Potential For Treatment Of Alzheimer's Disease Research Articles

Identification of Uncaria rhynchophylla in the Potential Treatment of Alzheimer's Disease by Integrating Virtual Screening and In Vitro Validation.

Uncaria rhynchophylla (Gouteng in Chinese, GT) is the main medicine in many traditional recipes in China. It is commonly used to alleviate central nervous system (CNS) disorders, although its mechanism in Alzheimer's disease is still unknown. This study was designed to predict and validate the underlying mechanism in AD treatment, thus illustrating the biological mechanisms of GT in treating AD. In this study, a PPI network was constructed, KEGG analysis and GO analysis were performed, and an "active ingredient-target-pathway" network for the treatment of Alzheimer's disease was constructed. The active ingredients of GT were screened out, and the key targets were performed by molecular docking. UHPLC-Q-Exactive Orbitrap MS was used to screen the main active ingredients and was compared with the network pharmacology results, which verified that GT did contain the above ingredients. A total of targets were found to be significantly bound up with tau, Aβ, or Aβ and tau through the network pharmacology study. Three SH-SY5Y cell models induced by okadaic acid (OA), Na2S2O4, and H2O2 were established for in vitro validation. We first found that GT can reverse the increase in the hyperphosphorylation of tau induced by OA to some extent, protecting against ROS damage. Moreover, the results also indicated that GT has significant neuroprotective effects. This study provides a basis for studying the potential mechanisms of GT in the treatment of AD.

Discovery of novel multifunctional ligands targeting GABA transporters, butyrylcholinesterase, β-secretase, and amyloid β aggregation as potential treatment of Alzheimer's disease

Alzheimer's disease (AD) is a global health problem in the medical sector that will increase over time. The limited treatment of AD leads to the search for a new clinical candidate. Considering the multifactorial nature of AD, a strategy targeting number of regulatory proteins involved in the development of the disease is an effective approach. Here, we present a discovery of new multi-target-directed ligands (MTDLs), purposely designed as GABA transporter (GAT) inhibitors, that successfully provide the inhibitory activity against butyrylcholinesterase (BuChE), β-secretase (BACE1), amyloid β aggregation and calcium channel blockade activity. The selected GAT inhibitors, 19c and 22a – N-benzylamide derivatives of 4-aminobutyric acid, displayed the most prominent multifunctional profile. Compound 19c (mGAT1 IC50 = 10 μM, mGAT4 IC50 = 12 μM and BuChE IC50 = 559 nM) possessed the highest hBACE1 and Aβ40 aggregation inhibitory activity (IC50 = 1.57 μM and 99 % at 10 μM, respectively). Additionally, it showed a decrease in both the elongation and nucleation constants of the amyloid aggregation process. In contrast compound 22a represented the highest activity and a mixed-type of eqBuChE inhibition (IC50 = 173 nM) with hBACE1 (IC50 = 9.42 μM), Aβ aggregation (79 % at 10 μM) and mGATs (mGAT1 IC50 = 30 μM, mGAT4 IC50 = 25 μM) inhibitory activity. Performed molecular docking studies described the mode of interactions with GATs and enzymatic targets. In ADMET in vitro studies both compounds showed acceptable metabolic stability and low neurotoxicity. Successfully, compounds 19c and 22a at the dose of 30 mg/kg possessed statistically significant antiamnesic properties in a mouse model of amnesia caused by scopolamine and assessed in the novel object recognition (NOR) task or the passive avoidance (PA) task.

2-Oxoquinoline-based-thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors.

Alzheimer's disease (AD) presents a multifactorial neurological disorder with multiple enzyme involvement in its onset. Conventional monotherapies fall short in providing long-term relief, necessitating the exploration of alternative multitargeting approaches to address the complexity of AD. Therefore, the design, synthesis, and in vitro and in silico evaluation of 2-oxoquinoline-based thiosemicarbazones 9a-r as multipotent analogs, able to simultaneously inhibit the cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of AD, are reported. In the in vitro experimental evaluation of MAO and ChE inhibition, all tested compounds demonstrated remarkable potency exhibiting nonselective inhibition of both MAO-A and MAO-B, and selective inhibition of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE), with 9d, 9j, and 9m evolving as lead compounds for MAO-A, MAO-B, and AChE, displaying IC50 values of 0.35 ± 0.92, 0.50 ± 0.02, and 0.25 ± 0.13 μM, respectively. Moreover, the kinetic studies revealed that all tested compounds inhibited all three enzymes through a competitive mode of inhibition. Furthermore, the molecular docking studies of the most active compounds revealed several crucial interactions, particularly hydrogen bonding interactions. These interactions were observed between the nitrogen and sulfur atoms of thiosemicarbazone and the nitrogen and oxygen atoms of the quinoline ring with various amino acids, suggesting the strong interactions of these compounds with the enzymes.

Transcranial Magnetic Stimulation (rTMS) on the Precuneus in Alzheimer's Disease: A Literature Review.

The current literature review aimed to evaluate the effectiveness of rTMS on the precuneus as a potential treatment for Alzheimer's disease (AD). Although the number of studies specifically targeting the precuneus is limited, the results from this review suggest the potential benefits of this approach. Future studies should focus on exploring the long-term effects of rTMS on the precuneus in Alzheimer's disease patients, as well as determining the optimal stimulation parameters and protocols for this population. Additionally, investigating the effects of rTMS on the precuneus in combination with other brain regions implicated in AD may provide valuable insights into the development of effective treatment for this debilitating neurodegenerative disorder.

Functionalized curcumin/ginsenoside Rb1 dual-loaded liposomes: Targeting the blood-brain barrier and improving pathological features associated in APP/PS-1 mice

The brain is a crucial organ in the body, shielded from external substances by the blood-brain barrier (BBB). However, this barrier also impedes the treatment of numerous brain diseases, including Alzheimer's disease (AD). Therefore, Mannose (MAN)-modified co-loaded Curcumin (CUR) and ginsenoside Rb1 (Rb1) liposomes were prepared to address the above situation. Glucose transporter 1 (GLUT 1) is a transmembrane glycoprotein overexpressed on the BBB. MAN is specifically recognized and efficiently transported by GULT1. In addition, the neuroprotective compounds CUR and Rb1 are co-loaded into liposomes, which can penetrate the blood-brain barrier (BBB) and potentially be used to treat AD. MAN-CUR/Rb1 liposomes were prepared using a thin film hydration method combined with an ammonium sulfate gradient. The resulting liposomes had a round shape and a diameter of 110 nm and showed good stability. Results from cellular uptake experiments, in vitro BBB models, and in vivo imaging in mice confirmed that MAN-CUR/Rb1 liposomes not only crossed the BBB but also accumulate in N2a cells/bEnd.3 cells. Furthermore, in vivo animal experiments showed that MAN-CUR/Rb1 liposomes improved AD-related pathological features, inhibited oxidative stress and neuroinflammation, and enhanced learning and cognition in APP/PS-1 mice. Based on these findings, MAN-CUR/Rb1 liposomes hold promise as a potential treatment for AD.

QSAR and DFT Studies of Some Tacrine-Hydroxamate Derivatives as Inhibitors of Cholinesterase (AChEs) in the Treatment of Alzheimer's Disease

Introduction: This work was devoted to an in silico investigation conducted on twenty-eight Tacrine-hydroxamate derivatives as a potential treatment for Alzheimer’s disease using DFT and QSAR modeling techniques. Methods: The data set was randomly partitioned into a training set (22 compounds) and a test set (6 compounds). Then, fourteen models were built and were used to compute the predicted pIC50 of compounds belonging to the test set. Results: All built models were individually validated using both internal and external validation methods, including the Y-Randomization test and Golbraikh and Tropsha's model acceptance criteria. Then, one model was selected for its higher R², R²test, and Q²cv values (R² = 0.768, R²adj = 0.713, MSE = 0.304, R²test=0.973, Q²cv = 0.615). From these outcomes, the activity of the studied compounds toward the main protease of Cholinesterase (AChEs) seems to be influenced by 4 descriptors, i.e., the total dipole moment of the molecule (μ), number of rotatable bonds (RB), molecular topology radius (MTR) and molecular topology polar surface area (MTPSA). The effect of these descriptors on the activity was studied, in particular, the increase in the total dipole moment and the topological radius of the molecule and the reduction of the rotatable bond and topology polar surface area increase the activity. Conclusion: Some newly designed compounds with higher AChEs inhibitory activity have been designed based on the best-proposed QSAR model. In addition, ADMET pharmacokinetic properties were carried out for the proposed compounds, the toxicity results indicate that 7 molecules are nontoxic.

Shifting the balance: soluble ADAM10 as a potential treatment for Alzheimer's disease.

Accumulation of amyloid β in the brain is regarded as a key initiator of Alzheimer's disease pathology. Processing of the amyloid precursor protein (APP) in the amyloidogenic pathway yields neurotoxic amyloid β species. In the non-amyloidogenic pathway, APP is processed by membrane-bound ADAM10, the main α-secretase in the nervous system. Here we present a new enzymatic approach for the potential treatment of Alzheimer's disease using a soluble form of ADAM10. The ability of the soluble ADAM10 to shed overexpressed and endogenous APP was determined with an ADAM10 knockout cell line and a human neuroblastoma cell line, respectively. We further examined its effect on amyloid β aggregation by thioflavin T fluorescence, HPLC, and confocal microscopy. Using N-terminal and C-terminal enrichment proteomic approaches, we identified soluble ADAM10 substrates. Finally, a truncated soluble ADAM10, based on the catalytic domain, was expressed in Escherichia coli for the first time, and its activity was evaluated. The soluble enzyme hydrolyzes APP and releases the neuroprotective soluble APPα when exogenously added to cell cultures. The soluble ADAM10 inhibits the formation and aggregation of characteristic amyloid β extracellular neuronal aggregates. The proteomic investigation identified new and verified known substrates, such as VGF and N-cadherin, respectively. The truncated variant also exhibited α-secretase capacity as shown with a specific ADAM10 fluorescent substrate in addition to shedding overexpressed and endogenous APP. Our in vitro study demonstrates that exogenous treatment with a soluble variant of ADAM10 would shift the balance toward the non-amyloidogenic pathway, thus utilizing its natural neuroprotective effect and inhibiting the main neurotoxic amyloid β species. The potential of such a treatment for Alzheimer's disease needs to be further evaluated in vivo.

Dimethyl Fumarate as Potential Treatment for Alzheimer's Disease: Rationale and Clinical Trial Design.

Alzheimer's Disease (AD) is a debilitating disease that leads to severe cognitive impairment and functional decline. The role of tau hyperphosphorylation and amyloid plaque deposition in the pathophysiology of AD has been well described; however, neuroinflammation and oxidative stress related to sustained microglial activation is thought to play a significant role in the disease process as well. NRF-2 has been identified in modulating the effects of inflammation and oxidative stress in AD. Activation of NRF-2 leads to an increased production of antioxidant enzymes, including heme oxygenase, which has been shown to have protective effects in neurodegenerative disorders such as AD. Dimethyl fumarate and diroximel fumarate (DMF) have been approved for the use in relapsing-remitting multiple sclerosis. Research indicates that they can modulate the effects of neuroinflammation and oxidative stress through the NRF-2 pathway, and as such, could serve as a potential therapeutic option in AD. We propose a clinical trial design that could be used to assess DMF as a treatment option for AD.

Carbamate JNK3 Inhibitors Show Promise as Effective Treatments for Alzheimer's Disease: In Vivo Studies on Mouse Models.

We have been developing new inhibitors for c-Jun N-terminal kinase 3 (JNK3) as a potential treatment for Alzheimer's disease (AD). We identified potential JNK3 inhibitors through pharmacodynamic optimization studies, including benzimidazole compounds 2 and 3, but their unreliable pharmacokinetic properties led us to develop carbamate inhibitors 2h and 3h. In vitro studies validated carbamate inhibitors 2h and 3h as potent and highly selective JNK3 inhibitors with favorable pharmacokinetic profiles. Oral administration of 2h and 3h to both APP/PS1 and 3xTg AD mouse models improved cognitive function, indicating their potential as effective treatments for Alzheimer's disease. Carbamate JNK3 inhibitor 3h, in particular, restored cognitive function to near-normal levels in the 3xTg mice model of AD and led to pTau reduction in the hippocampal tissues of 3xTg-AD mice during in vivo behavioral evaluations. We intend to further develop these carbamate JNK3 inhibitors in preclinical studies as a potential first-in-class treatment for AD.

Microorganism-Derived Molecules as Enzyme Inhibitors to Target Alzheimer's Diseases Pathways.

Alzheimer's disease (AD) is the most common form of dementia. It increases the risk of other serious diseases and causes a huge impact on individuals, families, and socioeconomics. AD is a complex multifactorial disease, and current pharmacological therapies are largely based on the inhibition of enzymes involved in the pathogenesis of AD. Natural enzyme inhibitors are the potential sources for targeting AD treatment and are mainly collected from plants, marine organisms, or microorganisms. In particular, microbial sources have many advantages compared to other sources. While several reviews on AD have been reported, most of these previous reviews focused on presenting and discussing the general theory of AD or overviewing enzyme inhibitors from various sources, such as chemical synthesis, plants, and marine organisms, while only a few reviews regarding microbial sources of enzyme inhibitors against AD are available. Currently, multi-targeted drug investigation is a new trend for the potential treatment of AD. However, there is no review that has comprehensively discussed the various kinds of enzyme inhibitors from the microbial source. This review extensively addresses the above-mentioned aspect and simultaneously updates and provides a more comprehensive view of the enzyme targets involved in the pathogenesis of AD. The emerging trend of using in silico studies to discover drugs concerning AD inhibitors from microorganisms and perspectives for further experimental studies are also covered here.

Synthesis and anti-Alzheimer potential of novel α-amino phosphonate derivatives and probing their molecular interaction mechanism with acetylcholinesterase

Pleiotropic interference may be a prerequisite for the efficient limitation of the progression of multi-factorial diseases such as Alzheimer's disease (AD). Concept of designing the single chemical entity acting on two or more targets of interest has potential advantage in AD therapy. In line with this, rational design and synthesis of frame work of hybrids bearing 2,3-disubstituted quinazolinone, vanillin and α-amino phosphonate scaffolds (5a─v) were carried out. A congeneric set of twenty-two synthetic derivatives (5a─v) were evaluated for their cholinesterase inhibitory, antioxidant, DNA nicking, DNA protection, neuroprotective and Aβ aggregation modulatory activities. Amongst tested activities, the most significant and worth mentioning is that the analogues 5m, 5p and 5u were found to be the most potent, selective, and mixed type inhibitors of EeAChE with IC50 values of 0.296 ± 0.030, 0.289 ± 0.027, and 0.306 ± 0.028 μM, respectively. Further, the biophysical approaches indicated that the compounds 5m, 5p, and 5u have a strong binding affinity towards AChE. Kinetic and Molecular docking studies have revealed that the most active congeners were well oriented in the AChE active site by interacting with both catalytic active site (CAS) and peripheral anionic site (PAS). A few parameters derived from molecular dynamics (MD) simulation trajectories emphasized the stability of AChE-5p and 5m complexes throughout the 100 ns simulations, and the local conformational changes of the residues of AChE validate the stability of AChE-5p and 5m complexes. Further, these derivatives significantly impacted ABTS radical scavenging capacities and maximal DNA protection activity. Importantly, Thioflavin T (ThT) assay and FE-SEM study demonstrated compounds 5m, 5p and 5u as effective Aβ1−42 fibril modulators at molecular level by the formation of micro size co-assembled mature structures, thus efficiently abolishing the cytotoxicity of Aβ1–42. Finally, these active compounds are determined to be non-toxic and highly neuroprotective against H2O2-induced cell death in SK-N-SH cell lines. Furthermore, in silico ADMET prediction studies have revealed that the targeted analogues satisfied most of the characteristics of CNS acting drugs. These multi-functional efficacies indicated worthiness of these α-amino phosphonate derivatives being chosen for further pharmacokinetics, toxicity, and behavioral research to test their potential for AD treatment.

Alzheimer’s Pathogenesis and Treatment by Transcranial Pulse Stimulation

The article discusses the use of transcranial pulse stimulation (TPS), a treatment method that uses ultrasound to penetrate the brain up to 8 cm. The article aims to review published studies on the effects of TPS on Alzheimer’s disease and to link the mechanism of the treatment with the pathophysiology of the disease. The discussion highlights the pathological triad of senile plaques, neurofibrillary tangles, and granular degeneration that causes Alzheimer’s disease. Patients with diabetes mellitus are predisposed to degenerative diseases, and the overlap between Alzheimer’s disease and obesity may be explained by the use of streptozotocin, which generates reactive oxygen species leading to DNA damage and cell death. The accumulation of beta-amyloid in the brain, mitochondrial malfunction, decreased production of ATP, and energy insufficiency is also discussed. The article concludes that TPS is a potential treatment for Alzheimer’s disease and that it can boost the expression of growth factors, enhance the flow of blood to the brain, trigger the creation of novel blood vessels, and promote the regeneration of nerves.

Safety, Feasibility, and Potential Clinical Efficacy of 40 Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study.

Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer's disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols. To investigate the safety, feasibility, and exploratory measures of efficacy. This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n = 3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n = 5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white light. Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: -2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/-2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: -0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo. Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials.

The Use of Dimethyl Biguanide as a Potential Treatment for Alzheimer's Disease in Rats

Amis: Alzheimer’s disease (AD) is one of the most rapidly growing diseases in recent times. Despite extensive research to find an appropriate medicine, there has been no effective drug until now.
 Study Design: The present study was designated to investigate the therapeutic impact of antihyperglycemic dimethyl biguanide on Alzheimer’s disease symptoms.
 Methodology: Alzheimer’s disease was induced in male rats by AlCl3 and D-galactose at doses of 50 and 120 mg/kg daily for one month. Then, for the next four weeks, rats were given oral dimethyl biguanide (200 mg/kg daily).
 Results: The obtained data indicated an increase in the arrival time of the AD rat group (G2) compared to the control group (G1). In addition, the AD rat group showed an elevation in glucose level, oxidative stress, liver, and kidney function. Importantly, dimethyl biguanide was able to ameliorate these unpleasant outcomes in G3. Interestingly, dimethyl biguanide was able to reduce GFAB immunoreactivity in the dimethyl biguanide -treated group (G3) compared to the AD group (G2).
 Conclusion: In fact, dimethyl biguanide can delay the symptomatology of AD.

Genetic removal of synaptic Zn2+ impairs cognition, alters neurotrophic signaling and induces neuronal hyperactivity.

Vesicular Zn2+ (zinc) is released at synapses and has been demonstrated to modulate neuronal responses. However, mechanisms through which dysregulation of zinc homeostasis may potentiate neuronal dysfunction and neurodegeneration are not well-understood. We previously reported that accumulation of soluble amyloid beta oligomers (AβO) at synapses correlates with synaptic loss and that AβO localization at synapses is regulated by synaptic activity and enhanced by the release of vesicular Zn2+ in the hippocampus, a brain region that deteriorates early in Alzheimer's disease (AD). Significantly, drugs regulating zinc homeostasis inhibit AβO accumulation and improve cognition in mouse models of AD. We used both sexes of a transgenic mouse model lacking synaptic Zn2+ (ZnT3KO) that develops AD-like cognitive impairment and neurodegeneration to study the effects of disruption of Zn2+ modulation of neurotransmission in cognition, protein expression and activation, and neuronal excitability. Here we report that the genetic removal of synaptic Zn2+ results in progressive impairment of hippocampal-dependent memory, reduces activity-dependent increase in Erk phosphorylation and BDNF mRNA, alters regulation of Erk activation by NMDAR subunits, increases neuronal spiking, and induces biochemical and morphological alterations consistent with increasing epileptiform activity and neurodegeneration as ZnT3KO mice age. Our study shows that disruption of synaptic Zn2+ triggers neurodegenerative processes and is a potential pathway through which AβO trigger altered expression of neurotrophic proteins, along with reduced hippocampal synaptic density and degenerating neurons, neuronal spiking activity, and cognitive impairment and supports efforts to develop therapeutics to preserve synaptic zinc homeostasis in the brain as potential treatments for AD.

Chapter 16 - Lessons from antiamyloid-β immunotherapies in Alzheimer's disease

The amyloid hypothesis, that established amyloid-β (Aβ) peptide as the primary cause of Alzheimer's disease (AD) and related dementia, has driven the development of treatments for neurodegeneration for 30 years. During the last decades, more than 200 clinical trials testing more than 30 anti-Aβ immunotherapies have been assessed as potential treatments for AD. A vaccine against Aβ was the first immunotherapy intended to avoid aggregation of Aβ into fibrils and senile plaques, but it dramatically failed. Several other vaccines have been proposed as potential AD treatments, targeting different domains or structural motifs of Aβ aggregates, but without clear clinical benefits or effectiveness. In contrast, anti-Aβ therapeutic antibodies have focused on recognizing and removing Aβ aggregates (oligomers, fibrils, or plaques) by eliciting immune clearance. In 2021, the first anti-Aβ antibody, aducanumab (branded as Aduhelm), received FDA approval under an accelerated approval process. The effectiveness and the overall processes regarding the approval of Aduhelm have been under major criticism and scrutiny, prompting a vote of no confidence by public and private health providers, limiting the coverage only to patients enrolled in clinical trials and not for the general elderly patients. Additionally, another three therapeutic anti-Aβ antibodies are following the same path for potential FDA approval. Here, we present the current status of anti-Aβ immunotherapies under evaluation in preclinical and clinical trials for the treatment of AD and related dementia, with a discussion of the main findings and critical lessons learned from the observations from Phase III, II, and I clinical trials of anti-Aβ vaccines and antibodies.

Amyloid precursor protein in Alzheimer's disease.

Amyloid precursor protein (APP) is a membrane protein expressed in several tissues. The occurrence of APP is predominant in synapses of nerve cells. It acts as a cell surface receptor and plays a vital role as a regulator of synapse formation, iron export and neural plasticity. It is encoded by the APP gene that is regulated by substrate presentation. APP is a precursor protein activated by proteolytic cleavage and thereby generating amyloid beta (Aβ) peptides which eventually form amyloid plaques that accumulate in Alzheimer's disease patients' brains. In this chapter, we highlight basic mechanism, structure, expression patterns and cleavage of amyloid plaques, and its diagnosis and potential treatment for Alzheimer's disease.

Translational Inhibition of Multiple Neurotoxic Proteins Leads to Improved Cognition in Alzheimer’s Disease

AbstractBackgroundOverexpression of neurotoxic proteins drives downstream events that dysregulate axonal transport, lead to inflammation, nerve cell death, and loss of function. By inhibiting the translation of amyloid precursor protein, tau and alpha‐synuclein, our drug restored axonal transport, lowered inflammation, and protected nerve cells from dying in animal models. Buntanetap’s reversal of the toxic cascade leading to nerve cell death did preserve and/or restore full function in 7 different animal models of neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD).MethodIn a double blind, placebo controlled Phase2a study, early AD patients were randomized into 80mg Buntanetap (n = 10) or placebo (n = 5) QD for 25±2 days. We evaluated the safety, pharmacokinetics of Buntanetap, biomarkers, and its efficacy.ResultIn clinical trials, Buntanetap was safe in over 200 subjects, both healthy volunteers and AD/PD patients. In our recent double‐blind, placebo controlled Phase2a study, patients randomized to either 80mg QD Buntanetap or placebo we measured biomarkers in AD patients and showed that Buntanetap can lower neurotoxic proteins, improve axonal integrity and synaptic function, and lower inflammation. Buntanetap has also improved AD patients’ cognitive functions as measured by ADASCog11 and WAIS coding test after 25±2 days treatment.ConclusionThese encouraging data support our further development of Buntanetap as a potential treatment for Alzheimer’s disease. We are planning three double‐blind, placebo‐controlled studies, a short 3‐month dose‐finding trial and two long‐term 12‐ and 18‐month trials in early and moderate AD patients.

A TNF receptor 2 agonist ameliorates neuropathology and improves cognition in an Alzheimer’s disease mouse model

Tumor necrosis factor-α (TNF-α) is a pleiotropic, proinflammatory cytokine related to different neurodegenerative diseases, including Alzheimer's disease (AD). Although the linkage between increased TNF-α levels and AD is widely recognized, TNF-α-neutralizing therapies have failed to treat AD. Previous research has associated this with the antithetic functions of the two TNF receptors, TNF receptor 1, associated with inflammation and apoptosis, and TNF receptor 2 (TNFR2), associated with neuroprotection. In our study, we investigated the effects of specifically stimulating TNFR2 with a TNFR2 agonist (NewStar2) in a transgenic Aβ-overexpressing mouse model of AD by administering NewStar2 in two different ways: centrally, via implantation of osmotic pumps, or systemically by intraperitoneal injections. We found that both centrally and systemically administered NewStar2 resulted in a drastic reduction in amyloid β deposition and β-secretase 1 expression levels. Moreover, activation of TNFR2 increased microglial and astrocytic activation and promoted the uptake and degradation of Aβ. Finally, cognitive functions were also improved after NewStar2 treatment. Our results demonstrate that activation of TNFR2 mitigates Aβ-induced cognitive deficits and neuropathology in an AD mouse model and indicates that TNFR2 stimulation might be a potential treatment for AD.

Blood-brain barrier Permeable nanoparticles for Alzheimer's disease treatment by selective mitophagy of microglia

Current treatments for Alzheimer's disease (AD) that focus on inhibition of Aβ aggregation failed to show effectiveness in people who already had Alzheimer's symptoms. Strategies that synergistically exert neuroprotection and alleviation of oxidative stress could be a promising approach to correct the pathological brain microenvironment. Based on the key roles of microglia in modulation of AD microenvironment, we describe here the development of Prussian blue/polyamidoamine (PAMAM) dendrimer/Angiopep-2 (PPA) nanoparticles that can regulate the mitophagy of microglia as a potential AD treatment. PPA nanoparticles exhibit superior blood-brain barrier (BBB) permeability and exert synergistic effects of ROS scavenging and restoration of mitochondrial function of microglia. PPA nanoparticles effectively reduce neurotoxic Aβ aggregate and rescue the cognitive functions in APP/PS1 model mice. Together, our data suggest that these multifunctional dendrimer nanoparticles exhibit efficient neuroprotection and microglia modulation and can be exploited as a promising approach for the treatment of AD.