuroplasticity, and neuroinflammation. BBR and BBR/PLGA-Tet NPs attenuated STZ-induced hippocampal damage, enhanced cognitive performance, and reduced Aβ42, Tau phosphorylation, and proinflammatory responses. BBR/PLGA-Tet NPs restored neuroplasticity, cholinergic, and monoaminergic function, which are critical for cognition and brain function. BBR/PLGA-Tet NPs may have superior therapeutic potential in alleviating sporadic AD than free BBR due to their bioavailability, absorption, and brain uptake.

Performance Comparison of Machine Learning Methods in Discovery of BACE-1 Inhibitors in Alzheimer's Disease Therapy

Performance Comparison of Machine Learning Methods in Discovery of BACE-1 Inhibitors in Alzheimer's Disease Therapy

Assessment of Preanalytical Cerebrospinal Fluid Handling and Storage Factors on Measurement of Aβ1-42, Aβ1-40, and pTau181 Using an Automated Chemiluminescent Platform.

Standardizing cerebrospinal fluid (CSF) laboratory protocols will improve the reliability and availability of clinical biomarker testing required for prescription of novel Alzheimer disease (AD) therapies. This study evaluated several preanalytical handling and storage factors common to β-amyloid1-42 (Aβ1-42), β-amyloid1-40 (Aβ1-40), and phosphorylated tau (pTau181) concentrations including storage at different temperatures, extended cap contact, various mixing methods, and multiple freeze-thaw cycles. Aβ1-42, Aβ1-40, and pTau181 concentrations were measured using LUMIPULSE G1200 automated assays. Samples were collected in polypropylene tubes of various volumes. Sample cap-contact was evaluated by storing samples in upright and inverted positions at either 4°C for 1 week or -80°C for 1 month. To assess mixing methods, samples were freeze-thawed and mixed by inversion, vortex, horizontal roller, or unmixed prior to assay sampling. The impact of successive freeze-thaw cycles was assessed through freezing, thawing, and analyzing CSF samples. Short-term storage at 4°C did not affect Aβ1-42, Aβ1-40, or pTau181 measurements in any tube type. Tube cap contact affected Aβ1-42 in 2.5 mL tubes and pTau181 levels in 10 mL tubes. No difference was observed between mixing methods. After 4 freeze-thaw cycles, Aβ1-42 significantly decreased but Aβ1-40 remained unchanged. Utilizing the Aβ1-42/Aβ1-40 ratio, Aβ1-42 values normalized, maintaining ratio values within ±5% of baseline measurements. Storage of CSF at 4°C for 1 week or -80°C for 1 month did not significantly affect Aβ1-42, Aβ1-40, pTau181, or associated ratio measurements. Tube cap-contact impacted pTau181 and pTau181/Aβ1-42 values in larger tubes. Mixing methods are equivalent. The Aβ1-42/Aβ1-40 ratio compensates for freeze-thaw variability up to 4 cycles.

The microtubule-dynamin binding inhibitor peptide PHDP5 rescues spatial learning and memory deficits in Alzheimer’s disease model mice

Dynamin is a microtubule (MT) binding protein playing a key role in vesicle endocytosis. In a brain slice model, tau loaded in presynaptic terminals assembles MTs, thereby impairing vesicle endocytosis via depletion of cytosolic dynamin. The peptide PHDP5, derived from the pleckstrin homology domain of dynamin 1, inhibits dynamin-MT interaction and rescues endocytosis and synaptic transmission impaired by tau when co-loaded in presynaptic terminals. We tested whether in vivo administration of PHDP5 could rescue the learning/memory deficits observed in Alzheimer’s disease (AD) model mice. A modified PHDP5 incorporating a cell-penetrating peptide (CPP) and a FITC fluorescent marker was delivered intranasally to Tau609 transgenic (Tg) and 3xTg-AD mice. FITC-positive puncta were observed in the hippocampus of mice infused with PHDP5 or scrambled (SPHDP5) peptide, but not in saline-infused controls. In the Morris water maze (MWM) test for spatial learning/memory, AD model mice treated with FITC-PHDP5-CPP showed prominent improvements in learning and memory, performing close to the level of saline-infused WT mice control. In contrast, mice treated with a scrambled construct (FITC-SPHDP5-CPP) showed no significant improvement. We conclude that PHDP5 can be a candidate for human AD therapy.

The Neuroprotective and Therapeutic Effects of Medicinal Plants and Natural Products against Aluminium Chloride-Induced Alzheimer’s Disease: Recent Update

Alzheimer's disease currently affects more than 35 million individuals worldwide. Aluminium has been implicated in the pathogenesis of various cognitive disorders. Meanwhile, aluminium chloride (AlCl3) has a significant impact on the progression of neurodegenerative diseases including Alzheimer's disease. The majority of Alzheimer's disease medications now on the market are cholinesterase inhibitors. However, the effectiveness of these drugs is limited because they can't totally arrest the progression of the disease. The utilization of medicinal plants and natural products may present excellent prospective options for Alzheimer's disease prevention and therapy. This study summarized medicinal plants and natural products for the prevention and treatment of AlCl3-induced Alzheimer’s disease as an alternative therapy using published data in the literature from the years 2021-2023. The medicinal plants and natural products help to reduce Alzheimer’s disease pathogenesis by controlling different pathways and could be used as a therapeutic agent against the symptoms. The majority of the medicinal plants and natural products discussed in this review have been shown to have neuroprotective, antioxidant, anti-amyloid, anti-inflammatory, anticholinesterase, anti-apoptotic, and therapeutic actions. Therefore, medicinal plants and natural products may offer neuroprotective and therapeutic effects in the treatment of Alzheimer’s disease.

Counteracting Alzheimer's disease via normalizing neurovascular unit with a self-regulated multi-functional nano-modulator

The neurovascular unit (NVU) is highly responsible for cerebral homeostasis and its dysfunction emerges as a critical contributor to Alzheimer's disease (AD) pathology. Hence, rescuing NVU dysfunction might be a viable approach to AD treatments. Here, we fabricated a self-regulated muti-functional nano-modulator (siR/PIO@RP) that can intelligently navigate to damaged blood-brain barrier and release therapeutical cargoes for synergetic AD therapy. The resulting siR/PIO@RP enables self-regulation of its distribution in accordance with the physio/pathological state (low/high RAGE expression) of the target site via a feedback loop. siR/PIO@RP is capable of performing intricate tasks and goes beyond the capabilities of single-target therapeutic agents utilized in AD therapy, such as reducing cerebral Aβ load, relieving neuroinflammation, and alleviating the dysfunction of NVU. Overall, the current study provides proof of concept that normalizing NVU holds promise as a means of alleviating AD symptoms.