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Melatonin is a hormone secreted by the pineal gland, it can be associated with circadian rhythms, aging and neuroprotection. Melatonin levels are decreased in sporadic Alzheimer's disease (sAD) patients, which suggests a relationship between the melatonergic system and sAD. Melatonin may reduce inflammation, oxidative stress, TAU protein hyperphosphorylation, and the formation of β-amyloid (Aβ) aggregates. Therefore, the objective of this work was to investigate the impact of treatment with 10 mg/kg of melatonin (i.p) in the animal model of sAD induced by the intracerebroventricular (ICV) infusion of 3 mg/kg of streptozotocin (STZ). ICV-STZ causes changes in the brain of rats similar to those found in patients with sAD. These changes include; progressive memory decline, the formation of neurofibrillary tangles, senile plaques, disturbances in glucose metabolism, insulin resistance and even reactive astrogliosis characterized by the upregulation of glucose levels and glial fibrillary acidic protein (GFAP). The results show that ICV-STZ caused short-term spatial memory impairment in rats after 30 days of STZ infusion without locomotor impairment which was evaluated on day 27 post-injury. Furthermore, we observed that a prolonged 30-day treatment with melatonin can improve the cognitive impairment of animals in the Y-maze test, but not in the object location test. Finally, we demonstrated that animals receiving ICV-STZ have high levels of Aβ and GFAP in the hippocampus and that treatment with melatonin reduces Aβ levels but does not reduce GFAP levels, concluding that melatonin may be useful to control the progression of amyloid pathology in the brain., Competing Interests: The authors report no conflicts of interest. This work was supported by grants from CNPq and CAPES, which had no further role in the study design, collection, analysis, and interpretation of the data, writing the report; and decision to submit the paper for publication. RA and MABFV are recipients of a CNPq fellowship., (© 2023 Published by Elsevier Ltd on behalf of International Brain Research Organization.)

Calcium plays a fundamental role in various signaling pathways and cellular processes in the human organism. In the nervous system, voltage-gated calcium channels such as L-type calcium channels (LTCCs) are critical elements in mediating neurotransmitter release, synaptic integration and plasticity. Dysfunction of LTCCs has been implicated in both aging and Alzheimer's Disease (AD), constituting a key component of calcium hypothesis of AD. As such, LTCCs are a promising drug target in AD. However, due to their structural and functional complexity, the mechanisms by which LTCCs contribute to AD are still unclear. In this review, we briefly summarize the structure, function, and modulation of LTCCs that are the backbone for understanding pathological processes involving LTCCs. We suggest targeting molecular pathways up-regulating LTCCs in AD may be a more promising approach, given the diverse physiological functions of LTCCs and the ineffectiveness of LTCC blockers in clinical studies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Calcitonin, a peptide hormone associated with medullary carcinoma of the thyroid, has the potential to form amyloid fibrils and may be a valuable model for investigating the role of peptide-membrane interactions in β-sheet and amyloid formation. Via a new model peptide system, bovine calcitonin, we found that the exposure of peptide to phospholipid membranes altered its structure relative to the structures formed in aqueous solutions. Of particular relevance to the amyloidoses, incubation of calcitonin with cholesterol-rich and ganglioside-containing membranes resulted in significant enrichment in the β-sheet and amyloid content of the peptide. The formation of amyloid was also accelerated in these systems. A correlation between the phospholipid-induced structural alterations and calcitonin binding affinities to phospholipid membranes was evident. Bovine calcitonin has considerably higher binding affinity for the phospholipid systems that enhanced its β-sheet and amyloid structure. Electrostatic forces were not the governing forces behind the observed behavior, as supported by the fact that the ionic strength did not affect the peptide structures or binding affinities. A Van't Hoff analysis of the temperature-dependent peptide binding affinities indicated that binding led to an increase in enthalpy and possibly an increase in entropy of the peptide-membrane systems. Experiments with other amyloid-forming peptides such as β-amyloid of Alzheimer's disease have also shown similar results and may indicate the need to manipulate peptide-membrane interactions in order to control amyloid formation and its associated disease. [ABSTRACT FROM AUTHOR]

Aggregation of β-amyloid (Aβ) into fibrillar deposits is widely believed to initiate a cascade of adverse biological responses associated with Alzheimer's disease. Although it was once assumed that the mature fibril was the toxic form of Aβ, recent evidence supports the hypothesis that Aβ oligomers, intermediates in the fibrillogenic pathway, are the dominant toxic species. In this work we used urea to reduce the driving force for Aβ aggregation, in an effort to isolate stable intermediate species. The effect of urea on secondary structure, size distribution, aggregation kinetics, and aggregate morphology was examined. With increasing urea concentration, β-sheet content and the fraction of aggregated peptide decreased, the average size of aggregates was reduced, and the morphology of aggregates changed from linear to a globular/linear mixture and then to globular. The data were analyzed using a previously published model of Aβ aggregation kinetics. The model and data were consistent with the hypothesis that the globular aggregates were intermediates in the amyloidogenesis pathway rather than alternatively aggregated species. Increasing the urea concentration from 0.4 M to 2 M decreased the rate of filament initiation the most; between 2 M and 4 M urea the largest change was in partitioning between the nonamyloid and amyloid pathways, and between 4 M and 6 M urea, the most significant change was a reduction in the rate of filament elongation. [ABSTRACT FROM AUTHOR]

As neuroscientists, we are taught that the brain is immune privileged and thus unlikely to be affected by the peripheral immune system. Accordingly, initial results demonstrating the effectiveness of β-amyloid (Aβ) immunotherapy in mouse models of Alzheimer’s disease (AD) were viewed with considerable surprise and some skepticism. Many groups have since demonstrated efficacy with Aβ immunotherapy in models of AD, using Aβ-based immunogens and anti-Aβ antibodies. Clinical trials involving Aβ immunotherapy for AD are in progress and are providing a wealth of information around the amyloid hypothesis of AD. Aβ immunotherapy is also raising new opportunities and questions about the general role of the immune system in neurodegenerative diseases. [Copyright &y& Elsevier]

The preponderance of evidence implicates protein misfolding in many unrelated human diseases. In all cases, normal correctly folded proteins transform from their proper native structure into an abnormal β-rich structure known as amyloid fibril. Here we introduce a computational algorithm to detect nonnative (hidden) sequence propensity for amyloid fibril formation. Analyzing sequence-structure relationships in terms of tertiary contact (TC), we find that the hidden β-strand propensity of a query local sequence can be quantitatively estimated from the secondary structure preferences of template sequences of known secondary structure found in regions of high TC. The present method correctly pinpoints the minimal peptide fragment shown experimentally as the likely local mediator of amyloid fibril formation in β-amyloid peptide, islet amyloid polypeptide (hIAPP), α-synuclein, and human acetylcholinesterase (AChE). It also found previously unrecognized β-strand propensities in the prototypical helical protein myoglobin that has been reported as amyloidogenic. Analysis of 2358 nonhomologous protein domains provides compelling evidence that most proteins contain sequences with significant hidden β-strand propensity. The present method may find utility in many medically relevant applications, such as the engineering of protein sequences and the discovery of therapeutic agents that specifically target these sequences for the prevention and treatment of amyloid diseases. [ABSTRACT FROM AUTHOR]

The neuropathological features associated with Alzheimer’s disease (AD) brain include the presence of extracellular neuritic plaques composed of amyloid β protein (Aβ), intracellular neurofibrillary tangles containing phosphorylated tau protein and the loss of basal forebrain cholinergic neurons which innervate regions such as the hippocampus and the cortex. Studies of the pathological changes that characterize AD and several other lines of evidence indicate that Aβ accumulation in vivo may initiate phosphorylation of tau protein, which by disrupting neuronal network may trigger the process of neurodegeneration observed in AD brains. However, the underlying cause of degeneration of the basal forebrain cholinergic neurons and their association, if any, to Aβ peptides or phosphorylated tau remains mostly unknown. In the present study, using rat primary septal cultures, we have shown that aggregated Aβ peptides, in a time (18–96 h)- and concentration (0.7–60 μM)-dependent manner, induce toxicity and decrease choline acetyltransferase enzyme activity in cultured neurons. Using immunocytochemistry and immunoblotting, we have also demonstrated that Aβ treatment can significantly increase the phosphorylation of tau protein in septal cultures. At the cellular level, hyperphosphorylated tau is mostly apparent in the somatodendritic compartment of the neurons. Aβ peptide (10 μM), in addition to tau phosphorylation, also activates mitogen-activated protein kinase and glycogen synthase kinase-3β, the two kinases which are known to be involved in the formation of hyperphosphorylated tau in the AD brain. Exposure to specific inhibitors of the mitogen-activated protein kinase (i.e. PD98059) or glycogen synthase kinase-3β (i.e. LiCl) attenuated the hyperphosphorylation of the tau protein in cultured neurons.Given the evidence that tau phosphorylation can induce cell loss by disrupting neuronal cytoskeleton, it is likely that aggregated Aβ peptide triggers degeneration of septal neurons, including those expressing the cholinergic phenotype, by phosphorylation of the tau protein activated by mitogen-activated protein kinase and glycogen synthase kinase-3β. These results, taken together, suggest that cultured septal cholinergic neurons are vulnerable to Aβ-mediated toxicity and tau phosphorylation may play an important role in Aβ-induced neurodegeneration. [Copyright &y& Elsevier]

Formyl peptide receptors are G-protein-coupled, seven-transmembrane domain receptors originally identified in leukocytes. Ligands for this class of receptors include the chemotactic peptide fMet-Leu-Phe, lipoxin A4, serum amyloid A and β-amyloid peptides. The formyl peptide receptor gene family contains three members in human and six members in mouse. By screening a mouse genomic library, we isolated two novel genes that were provisionally named Fpr-rs6 and Fpr-rs7. They encode putative seven-transmembrane domain proteins of 339 and 338 residues, respectively, and share between them 94% amino acid identity. The predicted amino acid sequences of Fpr-rs6 and Fpr-rs7 are 53–74% identical to other mouse formyl peptide receptors. The transcript of Fpr-rs6 is found in brain, spleen and skeletal muscle, and at high level in testis. The Fpr-rs7 transcript is more widely expressed in heart, liver, lung, spleen, smooth muscle and pancreas. Our data suggest that the expression of Fpr-rs6 and Fpr-rs7 is differentially regulated in mouse despite their high sequence homology. [Copyright &y& Elsevier]

The role of estrogen as a neurotrophic/neuroprotective agent in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases is increasingly being shown. In this study we examine the neuroprotective effects of β-estradiol on SHSY5Y neuroblastoma cells which have been exposed to the heavy metals cobalt and mercury. The results show that cobalt and mercury are able to induce oxidative stress and cell cytotoxicity and increase the secretion of β-amyloid 1–40 and 1–42. These deleterious effects are reversed by the pretreatment of cells with β-estradiol. It is further shown that β-estradiol exerts its neuroprotective action through mechanisms which reduce oxidative stress and reduce β-amyloid secretion. Pre-treatment of the cells with α-estradiol did not alleviate the toxic effects of the heavy metals.Our results are significant as they contribute to a better understanding of the mode of action of estrogen with relevance to its use in the treatment of neurodegenerative disorders. [Copyright &y& Elsevier]

Alzheimer’s disease is a progressively dementing illness characterized by the extracellular accumulation and deposition of β-amyloid. Early onset Alzheimer’s disease is linked to mutations in three genes, all of which lead to increased β-amyloid production. Inflammatory changes and gliosis may also play a role in the disease process, but the importance of these reactive events remains unclear. We recently reported that chronic cortical gliosis in heterotopic fetal rat cortical transplants is associated with significant changes in the levels of some of the proteins implicated in the pathogenesis of Alzheimer’s disease. Because rodent β-amyloid does not form extracellular amyloid deposits, we have now extended this model of chronic cortical gliosis to transgenic mice expressing the Swedish mutant form of human amyloid precursor protein. In addition, apolipoprotein E knockout mice were used to elucidate the role of this protein in reactive gliosis. The expression of mutant and murine proteins was assayed 6 or 10 months after transplantation using immunohistochemical and western blot methods.Heterotopic transplantation of fetal cortex onto the midbrain of neonatal mice consistently resulted in reactive gliosis, independent of apolipoprotein E status. In contrast, in homotopic cortex-to-cortex grafts there was little alteration in glial reactivity, a result similar to that obtained previously in rats. By 10 months post-transplantation the level of presenilin-1 expression was lower in heterotopic grafts than in host cortex and there was increased expression of transgenic amyloid precursor protein, but only in the gliotic cortex-to-midbrain grafts. Most importantly, increased levels of β-amyloid, and particularly its precursor, C-99, were selectively found in these heterotopic transplants.Our results show that chronic gliosis is associated with altered processing of the amyloid precursor protein in vivo and thus may initiate or exacerbate pathological changes associated with Alzheimer’s disease. [Copyright &y& Elsevier]

Seladin-1 is a gene recently shown to be down-regulated in brain regions selectively degenerated in Alzheimer’s disease. The sequence of seladin-1 shares similarities with flavin-adenine-dinucleotide-dependent oxidoreductases and it has been found to protect cells from apoptotic cell death. In this work, we show that the transcription of seladin-1 is selectively down-regulated in the brain areas affected in Alzheimer’s disease. The down-regulation in seladin-1 transcription was associated with hyperphosphorylated tau seen as linkage to immunohistochemically detected paired helical filament tau, neuritic plaques and neurofibrillary tangles. In contrast, no association was found between seladin-1 transcription and β-amyloid deposition when analyzing human samples or tissue from transgenic animals. Furthermore, the relative transcription of seladin-1 was found to fluctuate during aging in the transgenic mouse model of Alzheimer’s disease. The fluctuation was enhanced by Alzheimer’s disease causing mutations in presenilin-1 and amyloid precursor protein genes. Finally, seladin-1 transcription was found to be up-regulated in mouse N2a cells induced to undergo apoptosis with okadaic acid.The results presented here indicate that seladin-1 transcription is selectively down-regulated in brain regions vulnerable to Alzheimer’s disease and this down-regulation is associated with the hyperphosphorylation of tau protein. [Copyright &y& Elsevier]

Introduction: Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy., Objectives: A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined., Methods: Male TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT)., Results: Our pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing β-secretase, as well as enhancing Aβ-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO., Conclusion: Nano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.)

Neurodegenerative disorders such as Parkinson's and Alzheimer's disease, are fundamental health concerns all around the world. The development of novel treatments and new techniques to address these disorders, are being actively studied by researchers and medical personnel. In the present review we will discuss the application of induced Pluripotent Stem Cells (iPSCs) for cell-therapy replacement and disease modelling. The aim of iPSCs is to restore the functionality of the damaged tissue by replacing the impaired cells with competitive ones. To achieve this objective, iPSCs can be properly differentiated into virtually any cell fate and can be strongly translated into human health via in vitro and in vivo disease modeling for the development of new therapies, the discovery of biomarkers for several disorders, the elaboration and testing of new drugs as novel treatments, and as a tool for personalized medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2020 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting β -amyloid (A β ) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo . What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD., (© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Abnormalities in protein folding are involved in many localized and systemic diseases, all of which are characterized by insoluble amyloid formation and deposition. In immunoglobulin light chain (LC) amyloidosis, the most frequent systemic form of amyloidosis, the amyloid involvement of the heart dictates the prognosis and the elucidation of the mechanism of heart targeting and toxicity is essential for designing and testing new effective treatments. To this end, the availability of an appropriate animal model is crucial. We recently described the use ofC. elegansas an innovative experimental system to investigate in vivo the pathogenic effects of monoclonal LC. This idea stems from the knowledge that the worm's pharynx is an “ancestral heart” with the additional ability to recognize stressor compounds. The feeding of worms with LC purified from patients suffering from cardiomyopathy, selectively and permanently impaired the pharyngeal function. This irreversible damage resulted in time, in a significant reduction in the lifespan of worms. We also reported that the ability of LC to generate reactive oxygen species was associated with their toxic effects and was counteracted by anti-oxidant compounds. This new nematode-based assay represents a promising model for elucidating the heart-specific toxicity of LC and for a rapid screening of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Hippocampal atrophy is a well-known feature of Alzheimer's disease (AD), but sensitivity and specificity of hippocampal volumetry are limited. Neuropathological studies have shown that hippocampal subfields are differentially vulnerable to AD; hippocampal subfield volumetry may thus prove to be more accurate than global hippocampal volumetry to detect AD., Methods: CA1, subiculum and other subfields were manually delineated from 40 healthy controls, 18 AD, 17 amnestic Mild Cognitive Impairment (aMCI), and 8 semantic dementia (SD) patients using a previously developed high resolution MRI procedure. Non-parametric group comparisons and receiver operating characteristic (ROC) analyses were conducted. Complementary analyses were conducted to evaluate differences of hemispheric asymmetry and anterior-predominance between AD and SD patients and to distinguish aMCI patients with or without β-amyloid deposition as assessed by Florbetapir-TEP., Results: Global hippocampi were atrophied in all three patient groups and volume decreases were maximal in the CA1 subfield (22% loss in aMCI, 27% in both AD and SD; all p < 0.001). In aMCI, CA1 volumetry was more accurate than global hippocampal measurement to distinguish patients from controls (areas under the ROC curve = 0.88 and 0.76, respectively; p = 0.05) and preliminary analyses suggest that it was independent from the presence of β-amyloid deposition. In patients with SD, whereas the degree of CA1 and subiculum atrophy was similar to that found in AD patients, hemispheric and anterior-posterior asymmetry were significantly more marked than in AD with greater involvement of the left and anterior hippocampal subfields., Conclusions: The findings suggest that CA1 measurement is more sensitive than global hippocampal volumetry to detect structural changes at the pre-dementia stage, although the predominance of CA1 atrophy does not appear to be specific to AD pathophysiological processes.