Alzheimer's Disease Drug Development Research Articles

Drug development in Alzheimer's disease: the path to 2025.

The global impact of Alzheimer’s disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer.

Effects of memantine on the excitation-inhibition balance in prefrontal cortex

Memantine is one of the few drugs currently approved for treatment of Alzheimer's disease (AD). The clinical effects of memantine are thought to be associated with inhibition of NMDA receptors (NMDARs). Surprisingly, other open-channel NMDAR blockers have unacceptable side effects that prevent their consideration for AD treatment. One of the mechanisms proposed to explain the therapeutic benefits of memantine involves preferential decrease of excitatory drive to inhibitory neurons in the cortical circuitry and consequent changes in balance between excitation and inhibition (E/I). In this study we addressed effects of memantine on E/I balance in the prefrontal cortex (PFC). We found that a moderate concentration of memantine shifted E/I balance away from inhibition in the PFC circuitry. Indeed, memantine decreased the frequency and amplitude of spontaneous inhibitory postsynaptic currents in pyramidal neurons while leaving spontaneous excitatory postsynaptic currents unaffected. These circuitry effects of memantine were occluded by the competitive NMDAR inhibitor AP-5, and thus are associated with NMDAR inhibition. We also found that memantine decreased feed-forward disynaptic inhibitory input to pyramidal neurons, which is thought to be mediated by parvalbumin (PV)-positive interneurons. Accordingly, memantine caused a greater decrease of the amplitude of NMDAR-mediated synaptic responses in PV-positive interneurons than in pyramidal neurons. Finally, memantine reduced firing activity in PV-positive interneurons while increasing firing in pyramidal neurons. This study elucidates a novel mechanism of action of memantine associated with shifting of the E/I balance away from inhibition in neocortical circuitry, and provides important insights for AD drug development.

Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease.

Alzheimer’s disease (AD) is an incurable and debilitating chronic progressive neurodegenerative disorder which is the leading cause of dementia worldwide. AD is a heterogeneous and multifactorial disorder, histopathologically characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles composed of Aβ peptides and abnormally hyperphosphorylated tau protein, respectively. Independent of the various etiopathogenic mechanisms, neurodegeneration is a final common outcome of AD neuropathology. Synaptic loss is a better correlate of cognitive impairment in AD than Aβ or tau pathologies. Thus a highly promising therapeutic strategy for AD is to shift the balance from neurodegeneration to neuroregeneration and synaptic repair. Neurotrophic factors, by virtue of their neurogenic and neurotrophic activities, have potential for the treatment of AD. However, the clinical therapeutic usage of recombinant neurotrophic factors is limited because of the insurmountable hurdles of unfavorable pharmacokinetic properties, poor blood–brain barrier (BBB) permeability, and severe adverse effects. Neurotrophic factor small-molecule mimetics, in this context, represent a potential strategy to overcome these short comings, and have shown promise in preclinical studies. Neurotrophic factor small-molecule mimetics have been the focus of intense research in recent years for AD drug development. Here, we review the relevant literature regarding the therapeutic beneficial effect of neurotrophic factors in AD, and then discuss the recent status of research regarding the neurotrophic factor small-molecule mimetics as therapeutic candidates for AD. Lastly, we summarize the preclinical studies with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021). P021 is a neurogenic and neurotrophic compound which enhances dentate gyrus neurogenesis and memory processes via inhibiting leukemia inhibitory factor (LIF) signaling pathway and increasing brain-derived neurotrophic factor (BDNF) expression. It robustly inhibits tau abnormal hyperphosphorylation via increased BDNF mediated decrease in glycogen synthase kinase-3β (GSK-3β, major tau kinase) activity. P021 is a small molecular weight, BBB permeable compound with suitable pharmacokinetics for oral administration, and without adverse effects associated with native CNTF or BDNF molecule. P021 has shown beneficial therapeutic effect in several preclinical studies and has emerged as a highly promising compound for AD drug development.

VIRGIL ELECTRONIC CLINICAL OUTCOME ASSESSMENTS (ECOA) PLATFORM: IMPROVING SIGNAL DETECTION IN ALZHEIMER'S DISEASE CLINICAL TRIALS

The impact of Alzheimer's disease (AD) globally is astounding; the number of people living with the disease is predicted to quadruple by year 2050 to 106 million. Nonetheless, drug development for AD has had among the lowest success rate for any therapeutic area. The high failure rate in AD trials has, in part, been due to imprecision in endpoint measurements, which introduces noise. Clinical outcome assessments (COAs) that use traditional paper-based administrations are known to be cost- and time-inefficient, but they also are subject to human error, which creates variability in measurement. The Virgil Investigative Study Platform uses electronic source data collection with real-time clinical guidance to standardize outcome measurements and improve data quality. In the present study, we compared paper-based administrations against administration with Virgil to determine the extent to which the use of electronic assessments (eCOA) minimized scoring errors in primary and co-primary endpoints of AD trials. Paper-based assessments from a recent clinical trial of mild cognitive impairment (MCI) were compared against eCOA administrations of the same scales in separate MCI trials. All studies are phase II/III multinational trials. Score discrepancies in CDR, ADAS-Cog, ADCS-ADL-MCI, and MMSE were identified via review of audio recordings and worksheets by the same cohort of expert calibrated reviewers. For each scale, discrepancies were compared between paper-based and Virgil administrations. Percentages of reviews with at least one scoring discrepancy, as well as two or more discrepancies, were significantly and substantially lower in Virgil administrations compared to paper-based for all scales. Paper-based administrations create unnecessary variability around endpoint measurements, which can contribute to inconclusive results. The Virgil eCOA platform with real-time clinical guidance, auto-calculation of scores, and prompts for missing data and out-of-range errors can help standardize scale administration and scoring, thereby substantially reducing error variance and improving signal detection.

GLYMPHATIC FLUID PHARMACOLOGY: FACILITATION OF B-AMYLOID CLEARANCE

Accumulating evidence has unequivocally shown that aquaporin-4 (AQP-4) mediated glymphatic flow (GF) is responsible for beta-amyloid clearance. Further, disturbance in GF plays a significant role in the pathogenesis of Alzheimer disease (AD) (Figure 1). Accordingly, pharmacological agents capable of AQP-4 facilitation have become intense targets of drug development for AD. Studies on the molecular mechanisms of water dynamics within the Virchow-Robin space indicate that AQP-4 activities are inhibited by higher proton density mediated by an V-ATPase like proton channel (J Neuroimg 2015;25:861, PLOS ONE 10(5): e0123708). Therefore, effective agents capable of facilitating AQP-4 and, hence, beta-amyloid clearance, that can be targeted for development fall into in three distinct categories, namely, vacuolar ATPase inhibitors, extracellular proton buffering substrates, and direct AQP-4 facilitators (Figure 2). Using an MRI molecular imaging technique capable of quantitative assessment of GF non-invasively in vivo, H2O17 JJ Vicinal Coupling Proton Exchange (H2O17-JJVCPE), we investigated the effects and potencies of agents in these three categories in mice. Mice under urethane anesthesia( 1.2 g/kg) were maintained at a rectal temperature of 37°C ± 0.5 and oxygen saturation (SpO2) of above 93% throughout the study. Effects on GF of various agents in the three categories, given either as a single parenteral dose or multiple daily oral doses (5 days prior to the study), were measured using H2O17-JJVCPE. A detailed description of H2O17-JJVCPE can be found elsewhere (NeuroReport 2014;25:39). A direct AQP-4 facilitator, TGN-073, (Drugs Future 2008;33:897) given as a single parenteral dose, and an extracellular proton buffer, guanidinoethyl sulphonate (GES) (NeuroReport 1993;4:1035) given orally, daily for five days, unequivocally exhibited significant facilitation of GF. Neither agent had any adverse effects on animals.

Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer’s disease treatment

Amyloid-beta peptide (Aβ) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer’s disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10). Altered enzyme function caused by the Aβ-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood–brain barrier penetration.

Characterization of a sensitive mouse Aβ40 PD biomarker assay for Alzheimer's disease drug development in wild-type mice.

Transgenic mice that overexpress human amyloid precursor protein with Swedish or London (APPswe or APPlon) mutations have been widely used for preclinical Alzheimer's disease (AD) drug development. AD patients, however, rarely possess these mutations or overexpress APP. We developed a sensitive ELISA that specifically and accurately measures low levels of endogenous Aβ40 in mouse plasma, brain and CSF. In wild-type mice treated with a bispecific anti-TfR/BACE1 antibody, significant Aβ reductions were observed in the periphery and the brain. APPlon transgenic mice showed a slightly less reduction, whereas APPswe mice did not have any decrease. This sensitive and well-characterized mouse Aβ40 assay enables the use of wild-type mice for preclinical PK/PD and efficacy studies of potential AD therapeutics.

Novel Therapeutic Strategies for Dementia.

Dementia represents a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. Alzheimer disease (AD), the most prevalent form of dementia, is a polygenic/multifactorial/complex disorder in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions lead to amyloid deposition, neurofibrillary tangle formation and premature neuronal death, the major neuropathological hallmarks of AD. For the past 20 years, over 1,000 different compounds have been studied as potential candidate drugs for the treatment of AD. About 50% of these substances are novel molecules obtained from natural sources. The candidate compounds can be classified according to their pharmacological properties and/or the AD-related pathogenic cascade to which they are addressed to halt disease progression. In addition to the Food and Drug Administration (FDA)-approved drugs since 1993 (tacrine, donepezil, rivastigmine, galantamine, memantine), most candidate strategies fall into 6 major categories: (i) novel cholinesterase inhibitors and neurotransmitter regulators, (ii) anti-amyloid beta (Aβ) treatments (amyloid-β protein precursor (APP) regulators, Aβ breakers, active and passive immunotherapy with vaccines and antibodies, β - and γ - secretase inhibitors or modulators), (iii) anti-tau treatments, (iv) pleiotropic products (most of them of natural origin), (v) epigenetic intervention, and (vi) combination therapies. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.

The Case for Using Actigraphy Generated Sleep and Activity Endpoints in Alzheimer's Disease Clinical Trials.

More and more people in the industrialised world use wearables and smartphones to monitor their health and fitness. These devices are often used in combination with special apps to monitor and document daily activities and sleep. It would appear to be a logical step to assess the relevance of these devices in drug development trials. In contrast to the consumer devices, the technology used in clinical trials needs to be validated and compliant with the relevant regulations. Even under these complex requirements, wearables offer a number of new opportunities to objectively capture clinically relevant outcome measures -potentially with lower burden for patients and site staff. As an example, we describe the use in Alzheimer's disease drug development studies. This is an indication where there have been a number of failures, in part due to the difficulties this patient population has in reliably completing existing tools. In addition rater scales add complexity due to inter- and intra-rater variability.

AlzPathway, an Updated Map of Curated Signaling Pathways: Towards Deciphering Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a complex neurodegenerative disorder in which loss of neurons and synaptic function causes dementia in the elderly. To clarify AD pathogenesis and develop drugs for AD, thousands of studies have elucidated signaling pathways involved. However, knowledge of AD signaling pathways has not been compiled as a pathway map. In this chapter, we introduce the manual construction of a pathway map in AD which we call "AlzPathway", that comprehensively catalogs signaling pathways in the field of AD. We have collected and manually curated over 100 review articles related to AD, and have built the AD pathway map. AlzPathway is currently composed of thousands of molecules and reactions in neurons, brain blood barrier, presynaptic, postsynaptic, astrocyte, and microglial cells, with their cellular localizations. AlzPathway provides a systems-biology platform of comprehensive AD signaling and related pathways which is expected to contribute to clarification of AD pathogenesis and AD drug development.

Nanoscale Extracellular Vesicle Analysis in Alzheimer's Disease Diagnosis and Therapy.

Diagnostic assays that leverage bloodborne neuron-derived (neuronal) nanoscale extracellular vesicles (nsEVs) as “windows into the brain” can predict incidence of Alzheimer's Disease (AD) many years prior to onset. Beyond diagnostics, bloodborne neuronal nsEVs analysis may have substantial translational impact by revealing mechanisms of AD pathology; such knowledge could enlighten new drug targets and lead to new therapeutic approaches. The potential to establish three-dimensional nsEV analysis methods that characterize highly purified bloodborne nsEV populations in method of enrichment, cell type origin, and protein or RNA abundance dimensions could bring this promise to bear by yielding nsEV “omics” datasets that uncover new AD biomarkers and enable AD therapeutic development. In this review we provide a survey of both the current status of and new developments on the horizon in the field of neuronal nsEV analysis. This survey is supplemented by a discussion of the potential to translate such neuronal nsEV analyses to AD clinical diagnostic applications and drug development.

An Overview on Global Trends in Nanotechnological Approaches for Alzheimer Therapy.

Despite extensive research for over two decades, the medical science is yet to assign the exact aetiology and mode of progression of Alzheimer's disease (AD). The modern era of AD drug development began with the proposal of the cholinergic hypothesis of memory impairment. Since then, despite the proposal and phase trials of many therapeutic options, only few drugs have shown some efficacy and safety. The reasons behind this have been many including the ineffectiveness of tested drugs and inadequacy of clinical development methods. In this manuscript, we present an account of modern structural, functional and molecular imaging developed for AD therapy. A comprehensive review of all the current and future treatment options for AD, ranging from cholinergic drugs, NMDA receptor antagonist, immunotherapy, drugs reducing Aβ production, and drugs targeting tau protein and mitochondrial dysfunction has also been provided. However, the failure of all the proposed treatment options to provide a complete cure of AD has been pushing for the need of new therapies. The recent advent of nano-drugs has been proposed to provide crucial breakthroughs in AD therapy. Hence, a detailed outline of the usage and applications of nano-drugs in AD therapy, and outstanding developments in nanodrug metabolism and disposition has been discussed.

Mechanism of C-Terminal Fragments of Amyloid β-Protein as Aβ Inhibitors: Do C-Terminal Interactions Play a Key Role in Their Inhibitory Activity?

Targeting the early oligomerization of amyloid β protein (Aβ) is a promising therapeutic strategy for Alzheimer's disease (AD). Recently, certain C-terminal fragments (CTFs) derived from Aβ42 were shown to be potent inhibitors of Aβ-induced toxicity. The shortest peptide studied, Aβ(39-42), has been shown to modulate Aβ oligomerization and inhibit Aβ toxicity. Understanding the mechanism of these CTFs, especially Aβ(39-42), is of significance for future therapeutic development of AD and peptidomimetic-based drug development. Here we used ion mobility spectrometry-mass spectrometry to investigate the interactions between two modified Aβ(39-42) derivatives, VVIA-NH2 and Ac-VVIA, and full-length Aβ42. VVIA-NH2 was previously shown to inhibit Aβ toxicity, whereas Ac-VVIA did not. Our mass spectrometry analysis revealed that VVIA-NH2 binds directly to Aβ42 monomer and small oligomers while Ac-VVIA binds only to Aβ42 monomer. Ion mobility studies showed that VVIA-NH2 modulates Aβ42 oligomerization by not only inhibiting the dodecamer formation but also disaggregating preformed Aβ42 dodecamer. Ac-VVIA also inhibits and removes preformed Aβ42 dodecamer. However, the Aβ42 sample with the addition of Ac-VVIA clogged the nanospray tip easily, indicating that larger aggregates are formed in the solution in the presence of Ac-VVIA. Molecular dynamics simulations suggested that VVIA-NH2 binds specifically to the C-terminal region of Aβ42 while Ac-VVIA binds dispersedly to multiple regions of Aβ42. This work implies that C-terminal interactions and binding to Aβ oligomers are important for C-terminal fragment inhibitors.

Alzheimer's disease drug development based on Computer-Aided Drug Design

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the excessive deposition of amyloids in the brain. The pathological features mainly include the extracellular amyloid plaques and intracellular neurofibrillary tangles, which are the production of amyloid precursor protein (APP) processed by the α-, β- and γ-secretases. Based on the amyloid cascade hypotheses of AD, a large number of amyloid-β agents and secretase inhibitors against AD have been recently developed by using computational methods. This review article describes pathophysiology of AD and the structure of the Aβ plaques, β- and γ-secretases, and discusses the recent advances in the development of the amyloid agents for AD therapy and diagnosis by using Computer-Aided Drug Design approach.

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.

Advances in Alzheimer's disease drug development.

Alzheimer’s disease (AD) is the foremost cause of dementia worldwide. Clinically, AD manifests as progressive memory impairment followed by a gradual decline in other cognitive abilities leading to complete functional dependency. Recent biomarker studies indicate that AD is characterized by a long asymptomatic phase, with the development of pathology occurring at least a decade prior to the onset of any symptoms. Current FDA-approved treatments target neurotransmitter abnormalities associated with the disease but do not affect what is believed to be the underlying etiology. In this review, we briefly discuss the most recent therapeutic strategies being employed in AD clinical trials, as well the scientific rationale with which they have been developed.

Development of Novel Pharmaceutical Agents for Alzheimer’s Disease: The Impact of Regulatory Initiatives in Japan and the United States

PurposeThe incidence of Alzheimer’s disease (AD) has been steadily increasing worldwide. AD is a serious disease that has both societal and economic impacts. The greatest risk factor for AD is aging. Thus, because of the rapidly aging population in Japan, the development of new, effective drugs for AD is urgently needed. The goal of the present article was to analyze the status, clarify the problems, and discuss the scientific and political challenges of disease-modifying drug development for AD. MethodsPublic data, official documents, literature, and news releases were surveyed and discussed. FindingsCompared with diabetes mellitus drugs, there is a lack of quantitative surrogate end points among AD drugs. Much AD drug development has focused on amyloid-β and its associated pathways; however, these drugs have not shown efficacy in Phase III clinical trials. Thus, the US Food and Drug Administration has appealed for a new draft industrial guidance for the development of AD drugs, including those for early-stage AD. In Japan, the Minister of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency have also taken action, including the publication of potential new guidelines for clinical evaluation and development of new AD therapeutics, including drugs. Moreover, scientific initiatives to develop novel AD drugs are ongoing. ImplicationsThe development of quantitative surrogate end points remains necessary to improve the development of AD drugs. Therefore, collaboration among industry, government, and academia should be encouraged. Following the principles of regulatory science, strategies to develop drugs for illnesses with unmet needs can be framed by investigating the effects of past, current, and future AD drug development initiatives.

Rejuvenating procholinergic treatments for cognition enhancement in AD: current challenges and future prospects.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by global cognitive decline, with predominant impairments arising in attention and memory (Perry and Hodges, 1999). It is the sixth largest cause of death, and currently there is no way to prevent, cure, or even slow the progression (Klafki et al., 2006; Alzheimer's Association, 2014). Although there is a widespread decline in various neurotransmitter-containing cell bodies and axonal terminals in AD, the most consistent losses are seen in the basal forebrain (BF) cholinergic neurons and its projections (Mesulam, 2004; Schliebs and Arendt, 2011). Because of the documented role of the BF cholinergic system in learning and memory, the “cholinergic hypothesis” of AD was established (Bartus et al., 1982) and has been the primary directive for drug development and treatment in AD for almost three decades. While cholinomimetic drugs such as acetylcholinesterase (AChE) inhibitors, which elevate extracellular levels of the neurotransmitter acetylcholine (ACh), are the viable treatment option for AD and provide moderate alleviation to cognitive impairment, the magnitude of cognitive improvements with these drugs has remained limited (McGleenon et al., 1999; Raina et al., 2008). Additionally, these drugs are not successful in halting the progression of AD. Furthermore, the evidence that non-specific blockade of either muscarinic or nicotinic ACh receptors (mAChRs and nAChRs) alone produce dementia-like symptoms has remained inconsistent (Little et al., 1998; Erskine et al., 2004; Roegge and Levin, 2006). These issues have raised questions concerning the validity of the cholinergic hypothesis and whether the development of procholinergic therapies as cognition enhancers should be considered for AD. Here we argue that psychopharmacological approaches targeting the cholinergic system are based on previous conceptualizations of ACh regulating arousal states. We urge that emerging views from recent studies that refine our understanding of the cholinergic mediation of specific cognitive processes, and how cholinergic mechanisms interact with other pathological markers during the progression of AD, should be considered while designing procholinergic therapies. This discussion will also focus on the development of new drug candidates such as cholinergic receptor subtype-specific agonists, choline transporter (CHT) modulators and neurotrophin-based therapeutics to normalize cholinergic function in AD. Additionally, the need to combine multiple therapeutic approaches to slow AD progression and maximize cognitive benefits will be emphasized.

The resveratrol trimer miyabenol C inhibits β-secretase activity and β-amyloid generation.

Accumulation and deposition of amyloid-β peptide (Aβ) in the brain is a primary cause of the pathogenesis of Alzheimer’s disease (AD). Aβ is generated from amyloid-β precursor protein (APP) through sequential cleavages first by β-secretase and then by γ-secretase. Inhibiting β-secretase activity is believed to be one of the most promising strategies for AD treatment. In the present study, we found that a resveratrol trimer, miyabenol C, isolated from stems and leaves of the small-leaf grape (Vitisthunbergii var. taiwaniana), can markedly reduce Aβ and sAPPβ levels in both cell cultures and the brain of AD model mice. Mechanistic studies revealed that miyabenol C affects neither protein levels of APP, the two major α-secretases ADAM10 and TACE, and the γ-secretase component Presenilin 1, nor γ-secretase-mediated Notch processing and TACE activity. In contrast, although miyabenol C has no effect on altering protein levels of the β-secretase BACE1, it can inhibit both in vitro and in vivo β-secretase activity. Together, our results indicate that miyabenol C is a prominent β-secretase inhibitor and lead compound for AD drug development.

Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer’s disease

Development of Multi-Target Directed Ligands (MTDLs) has emerged as a promising approach for targeting complex etiology of Alzheimer’s disease (AD). Following this approach, a new series of N′-(4-benzylpiperidin-/piperazin-/benzhydrylpiperazin-1-yl)alkylamine derivatives were designed, synthesized and biologically evaluated as inhibitors of cholinesterases (ChEs), amyloid-beta (Aβ) self aggregation and also for their radical scavenging activity. The in vitro studies showed that the majority of synthesized derivatives strongly inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values in the low-nanomolar range, and were clearly more potent than the reference compound donepezil in this regard. Among them, inhibitors 5h and 5k, strongly inhibited AChE, with IC50 value of 6.83nM and 2.13nM, respectively, and particularly, compound 5k was found to be highly selective for AChE (∼38-fold). Moreover, both kinetic analysis of AChE inhibition and the docking study suggested that 5k binds simultaneously to catalytic active site and peripheral anionic site of AChE. Besides, these compounds also exhibited greater ability to inhibit self-induced Aβ1–42 aggregation at 25μM with percentage inhibition from ∼54% to 89% and specially compound 5k provided highest inhibition (88.81%). Also, the derivatives containing methoxy and hydroxy groups showed potent oxygen radical absorbance capacity (ORAC) ranging from 2.2- to 4.4-fold of the Trolox value. Furthermore, results of ADMET studies suggested that all compounds exhibited appropriate drug like properties. Taken together, these results suggest that 5k might be a promising lead compound for further AD drug development.