Development Of Alzheimer's Disease Therapeutics Research Articles

Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the build-up of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Ferroptosis, an iron (Fe)-dependent form of cell death plays a significant role in the multifaceted AD pathogenesis through generation of reactive oxygen species (ROS), mitochondrial damage, lipid peroxidation, and reduction in glutathione peroxidase 4 (GPX4) enzyme activity and levels. Aberrant liquid-liquid phase separation (LLPS) of tau drives the growth and maturation of NFTs contributing to AD pathogenesis. In this study, we strategically combined the structural and functional properties of gallic acid (GA) and cyclic dipeptides (CDPs) to synthesize hybrid molecules that effectively target both ferroptosis and amyloid toxicity in AD. This innovative approach marks a paradigm shift from conventional therapeutic strategies. This is the first report of a synthetic small molecule (GCTR) that effectively combats ferroptosis, simultaneously restoring enzymatic activity and enhancing cellular levels of its master regulator, GPX4. Further, GCTR disrupts Fe3+-induced LLPS of tau, and aids in attenuation of abnormal tau fibrillization. The synergistic action of GCTR in combating both ferroptosis and amyloid toxicity, bolstered by GPX4 enhancement and modulation of Fe3+-induced tau LLPS, holds promise for the development of small molecule-based novel therapeutics for AD.

Classifying Beta-Secretase 1 Inhibitor Activity for Alzheimer’s Drug Discovery with LightGBM

This study explores the utilization of LightGBM, a gradient-boosting framework, to classify the inhibitory activity of beta-secretase 1 inhibitors, addressing the challenges of Alzheimer's disease drug discovery. The study aims to enhance classification performance by focusing on overcoming the limitations of traditional statistical models and conventional machine-learning techniques in handling complex molecular datasets. By sourcing a dataset of 7298 compounds from the ChEMBL database and calculating molecular descriptors for each compound as features, we employed LightGBM in conjunction with a set of carefully selected molecular descriptors to achieve a nuanced analysis of compound activities. The model's efficiency was benchmarked against traditional machine-learning algorithms, revealing LightGBM's superior accuracy (84.93%), precision (87.14%), sensitivity (89.93%), specificity (77.63%), and F1-score (88.17%) in classifying beta-secretase 1 inhibitor activity. The study underscores the critical role of molecular descriptors in understanding drug efficacy, highlighting LightGBM's potential in streamlining the virtual screening process. Conclusively, the findings advocate for LightGBM's adoption in computational drug discovery, offering a promising avenue for advancing Alzheimer's disease therapeutic development by facilitating the identification of potential drug candidates with enhanced precision and reliability.

An In Silico Study for Expanding the Utility of Cannabidiol in Alzheimer's Disease Therapeutic Development.

Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer's disease (AD). In this study, we identified potential CBD targets associated with AD using a drug-target binding affinity prediction model and generated CBD analogs using a genetic algorithm combined with a molecular docking system. As a result, we identified six targets associated with AD: Endothelial NOS (ENOS), Myeloperoxidase (MPO), Apolipoprotein E (APOE), Amyloid-beta precursor protein (APP), Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), and Presenilin-1 (PSEN1). Furthermore, we generated CBD analogs for each target that optimize for all desired drug-likeness properties and physicochemical property filters, resulting in improved pIC50 values and docking scores compared to CBD. Molecular dynamics (MD) simulations were applied to analyze each target's CBD and highest-scoring CBD analogs. The MD simulations revealed that the complexes of ENOS, MPO, and ADAM10 with CBD exhibited high conformational stability, and the APP and PSEN1 complexes with CBD analogs demonstrated even higher conformational stability and lower interaction energy compared to APP and PSEN1 complexes with CBD. These findings demonstrated the capable binding of the six identified targets with CBD and the enhanced binding stability achieved with the developed CBD analogs for each target.

Cyclic β-hairpin peptide loaded PLGA nanoparticles: A potential anti-amyloid therapeutic

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by β-amyloid peptide (Aβ1–42) deposits, with no definitive therapies. Recently, cyclic peptides have been considered potential therapeutics because of proteolytic stability and tight and precise binding to Aβ1–42. We modified the classic cyclic peptide viz., PPLeu, via a directed approach to arrive at a new β-hairpin cyclic peptide BSBP8 (Mw 1450 Da), a potent anti-amyloidogenic agent. BSBP8 also disassembled pre-formed Aβ1–42 fibrils and rescued neuronal cells from Aβ1–42 induced cytotoxicity. In the Thioflavin T assay, BSBP8 showed ∼82 % aggregation reduction when co-incubated with Aβ1–42. Biophysical techniques, viz. Circular Dichroism, Fourier Transform Infrared Spectroscopy, and Atomic Force Microscopy substantiated these results. To achieve permeation of BSBP8 across the blood-brain barrier, the peptide was loaded onto poly D,L-lactide-co-glycolide nanoparticles (PLGA NPs). Compared to BSBP8 alone, the negatively charged (−8.96 ± 1.22 mV) spherical particles with a mean diameter of 223.2 ± 3.52 nm, loaded with BSBP8 (2.86 % w/w) permeated across the BBB formed by the Madin-Darby canine kidney cells. In vivo biodistribution profile indicated ∼9 %, 52 % and 20 % particle accumulation in the brain, liver, and kidney. Tissue retention of BSBP8-PLGA NPs was observed for at least seven days. It can be anticipated that this study will significantly promote the development of therapeutics for AD.

Moving Beyond Amyloid in Alzheimer's Therapeutics

Moving Beyond Amyloid in Alzheimer's Therapeutics

Cellular response to β-amyloid neurotoxicity in Alzheimer's disease and implications in new therapeutics.

β-Amyloid (Aβ) is a specific pathological hallmark of Alzheimer's disease (AD). Because of its neurotoxicity, AD patients exhibit multiple brain dysfunctions. Disease-modifying therapy (DMT) is the central concept in the development of AD therapeutics today, and most DMT drugs that are currently in clinical trials are anti-Aβ drugs, such as aducanumab and lecanemab. Therefore, understanding Aβ's neurotoxic mechanism is crucial for Aβ-targeted drug development. Despite its total length of only a few dozen amino acids, Aβ is incredibly diverse. In addition to the well-known Aβ1-42 , N-terminally truncated, glutaminyl cyclase (QC) catalyzed, and pyroglutamate-modified Aβ (pEAβ) is also highly amyloidogenic and far more cytotoxic. The extracellular monomeric Aβx-42 (x=1-11) initiates the aggregation to form fibrils and plaques and causes many abnormal cellular responses through cell membrane receptors and receptor-coupled signal pathways. These signal cascades further influence many cellular metabolism-related processes, such as gene expression, cell cycle, and cell fate, and ultimately cause severe neural cell damage. However, endogenous cellular anti-Aβ defense processes always accompany the Aβ-induced microenvironment alterations. Aβ-cleaving endopeptidases, Aβ-degrading ubiquitin-proteasome system (UPS), and Aβ-engulfing glial cell immune responses are all essential self-defense mechanisms that we can leverage to develop new drugs. This review discusses some of the most recent advances in understanding Aβ-centric AD mechanisms and suggests prospects for promising anti-Aβ strategies.

Etiology of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the primary cause of dementia in the elderly. The research on AD has markedly evolved since discovering the pathological hallmarks in the brain over the past years. However, the etiology of AD has not been completely elucidated, and presently there is no cure for AD. Furthermore, despite the disease hallmarks commonly manifested in all AD cases, considerable evidence suggests complex heterogeneity of AD pathogenesis. Specifically, studies have identified several disease genes that cause or associate with AD and discovered multiple modifiable risk factors of AD, which may further aggregate the complex etiology of AD. Understanding molecular mechanisms of AD genes and modifying risk factors of AD are making it possible to develop effective interventions to prevent or cure the disease, which may in turn help understand the disease etiology. Recently, there has been keen interest in carrying out multidisciplinary investigations on AD, e.g., the studies on the molecular basis in association with neural network abnormalities in AD. Furthermore, the molecular findings on the pathogenetics of AD have provided translational proof-of-concept to intervene in AD, which has inspired clinical trials by reducing disease neuropathology related to AD genes or risk factors of AD. This article's main aim is to highlight recent progress on the mechanisms and approaches with an attempt to gain an integrated perspective of AD etiology. We envision that this article and its referenced reports may provide a valuable point of reflection that may not only acknowledge past discoveries, but also stimulate future studies, advancing the understanding of the complex etiology of AD and the development of effective therapeutics for AD.

Brain‐region‐specific, glycosylation‐related transcriptomic alterations in Alzheimer's disease

Glycosylation aberrations have been found to be associated with Alzheimer's Disease (AD). In this study, three large public datasets that include RNA-seq data were used to investigate which glycosylation pathways are differentially expressed in AD patients in the brain. RNA-Seq data for six brain regions from hundreds of control, AD, and other neurodegenerative disease cases from Mayo RNASeq, MSBB, and ROSMAP were analyzed. The differential expression of glycosylation-related mRNAs between control and disease groups was analyzed for each brain region using the negative binomial model and a quasi-likelihood F-test using the edgeR package. The TMM method was used for normalization and the Benjamini-Hochberg method was used for multiple testing correction. The total number of genes involved in glycosylation or proteoglycans for each brain region varied from 457 to 467. The number of genes found to be differentially expressed exclusively in controls vs. AD varied between brain regions, with the dorsolateral prefrontal cortex (DLPFC), anterior prefrontal cortex (aPFC), primary auditory cortex, and temporal cortex (TC) having 83, 105, 61, and 99 differentially expressed genes respectively, while in Broca's area and the perirhinal cortex, only 12 and 27 genes were differential respectively. Polypeptide N-acetylgalactosaminyltransferase like 6 (GALNTL6), a gene involved in the initiation of O-glycosylation, was found differentially expressed exclusively in AD in four brain regions (adjusted p-value): DLPFC (p=2.88e-6), TC (p=0.00346), aPFC (p=0.000507) and primary auditory cortex (p=0.00446). GALNTL6 was down-regulated in DLPFC (logFC=-0.29) and TC (logFC=-0.40) and up-regulated in aPFC (logFC=0.24) and primary auditory cortex (logFC=0.27). Alpha-2,3-sialyltransferase 3 (ST3GAL3) and alpha-2,6-sialyltransferase 2 (ST6GAL2) are involved in the sialylation of both N- and O-glycans, and their mRNA was exclusively down-regulated in AD in DLPFC (ST3GAL3, logFC=-0.10, adjusted p-value=0.00275; ST6GAL2, logFC=-0.24, adjusted p-value=6.43-e-06) and TC (ST3GAL3, logFC=-0.22, adjusted p-value=0.000250; ST6GAL2, logFC=-0.41, adjusted p-value=1.30e-06). mRNAs for other O-glycan biosynthesis genes, such as GALNT17, POMT2, GXYLT1, and B3GAT2 were altered in AD in multiple brain regions. Interestingly several enzymes involved in O- and N- glycosylation were significantly down regulated in the dorsolateral prefrontal cortex and temporal cortex, areas significantly impaired in AD. These findings may facilitate future development of AD therapeutics.

Normal and Abnormal Sharp Wave Ripples in the Hippocampal-Entorhinal Cortex System: Implications for Memory Consolidation, Alzheimer's Disease, and Temporal Lobe Epilepsy

The appearance of hippocampal sharp wave ripples (SWRs) is an electrophysiological biomarker for episodic memory encoding and behavioral planning. Disturbed SWRs are considered a sign of neural network dysfunction that may provide insights into the structural connectivity changes associated with cognitive impairment in early-stage Alzheimer's disease (AD) and temporal lobe epilepsy (TLE). SWRs originating from hippocampus have been extensively studied during spatial navigation in rodents, and more recent studies have investigated SWRs in the hippocampal-entorhinal cortex (HPC-EC) system during a variety of other memory-guided behaviors. Understanding how SWR disruption impairs memory function, especially episodic memory, could aid in the development of more efficacious therapeutics for AD and TLE. In this review, we first provide an overview of the reciprocal association between AD and TLE, and then focus on the functions of HPC-EC system SWRs in episodic memory consolidation. It is posited that these waveforms reflect rapid network interactions among excitatory projection neurons and local interneurons and that these waves may contribute to synaptic plasticity underlying memory consolidation. Further, SWRs appear altered or ectopic in AD and TLE. These waveforms may thus provide clues to understanding disease pathogenesis and may even serve as biomarkers for early-stage disease progression and treatment response.

Gut Microbiota Composition and Epigenetic Molecular Changes Connected to the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, and its pathogenesis is not fully known. Although there are several hypotheses, such as neuroinflammation, tau hyperphosphorylation, amyloid-β plaques, neurofibrillary tangles, and oxidative stress, none of them completely explain the origin and progression of AD. Emerging evidence suggests that gut microbiota and epigenetics can directly influence the pathogenesis of AD via their effects on multiple pathways, including neuroinflammation, oxidative stress, and amyloid protein. Various gut microbes such as Actinobacteria, Bacteroidetes, E. coli, Firmicutes, Proteobacteria, Tenericutes, and Verrucomicrobia are known to play a crucial role in the pathogenesis of AD. These microbes and their metabolites modulate various physiological processes that contribute to AD pathogenesis, such as neuroinflammation and other inflammatory processes, amyloid deposition, cytokine storm syndrome, altered BDNF and NMDA signaling, impairing neurodevelopmental processes. Likewise, epigenetic markers associated with AD mainly include histone modifications and DNA methylation, which are under the direct control of a variety of enzymes, such as acetylases and methylases. The activity of these enzymes is dependent upon the metabolites generated by the host's gut microbiome, suggesting the significance of epigenetics in AD pathogenesis. It is interesting to know that both gut microbiota and epigenetics are dynamic processes and show a high degree of variation according to diet, stressors, and environmental factors. The bidirectional relation between the gut microbiota and epigenetics suggests that they might work in synchrony to modulate AD representation, its pathogenesis, and progression. They both also provide numerous targets for early diagnostic biomarkers and for the development of AD therapeutics. This review discusses the gut microbiota and epigenetics connection in the pathogenesis of AD and aims to highlight vast opportunities for diagnosis and therapeutics of AD.

Multi-target inhibition ability of neohesperidin dictates its neuroprotective activity: Implication in Alzheimer's disease therapeutics

The polygenic nature of Alzheimer's disease (AD) and cross-talk between several signaling cascades make it harder to decode the disease pathogenesis. β-secretase (BACE1) works upstream in the amyloidogenic processing of amyloid precursor protein (APP) to generate Aβ that rapidly aggregates to form fibrils, the most abundant component of plaques observed in AD brains. Here, we report dual inhibition of BACE1 and Aβ aggregation by neohesperidin, a flavonoid glycoconjugate, using multi-spectroscopic approaches, force microscopy, molecular modeling, and validated the potency in SH-SY5Y neuroblastoma cell lines. Steady-state and time-resolved fluorescence reveal that neohesperidin binds close to the catalytic aspartate dyad. This binding conformationally restricts the protein in closed form which possibly precludes APP recognition and thereby inhibits BACE1 activity. Neohesperidin also dose-dependently inhibits the amyloid fibril formation, as evident from ANS, ThT assay, and AFM. Neohesperidin ameliorates aggregated Aβ25–35 induced ROS generation and mitochondrial dysfunction in the SH-SY5Y cell line. As a result, the amyloid induced apoptosis is significantly prohibited and normal neuronal morphology is rescued. These findings suggest neohesperidin as an inhibitor of the pathogenic conversion of Aβ to fibrillar amyloid assembly. Neohesperidin thus emerges as a non-toxic multi-potent scaffold for the development of AD therapeutics.

Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing.

Following two decades of more than 400 clinical trials centered on the "one drug, one target, one disease" paradigm, there is still no effective disease-modifying therapy for Alzheimer's disease (AD). The inherent complexity of AD may challenge this reductionist strategy. Recent observations and advances in network medicine further indicate that AD likely shares common underlying mechanisms and intermediate pathophenotypes, or endophenotypes, with other diseases. In this review, we consider AD pathobiology, disease comorbidity, pleiotropy, and therapeutic development, and construct relevant endophenotype networks to guide future therapeutic development. Specifically, we discuss six main endophenotype hypotheses in AD: amyloidosis, tauopathy, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and lysosomal dysfunction. We further consider how this endophenotype network framework can provide advances in computational and experimental strategies for drug-repurposing and identification of new candidate therapeutic strategies for patients suffering from or at risk for AD. We highlight new opportunities for endophenotype-informed, drug discovery in AD, by exploiting multi-omics data. Integration of genomics, transcriptomics, radiomics, pharmacogenomics, and interactomics (protein-protein interactions) are essential for successful drug discovery. We describe experimental technologies for AD drug discovery including human induced pluripotent stem cells, transgenic mouse/rat models, and population-based retrospective case-control studies that may be integrated with multi-omics in a network medicine methodology. In summary, endophenotype-based network medicine methodologies will promote AD therapeutic development that will optimize the usefulness of available data and support deep phenotyping of the patient heterogeneity for personalized medicine in AD.

Leveraging preclinical models for the development of Alzheimer disease therapeutics.

A large number of mouse models have been engineered, characterized and used to advance biomedical research in Alzheimer disease (AD). Early models simply damaged the rodent brain through toxins or lesions. Later, the spread of genetic engineering technology enabled investigators to develop models of familial AD by overexpressing human genes such as those encoding amyloid precursor protein (APP) or presenilins (PSEN1 or PSEN2) carrying mutations linked to early-onset AD. Recently, more complex models have sought to explore the impact of multiple genetic risk factors in the context of different biological challenges. Although none of these models has proven to be a fully faithful reproduction of the human disease, models remain essential as tools to improve our understanding of AD biology, conduct thorough pharmacokinetic and pharmacodynamic analyses, discover translatable biomarkers and evaluate specific therapeutic approaches. To realize the full potential of animal models as new technologies and knowledge become available, it is critical to define an optimal strategy for their use. Here, we review progress and challenges in the use of AD mouse models, highlight emerging scientific innovations in model development, and introduce a conceptual framework for use of preclinical models for therapeutic development.

Friend, Foe or Both? Immune Activity in Alzheimer's Disease.

Alzheimer’s disease (AD) is marked by the presence of amyloid beta (Aβ) plaques, neurofibrillary tangles (NFT), neuronal death and synaptic loss, and inflammation in the brain. AD research has, in large part, been dedicated to the understanding of Aβ and NFT deposition as well as to the pharmacological reduction of these hallmarks. However, recent GWAS data indicates neuroinflammation plays a critical role in AD development, thereby redirecting research efforts toward unveiling the complexities of AD-associated neuroinflammation. It is clear that the innate immune system is intimately associated with AD progression, however, the specific roles of glia and neuroinflammation in AD pathology remain to be described. Moreover, inflammatory processes have largely been painted as detrimental to AD pathology, when in fact, many immune mechanisms such as phagocytosis aid in the reduction of AD pathologies. In this review, we aim to outline the delicate balance between the beneficial and detrimental aspects of immune activation in AD as a more thorough understanding of these processes is critical to development of effective therapeutics for AD.

Amyloid-β-independent regulators of tau pathology in Alzheimer disease.

The global epidemic of Alzheimer disease (AD) is worsening, and no approved treatment can revert or arrest progression of this disease. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Genetic data, as well as autopsy and neuroimaging studies in patients with AD, indicate that Aβ plaque deposition precedes cortical tau pathology. Because Aβ accumulation has been considered the initial insult that drives both the accumulation of tau pathology and tau-mediated neurodegeneration in AD, the development of AD therapeutics has focused mostly on removing Aβ from the brain. However, striking preclinical evidence from AD mouse models and patient-derived human induced pluripotent stem cell models indicates that tau pathology can progress independently of Aβ accumulation and arises downstream of genetic risk factors for AD and aberrant metabolic pathways. This Review outlines novel insights from preclinical research that implicate apolipoprotein E, the endocytic system, cholesterol metabolism and microglial activation as Aβ-independent regulators of tau pathology. These factors are discussed in the context of emerging findings from clinical pathology, functional neuroimaging and other approaches in humans. Finally, we discuss the implications of these new insights for current Aβ-targeted strategies and highlight the emergence of novel therapeutic strategies that target processes upstream of both Aβ and tau.

APOE4 ACCELERATES NEURODEGENERATION AND EXACERBATES ALZHEIMER’S DISEASE RELATED PATHOLOGY IN CEREBRAL ORGANOIDS

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) compared to the common APOE3 allele. The cerebral organoids derived from human induced pluripotent stem cells (iPSCs) have been shown to be a novel model system closely resembling the physiological condition of human brains. To understand how human apoE isoforms differentially impact neuron viability and AD-related pathologies, we developed iPSC lines with different APOE genotypes from individuals with either normal cognition or sporadic AD and further into cerebral organoids. We found that cerebral organoids from AD patients with APOE ε4/4 genotype showed accelerated differentiation pattern and had enhanced neuronal apoptosis in the ventricular zone-like area at day 90 when compared to those from normal controls or AD with the APOE ε3/3 genotype. Cerebral organoids from AD patients also had increased AD-related pathologies including the levels of Aβ40, Aβ42, and phosphorylation tau. More interestingly, we found that apoE4 exacerbates tau pathology in a disease status-independent manner. Transcriptomic analysis by RNA-sequencing revealed an enrichment of apoptosis pathway in cerebral organoids from AD patients with the APOE ε4/4 genotype. Together, our results using the cerebral organoids suggest that apoE4 accelerates neurodegeneration in addition to impacting AD-related pathology in a human-relevant model system. Both the cerebral organoid model system and the information on apoE4-relevant disease pathways should help the development of new therapeutics for AD.

Translating the biology of aging into novel therapeutics for Alzheimer disease.

Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer disease (AD), a progressive neurodegenerative disease with currently no therapies that prevent, slow, or halt disease progression. Like other chronic diseases of old age, the progressive pathology of AD begins decades before the onset of symptoms. Many decades of research in biological gerontology have revealed common processes that are relevant to understanding why the aging brain is vulnerable to AD. In this review, we frame the development of novel therapeutics for AD in the context of biological gerontology. The many therapies currently in development based on biological gerontology principles provide promise for the development of a new generation of therapeutics to prevent and treat AD.

Ganglioside Hp-s1 Analogue Inhibits Amyloidogenic Toxicity in Alzheimer's Disease Model Cells.

Alzheimer's disease (AD) is characterized by extracellular deposition of amyloid plaques, which are predominantly composed of amyloid-β (Aβ) peptide derived from amyloid precursor protein (APP) cleavage. APP interacts with tropomyosin receptor kinase A, a neurotrophic receptor associated with gangliosides and mediating neuronal survival and differentiation through the extracellular signal-regulated protein kinase (ERK) pathway. The ganglioside Hp-s1's analogue Hp-s1A exerts neuritogenic activity; however, its effect on AD pathology remains unknown. To test the hypothesis that Hp-s1A is a potential candidate to treat AD, we established the AD-modeled cell line by expressing human Swedish and Indiana APP gene (APP-Swe/Ind) in N2a mouse neuroblastoma cells. The cells were treated with Hp-s1A or monosialoganglioside GM1 for comparison. The AD model cells expressing APP-Swe/Ind exhibited a significant reduction in viability, as well as neurite outgrowth rate, in comparison to the control cells expressing APP-695. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. With the treatment of either Hp-s1A or GM1 at 1 μM, the AD model cells showed a significant increase in viability; however, only Hp-s1A reduced CTFβ levels in these cells. Further analysis of the culture media revealed that Hp-s1A also reduced Aβ42 production from AD model cells. The phosphorylation of ERK was elevated and the neurite outgrowth rate was restored with Hp-s1A treatment. In conclusion, the ganglioside analogue Hp-s1A inhibited amyloidogenic processing of APP and promoted neurotrophic activity and survival of AD model cells. Hp-s1A has great potential in AD therapeutic development.

Free Energy Landscape for Alpha-Helix to Beta-Sheet Interconversion in Small Amyloid Forming Peptide under Nanoconfinement.

Understanding the mechanism of fibrillization of amyloid forming peptides could be useful for the development of therapeutics for Alzheimer's disease (AD). Taking this standpoint, we have explored in this work the free energy profile for the interconversion of monomeric and dimeric forms of amyloid forming peptides into different secondary structures namely beta-sheet, helix, and random coil in aqueous solution using umbrella sampling simulations and density functional theory calculations. We show that the helical structures of amyloid peptides can form β sheet rich aggregates through random coil conformations in aqueous condition. Recent experiments ( Chem. Eur. J. 2018, 24, 3397-3402 and ACS Appl. Mater. Interfaces 2017, 9, 21116-21123) show that molybdenum disulfide nanosurface and nanoparticles can reduce the fibrillization process of amyloid beta peptides. We have unravelled the free energy profile for the interconversion of helical forms of amyloid forming peptides into beta-sheet and random coil in the presence of a two-dimensional nanosurface of MoS2. Results indicate that the monomer and dimeric forms of the peptides adopt the random coil conformation in the presence of MoS2 while the helical form is preferable for the monomeric form and that the beta-sheet and helix forms are the preferable forms for dimers in aqueous solution. This is due to strong interaction with MoS2 and intramolecular hydrogen bonds of random coil conformation. The stabilization of random coil conformation does not lead to a β sheet like secondary structure for the aggregate. Thus, the confinement of MoS2 promotes deaggregation of amyloid beta peptides rather than aggregation, something that could be useful for the development of therapeutics for AD.

Challenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects.

Alzheimer's disease (AD), the most common form of dementia in late life, will become even more prevalent by midcentury, constituting a major global health concern with huge implications for individuals and society. Despite scientific breakthroughs during the past decades that have expanded our knowledge on the cellular and molecular bases of AD, therapies that effectively halt disease progression are still lacking, and focused efforts are needed to address this public health challenge. Because AD is classically recognized as a disease of memory, studies have mainly focused on investigating memory-associated brain defects. However, compelling evidence has indicated that additional brain regions, not classically linked to memory, are also affected in the course of disease. In this review, we outline the current understanding of key pathophysiological mechanisms in AD and their clinical manifestation. We also highlight how considering the complex nature of AD pathogenesis, and exploring repurposed drug approaches can pave the road toward the development of novel therapeutics for AD.