Accumulation Of Amyloid Beta Protein Research Articles

The case for regulatory approval of amyloid-lowering immunotherapies in Alzheimer's disease based on clearcut biomarker evidence.

Decades of research have provided evidence that Alzheimer's disease (AD) is caused in part by cerebral accumulation of amyloid beta-protein (Aβ). In 2023, the US Food and Drug Administration gave full regulatory approval to a disease-modifying Aβ antibody for early AD. Secondary prevention trials with Aβ antibodies are underway. We summarize peer-reviewed evidence for targeting Aβ and argue that regulators should consider approving new agents working by similar mechanisms (Aβantibodies and vaccines) based on robust amyloid lowering and reasonable safety. The urgent need to provide treatments to millions of mildly symptomatic patients suggests that AD should join other diseases for which standard approval is based on significant changes in mechanistically meaningful biomarkers coupled with safety. Robust amyloid lowering in secondary prevention trials of people who have amyloid plaques but are asymptomatic could also provide evidence of a change in the pathophysiological progression of AD as a basis for regulatory approval. HIGHLIGHTS: Thirteen key findings support amyloid beta as a cause of Alzheimer's disease (AD). Three immunotherapies lower amyloid and slow decline, allowing regulatory approval. New such agents could be considered for approval due to amyloid lowering and safety. Urgency suggests AD may join diseases with approval due to a key biomarker + safety.

Herbal Medicine: A Promising Approach for the Treatment of Alzheimer's Disease

Alzheimer's disease is a progressive neurodegenerative disease manifesting in cognitive decline, impairment of memory, and behavioural deterioration. Alzheimer’s is a relatively common type of dementia. The pathological basis for the progression of Alzheimer's disease is beta-amyloid protein accumulation, phosphorylation of tau protein, abnormal glial cell function, inflammation, neurotransmitter imbalance, along with oxidative stress in brain tissue. Current available therapies are targeted at amelioration of symptoms alone and focus on a limited spectrum of pathophysiological processes. It is evident that it is essential to develop a multi-target therapeutic option in managing Alzheimer's disease, in view of the broad range of factors in disease progression and sever consequences for sufferers. Herbal medicines are seen as a potential resource in the treatment of Alzheimer's disease, in view of their historical use in traditional medicine as neuroprotectants. Herbal medicines have been evaluated in animal studies designed to determine their capacity to prevent neurodegenerative disease and ameliorate memory defects. This review elaborates on the studies conducted on several medicinal plants that have been investigated for their potential in the prevention and treatment of memory defects in animal models.

Lipid-polymer hybrid nanoparticles loaded with N-acetylcysteine for the modulation of neuroinflammatory biomarkers in human iPSC-derived PSEN2 (N141I) astrocytes as a model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment associated with the accumulation of beta-amyloid protein (Aβ). Aβ activates glial cells in the brain, increasing the secretion of proinflammatory cytokines, which leads to neuroinflammation and neuronal death. Currently, there are no effective treatments that cure or stop its progression; therefore, AD is considered a global health priority. The main limitations are the low drug bioavailability and impermeability of the blood-brain barrier (BBB). Fortunately, nanomedicine has emerged as a promising field for the development of new nanosystems for the controlled and targeted delivery of drugs to the brain. Therefore, in this work, lipid-polymer hybrid nanoparticles (LPHNPs) conjugated with transferrin (Tf) to facilitate crossing the BBB and loaded with N-acetylcysteine (NAC) for its anti-inflammatory effect were synthesized, and their physicochemical characterization was carried out. Subsequently, an in vitro model involving human astrocytes derived from induced pluripotent stem cells (iPSC) from an AD-diagnosed patient was developed, which was brought to a reactive state by stimulation with lipopolysaccharides (LPSs). The cell culture was treated with either Tf-conjugated LPHNPs loaded with NAC (NAC-Tf-LPHNPs) at 0.25 mg mL-1, or free NAC at 5 mM. The results showed that NAC-Tf-LPHNPs favorably modulated the expression of proinflammatory genes such as interleukin-1β (IL-1β), amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP). In addition, they reduced the secretion of the proinflammatory cytokines interleukin 6 (IL-6), IL-1β and interferon-gamma (INF-γ). Results for both cases were compared to the group of cells that did not receive any treatment. In contrast, free NAC only had this effect on the expression of IL-1β and the secretion of the cytokines IL-6 and INF-γ. These results indicate the potential of NAC-Tf-LPHNPs for AD treatment.

Multimodal analysis of disease onset in Alzheimer’s disease using Connectome, Molecular, and genetics data

Alzheimer’s disease (AD) and its related age at onset (AAO) are highly heterogeneous, due to the inherent complexity of the disease. They are affected by multiple factors, such as neuroimaging and genetic predisposition. Multimodal integration of various data types is necessary; however, it has been nontrivial due to the high dimensionality of each modality. We aimed to identify multimodal biomarkers of AAO in AD using an extended version of sparse canonical correlation analysis, in which we integrated two imaging modalities, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), and genetic data in the form of single-nucleotide polymorphisms (SNPs) obtained from the Alzheimer’s disease neuroimaging initiative database. These three modalities cover low-to-high-level complementary information and offer multiscale insights into the AAO. We identified multivariate markers of AAO in AD using fMRI, PET, and SNP. Furthermore, the markers identified were largely consistent with those reported in the existing literature. In particular, our serial mediation analysis suggests that genetic variants influence the AAO in AD by indirectly affecting brain connectivity by mediation of amyloid-beta protein accumulation, supporting a plausible path in existing research. Our approach provides comprehensive biomarkers related to AAO in AD and offers novel multimodal insights into AD.

Insights into Neurocognitive Sequelae of COVID‐19 Infection from Studies of Brain Organoids

AbstractBackgroundCOVID‐19 has been associated with chronic neurocognitive changes which persist after resolution of the acute infection. Brain organoids composed of different neuronal cell types serve as a useful model to evaluate the underlying effects of SARS‐CoV‐2 infection to the brain and facilitate insights into the neurocognitive sequelae of COVID‐19.MethodA review of studies which used brain organoids to evaluate the effects of COVID‐19 was conducted. The studies were identified from the PubMed/MEDLINE database using the search terms “SARS‐CoV‐2” or “COVID‐19” in combination with “organoid” or “brain” or “3D” or “iPSC”. Articles published in English between 1 Jan 2020 and 31 Mar 2023 were included.ResultWe identified a total of 16 studies which used brain organoids to study SARS‐CoV‐2 neurotropism and downstream effects. Although SARS‐CoV‐2 was able to infect neurons, the extent of neurotropism was limited. Instead, choroidal epithelial cells and glial cells including, astrocytes and microglial, demonstrated significant susceptibility to SARS‐CoV‐2 infection. Furthermore it was observed that certain downstream effects of SARS‐CoV‐2 infection were associated with pathways seen in neurodegenerative diseases like Alzheimer’s Disease (AD). These included findings of reactive astrogliosis, impairment of glutamate and choline transporters, microglial‐mediated synapse loss, increased pTau expression and beta amyloid protein accumulation. Overall, the studies suggested that the neurocognitive manifestations of COVID‐19 may be contributed by neuroinflammatory processes and pathways that are found in chronic neurodegenerative conditions like AD.ConclusionAlthough brain organoid technology remains a relatively new tool, it has provided important insights into the pathophysiology of COVID‐19. The use of “assembloids” to recapitulate interactions between different brain regions and development of high throughput evaluation to analyse transcriptome and epigenome changes of infected brain organoids may be further expanded to allow a better understanding of potential neurodegenerative pathways that may result in neurocognitive changes after a viral infection.

Effect of Bacterial Amyloid Protein Phenol-Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer's Disease.

Since the proposal of the brainstem axis theory, increasing research attention has been paid to the interactions between bacterial amyloids produced by intestinal flora and the amyloid β-protein (Aβ) related to Alzheimer's disease (AD), and it has been considered as the possible cause of AD. Therefore, phenol-soluble modulin (PSM) α3, the most virulent protein secreted by Staphylococcus aureus, has attracted much attention. In this work, the effect of PSMα3 with a unique cross-α fibril architecture on the aggregation of pathogenic Aβ40 of AD was studied by extensive biophysical characterizations. The results proposed that the PSMα3 monomer inhibited the aggregation of Aβ40 in a concentration-dependent manner and changed the aggregation pathway to form granular aggregates. However, PSMα3 oligomers promoted the generation of the β-sheet structure, thus shortening the lag phase of Aβ40 aggregation. Moreover, the higher the cross-α content of PSMα3, the stronger the effect of the promotion, indicating that the cross-α structure of PSMα3 plays a crucial role in the aggregation of Aβ40. Further molecular dynamics (MD) simulations have shown that the Met1-Gly20 region in the PSMα3 monomer can be combined with the Asp1-Ala2 and His13-Val36 regions in the Aβ40 monomer by hydrophobic and electrostatic interactions, which prevents the conformational conversion of Aβ40 from the α-helix to β-sheet structure. By contrast, PSMα3 oligomers mainly combined with the central hydrophobic core (CHC) and the C-terminal region of the Aβ40 monomer by weak H-bonding and hydrophobic interactions, which could not inhibit the transition to the β-sheet structure in the aggregation pathway. Thus, the research has unraveled molecular interactions between Aβ40 and PSMα3 of different structures and provided a deeper understanding of the complex interactions between bacterial amyloids and AD-related pathogenic Aβ.

Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model

Accumulation of amyloid beta protein (Aβ) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aβ and produce disease-modifying mediators. Herein, we report that Aβ40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.

Is Alzhezimer’s disease a New Type Diabetes? Crosstalk between two serious disorders: review

Introduction and purpose: More and more reports suggest that diabetes plays an important role in the pathogenesis of Alzheimer's disease (AD). Understanding this link may provide a new approach to modulating the onset and progression of sporadic AD cases. The aim of the study is to present the current state of knowledge on the basic mechanisms and factors influencing the development of AD in patients with type 2 diabetes in the context of clinical practice.
 State of knowledge: It is estimated that up to 80% of Alzheimer's patients have glucose intolerance or diabetes. Impaired insulin signaling can lead to abnormal processing and accumulation of beta-amyloid protein, which can result in memory deficits and cognitive decline. Insulin deficiency can also cause over-activity of the GSK3 enzyme, leading to tau hyperphosphorylation and senile plaque accumulation. Diabetes can also cause fibrotic changes in cerebral vessels, disrupting brain metabolism and potentially leading to hippocampus atrophy. The release of cytokines during the metabolic syndrome can also cause oxidative stress and neuroinflammation, which may contribute to neuronal atrophy. It has been reported that healthy diet, physical exercises and prevention of metabolic diseases may reduce the incidence of AD.
 Conclusions: Epidemiological data and pathophysiological studies indicate a significant relationship between these diseases that AD is sometimes called Type 3 diabetes. Early detection of hyperglycemia and its proper management, may be crucial in the context of the clinical prevention of dementia diseases. It is essential to pay attention to the cognitive abilities of patients with metabolic diseases.

Neuroprotective activity of selenium nanoparticles against the effect of amino acid enantiomers in Alzheimer's disease.

Alzheimer's disease (AD), the most prevalent neurodegenerative disease, is characterized by extracellular accumulation of amyloid-beta protein (Aβ), which is believed to be the very starting event of AD neurodegeneration. In this work, D-Phe, D-Ala, and D-Glu amino acids, which are the non-occurring enantiomeric form in the human body, and also D-Asp and DL-SeMet, have proved to be amyloidogenic regarding Aβ42 aggregation in TEM studies. These amyloidogenic amino acid enantiomers also widened Aβ42 fibrils up to 437% regarding Aβ42 alone, suggesting that Aβ42 aggregation is enantiomerically dependent. To inhibit enantiomeric-induced amyloid aggregation, selenium nanoparticles stabilized with chitosan (Ch-SeNPs) were successfully synthesized and employed. Thus, Ch-SeNPs reduced and even completely inhibited Aβ42 aggregation produced in the presence of some amino acid enantiomers. In addition, through UV-Vis spectroscopy and fluorescence studies, it was deduced that Ch-SeNPs were able to interact differently with amino acids depending on their enantiomeric form. On the other hand, antioxidant properties of amino acid enantiomers were evaluated by DPPH and TBARS assays, with Tyr enantiomers being the only ones showing antioxidant effect. All spectroscopic data were statistically analysed through experimental design and response surface analysis, showing that the interaction between the Ch-SeNPs and the amino acids studied was enantioselective and allowing, in some cases, to establish the concentration ratios in which this interaction is maximum.

Food for Thought

This paper describes the connection between the foods we eat and our brain health. It asses the effects of certain nutrient groups on th ebrain and their role in the pathogenesis of Alzheimer's Disease (AD), specifically the brain abnormalities associated with it, including Tau Tangles, Amyloid-Beta Plaques, and oxidative stress. The intake of a high fat diet, with saturated fats in particular, has been shown to aggravate Beta-Amyloid Protein accumulation and the formation of Tau Tangles, whereas a diet low in saturated fat and high in N-3 fatty acids has been shown to reduce Amyloid-Beta Plaque formation and lessen cognitive decline. An antioxidant-ruch diet improves learning and memory in mice and combats the heightened oxidative dress found in AD brains. The mind and bash diets have both been shown to diminish Alzheimer's incidences, but the mind diet proves itself to be more impactful than the dash due to its specific emphasis on the consumption of foods high in antioxidants.

Amyloidosis in Alzheimer's Disease: Pathogeny, Etiology, and Related Therapeutic Directions.

The amyloid hypothesis of Alzheimer’s disease has long been the predominant theory, suggesting that Alzheimer’s disease is caused by the accumulation of amyloid beta protein (Aβ) in the brain, leading to neuronal toxicity in the central nervous system (CNS). Because of breakthroughs in molecular medicine, the amyloid pathway is thought to be central to the pathophysiology of Alzheimer’s disease (AD). Currently, it is believed that altered biochemistry of the Aβ cycle remains a central biological feature of AD and is a promising target for treatment. This review provides an overview of the process of amyloid formation, explaining the transition from amyloid precursor protein to amyloid beta protein. Moreover, we also reveal the relationship between autophagy, cerebral blood flow, ACHE, expression of LRP1, and amyloidosis. In addition, we discuss the detailed pathogenesis of amyloidosis, including oxidative damage, tau protein, NFTs, and neuronal damage. Finally, we list some ways to treat AD in terms of decreasing the accumulation of Aβ in the brain.

Semax, a Synthetic Regulatory Peptide, Affects Copper-Induced Abeta Aggregation and Amyloid Formation in Artificial Membrane Models

Alzheimer’s disease, the most common form of dementia, is characterized by the aggregation of amyloid beta protein (Aβ). The aggregation and toxicity of Aβ are strongly modulated by metal ions and phospholipidic membranes. In particular, Cu2+ ions play a pivotal role in modulating Aβ aggregation. Although in the last decades several natural or synthetic compounds were evaluated as candidate drugs, to date, no treatments are available for the pathology. Multifunctional compounds able to both inhibit fibrillogenesis, and in particular the formation of oligomeric species, and prevent the formation of the Aβ:Cu2+ complex are of particular interest. Here we tested the anti-aggregating properties of a heptapeptide, Semax, an ACTH-like peptide, which is known to form a stable complex with Cu2+ ions and has been proven to have neuroprotective and nootropic effects. We demonstrated through a combination of spectrofluorometric, calorimetric, and MTT assays that Semax not only is able to prevent the formation of Aβ:Cu2+ complexes but also has anti-aggregating and protective properties especially in the presence of Cu2+. The results suggest that Semax inhibits fiber formation by interfering with the fibrillogenesis of Aβ:Cu2+ complexes.

A review on phyto-nanotechnology for therapy of alzheimer’s disease

Alzheimer’s disease (AD) is a common chronic neurodegenerative disease (ND) that is mainly investigated nowadays because of its increased incidence and burden on the elderly population. It leads to atrophy of the brain. Clinical features of AD include loss of memory with impaired cognition and behaviour, which leads to mood instability and death. Aggregation of beta-amyloid protein(Aβ) and neurofibrillary tangles within the neuronal cells are the accepted pathophysiological process of AD. Studies have demonstrated that medicinal plants and herbs could improve memory and cognitive function affected by AD. The bioavailability of active herbal components is affected by rapid metabolism, less permeability, and decreased stability within the CNS. Many studies have reported that the application of nanotechnology to plant extracts enhances the efficacy of extracts. Adding herbal extracts into the nanoparticle system could improve the action of extracts, promote the sustained release of bioactive components, decrease the required dose, and lower the side effects. Using published articles from trustworthy resources like PubMed, Google Scholar, Research Gate, Web of Science, and Wiley Online Library, with keywords like "natural products," "Alzheimer's disease," and "nanotechnology," herein we reviewed and summarized recent nano-drug delivery treatment strategies for AD using natural products.

Neuroinflammatory and Neurometabolomic Consequences From Inhaled Wildfire Smoke-Derived Particulate Matter in the Western United States.

Utilizing a mobile laboratory located >300 km away from wildfire smoke (WFS) sources, this study examined the systemic immune response profile, with a focus on neuroinflammatory and neurometabolomic consequences, resulting from inhalation exposure to naturally occurring wildfires in California, Arizona, and Washington in 2020. After a 20-day (4 h/day) exposure period in a mobile laboratory stationed in New Mexico, WFS-derived particulate matter (WFPM) inhalation resulted in significant neuroinflammation while immune activity in the peripheral (lung, bone marrow) appeared to be resolved in C57BL/6 mice. Importantly, WFPM exposure increased cerebrovascular endothelial cell activation and expression of adhesion molecules (VCAM-1 and ICAM-1) in addition to increased glial activation and peripheral immune cell infiltration into the brain. Flow cytometry analysis revealed proinflammatory phenotypes of microglia and peripheral immune subsets in the brain of WFPM-exposed mice. Interestingly, endothelial cell neuroimmune activity was differentially associated with levels of PECAM-1 expression, suggesting that subsets of cerebrovascular endothelial cells were transitioning to resolution of inflammation following the 20-day exposure. Neurometabolites related to protection against aging, such as NAD+ and taurine, were decreased by WFPM exposure. Additionally, increased pathological amyloid-beta protein accumulation, a hallmark of neurodegeneration, was observed. Neuroinflammation, together with decreased levels of key neurometabolites, reflect a cluster of outcomes with important implications in priming inflammaging and aging-related neurodegenerative phenotypes.

The Female Impact in the World of Neurodegeneration.

Scientific research fuels advances in medicine, but the contributions of individual scientists, especially women, are often underappreciated. The field of neuroscience is vast, with many important gaps in knowledge remaining; thus, it is imperative for women to be able to contribute. A pivotal 2018 study revealed that women were still shockingly underrepresented in academic neurology, representing only 30.8% of academic neurologists (McDermott et al., 2018). Of additional concern, this gender gap grows with increasing academic rank, with only 13.8% of neurology professors being women (McDermott et al., 2018). Although women have faced much adversity in the field of neuroscience, there have been pioneers who have paved a path for other women. Moreover, these women made important contributions that enhanced scientific understanding of neurodegeneration and neurodegenerative diseases. The purpose of this paper is to highlight notable, but underappreciated, female neuroscientists and their important contributions to modern understanding of neurodegeneration. Overview of Neurodegeneration The term neurodegeneration is a mixture of two words—“neuro”, which refers to nerve cells and then “degeneration”, which refers to progressive damage. The term in its entirety, “neurodegeneration”, can be used to describe various conditions that result in the loss of nerve structure and function. This deterioration of neural structures results in a loss of cognitive abilities such as memory and decision making (Murman, 2015). Loss of neural function is a key hallmark in many neurodegenerative diseases, including Parkinson's disease (PD), Huntington's disease (HD), Multiple Sclerosis (MS), Alzheimer's disease (AD), and many rare disorders (Przedborski et al., 2003). An important area of research is exploring the mechanisms that underlie neurodegeneration and plasticity; this includes investigation of proteins implicated in AD (e.g., tau; amyloid-beta) and Parkinson's (e.g., alpha-synuclein). Tau is a protein found in the brain that serves to stabilize microtubules (Gao et al., 2018); tau hyperphosphorylation results in its aggregation into insoluble tangles, a characteristic biomarker of AD. Another characteristic feature of AD is the aggregation of amyloid beta protein into extracellular deposits known as amyloid plaques (Bloom, 2014). Alpha-synuclein is a neuronal protein that normally regulates trafficking of synaptic vesicles for neurotransmitter release. If mutated, the once soluble protein aggregates into insoluble fibrils forming Lewy bodies, a hallmark feature of PD (Stefanis, 2012). Notably, there are currently no known therapies that can prevent or reverse neurodegeneration. Rather, for each particular disease, medications may be available that reduce symptom burden and improve quality of life. Ongoing research efforts focus on the similarities between neurodegenerative these diseases in the hope of 1 day finding a cure. In this manuscript, notable contributions of women to neurodegeneration research are highlighted. These contributions are vast and include discoveries about neuronal pathways, proteins, vascular effects on neurodegeneration, nerve growth factor, and novel imaging techniques. In total, 12 female neuroscientists are celebrated below, namely: Rita Levi-Montalcini, Valina L. Dawson, Eva-Maria Mandelkow, Tara Spires-Jones, Maria Grazia Spillantini, Miia K. Kivipelto, Vivian Tabar, Marian Diamond, Elizabeth Roboz-Einstein, Cecile Vogt-Mugnier, Patricia Goldman-Rakic, and Anita Harding. A timeline of select key advancements in neurodegeneration research is provided below (see Figure 1). Open in a separate window Figure 1 The above timeline outlines a few key events that contributed to knowledge of neurodegeneration. Some of the events shown are the first descriptions of neurodegenerative diseases, others are key discoveries regarding the mechanisms of neurodegeneration, one is a clinical trial.

Alzheimer’s Disease Treated with Autologous and Allogeneic TelomerasePositive Stem Cells

Alzheimer’s disease is an insidious and progressive loss of balance and cognitive memories from present time to distant past that occurs in reverse chronological order. While the cause for AD is poorly understood, the presence of tau, aggregation of beta-amyloid protein, activated microglia, and massive losses of neurons and their synaptic processes have been associated with the disease. Genetics appear to play a major role in AD, but comorbidities intervene as well. There are five drug treatments approved to control the symptoms of the disease, but none were clinically proven to alter the course or decrease the risk for AD. Death eventually occurs, usually 3-9 years after initial diagnosis. Stem cells, e.g., embryonic stem cells, induced pluripotent stem cells; mesenchymal stem cells, medicinal signaling cells, and neural stem cells have been suggested as potential treatments for AD. While clinical trials demonstrated safety of administering some of these stem cells, none demonstrated any efficacy for reversing the symptoms of AD. We report the use of adult telomerase positive stem cells as a treatment modality for reversing the symptoms of AD. In a small cohort clinical trial (n=4), there were no adverse reactions reported for any individual treated. In addition, efficacy for telomerase positive stem cells approximated 50% for reduction in symptoms of Alzheimer’s disease up to four months after their last telomerase positive stem cell treatment.

Bioactive Compounds and Traditional Herbal Medicine: Promising Approaches for the Treatment of Dementia.

Dementia is a term that encompasses a group of clinical symptoms affecting memory, thinking and social abilities, characterized by progressive impairment of memory performance and cognitive functions. There are several factors involved in the pathogenesis and progression of dementia, such as old age, brain ischemia, toxin exposure, and oxidative stress. There are extensive similarities between dementia and Alzheimer’s disease (AD) either in clinical manifestations or experimental animal models. AD is the most dominant form of dementia, characterized by the accumulation of beta-amyloid protein and cholinergic neurotransmission deficits in the brain. Currently available medications for the treatment of dementia, such as choline esterase inhibitors, N-methyl-D-aspartate (NMDA) antagonists (memantine), have short-term efficacy and only relieve symptoms rather than targeting the main underlying pathogenesis. Several animal studies and clinical trials are being conducted to provide a rational approach to these medicinal plants in the prevention or treatment of memory deficits. This review highlights the potential effects of medicinal plants and their derived lead molecules, and explains the related mechanisms and effects reviewed from published literature as major thrust aspects and hopeful strategies in the prevention or treatment of dementia.

Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer's disease

The pathogenesis of Alzheimer's disease (AD) is correlated with the misfolding and aggregation of amyloid-beta protein (Aβ). Here we report that the antibiotic benzylpenicillin (BP) can specifically bind to Aβ, modulate the process of aggregation and supress its cytotoxic effect, initially via a reversible binding interaction, followed by covalent bonding between specific functional groups (nucleophiles) within the Aβ peptide and the beta-lactam ring. Mass spectrometry and computational docking supported covalent modification of Aβ by BP. BP was found to inhibit aggregation of Aβ as revealed by the Thioflavin T (ThT) fluorescence assay and atomic force microscopy (AFM). In addition, BP treatment was found to have a cytoprotective activity against Aβ-induced cell cytotoxicity as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell toxicity assay. The specific interaction of BP with Aβ suggests the possibility of structure-based drug design, leading to the identification of new drug candidates against AD. Moreover, good pharmacokinetics of beta-lactam antibiotics and safety on long-time use make them valuable candidates for drug repurposing towards neurological disorders such as AD.

Study on the neuroprotective effects of Genistein on Alzheimer's disease.

Along with the aging of the world population, the incidence rate of Alzheimer's disease (AD) has been increasing. At present, AD has become one of the most serious problems faced by modern medicine. Studies have shown that estrogen has a positive effect on AD, but estrogen has the side effect of leading to tumors. Recent in vivo studies have shown that genistein, one of the selective estrogen receptor modulators (SERMs), can improve brain function through the blood–brain barrier (BBB), antagonize the toxicity of amyloid β‐protein (Aβ), that is, to inhibit neurotoxicity due to aggregation of beta amyloid protein, and have neuroprotective effects. In addition, the use of Gen can avoid the risk of endometrial cancer and breast cancer caused by estrogen therapy while exerting an estrogen‐like effect, which has some potential for the delay and treatment of AD.

Pharmacological intervention in a transgenic mouse model improves Alzheimer's-associated pathological phenotype: Involvement of proteasome activation

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by a progressive decline in a variety of cognitive and non-cognitive functions. The amyloid beta protein cascade hypothesis places the formation of amyloid beta protein aggregates on the first position in the complex pathological cascade leading to neurodegeneration, and therefore AD might be considered to be a protein-misfolding disease. The Ubiquitin Proteasome System (UPS), being the primary protein degradation mechanism with a fundamental role in the maintenance of proteostasis, has been identified as a putative therapeutic target to delay and/or to decelerate the progression of neurodegenerative disorders that are characterized by accumulated/aggregated proteins. The purpose of this study was to test if the activation of proteasome in vivo can alleviate AD pathology. Specifically by using two compounds with complementary modes of proteasome activation and documented antioxidant and redox regulating properties in the 5xFAD transgenic mice model of AD, we ameliorated a number of AD related deficits. Shortly after proteasome activation we detected significantly reduced amyloid-beta load correlated with improved motor functions, reduced anxiety and frailty level. Essentially, to our knowledge this is the first report to demonstrate a dual activation of the proteasome and its downstream effects. In conclusion, these findings open up new directions for future therapeutic potential of proteasome-mediated proteolysis enhancement.