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Amyloid fibrils of tau are increasingly accepted as a cause of neuronal death and brain atrophy in Alzheimer's disease (AD). Diminishing tau aggregation is a promising strategy in the search for efficacious AD therapeutics. Previously, our laboratory designed a six-residue, nonnatural amino acid inhibitor D-TLKIVW peptide (6-DP), which can prevent tau aggregation in vitro. However, it cannot block cell-to-cell transmission of tau aggregation. Here, we find D-TLKIVWC (7-DP), a d-cysteine extension of 6-DP, not only prevents tau aggregation but also fragments tau fibrils extracted from AD brains to neutralize their seeding ability and protect neuronal cells from tau-induced toxicity. To facilitate the transport of 7-DP across the blood-brain barrier, we conjugated it to magnetic nanoparticles (MNPs). The MNPs-DP complex retains the inhibition and fragmentation properties of 7-DP alone. Ten weeks of MNPs-DP treatment appear to reverse neurological deficits in the PS19 mouse model of AD. This work offers a direction for development of therapies to target tau fibrils.

The substantia nigra is generally considered to show significant cell loss not only in Parkinson's but also in Alzheimer's disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo. The part of the molecule responsible for these actions has been identified as a 14-mer peptide, T14, cleaved from the AChE C-terminus and acting at an allosteric site on alpha-7 nicotinic receptors, with consequences implicated in neurodegeneration. Here, we show that free T14 is co-localized with tyrosine hydroxylase in rodent pars compacta neurons. In brains with Alzheimer's pathology, the T14 immunoreactivity in these neurons increases in density as their number decreases with the progression of the disease. To explore the functional implications of raised T14 levels in the substantia nigra, the effect of exogenous peptide on electrically evoked neuronal activation was tested in rat brain slices using optical imaging with a voltage-sensitive dye (Di-4-ANEPPS). A significant reduction in the activation response was observed; this was blocked by the cyclized variant of T14, NBP14. In contrast, no such effect of the peptide was seen in the striatum, a region lacking the T14 target, alpha-7 receptors. These findings add to the accumulating evidence that T14 is a key signaling molecule in neurodegenerative disorders and that its antagonist NBP14 has therapeutic potential.

Introduction: The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood., Methods: Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts-AD and a transgenic mouse model-to investigate T14, a 14mer peptide, as a key signaling molecule in the neuropathology., Results: T14 increases in AD brains as the disease progresses and is conspicuous in 5XFAD mice, where its immunoreactivity corresponds to that seen in AD: neurons immunoreactive for T14 in proximity to T14-immunoreactive plaques. NBP14 is a cyclized version of T14, which dose-dependently displaces binding of its linear counterpart to alpha-7 nicotinic receptors in AD brains. In 5XFAD mice, intranasal NBP14 for 14 weeks decreases brain amyloid and restores novel object recognition to that in wild-types., Discussion: These findings indicate that the T14 system, for which the signaling pathway is described here, contributes to the neuropathological process and that NBP14 warrants consideration for its therapeutic potential., Competing Interests: Susan Greenfield is the founder and CEO of Neuro‐Bio Limited and holds shares in the Company. She is the inventor in all Neuro‐Bio patents. Neuro‐Bio has a patent portfolio that currently includes 15 patent families (granted patents in Australia ( AU), China (CN), Europe (EP), Japan (JP), Mexico (MX), and United States of America (USA)). The bulk of this patent protection is in the field of neurodegeneration and, in particular, Alzheimer's disease. Of these, there are granted patents (in AU x2, CN, EP, JP, MX, and USA) and pending patent applications (in Brazil (BR), Canada (CA), India (IN), Republic of Korea (KR), New Zeland (NZ), and South Africa (ZA)) all based on WO2015/004430 (use of cyclic peptides from the C‐terminus of AChE for the diagnosis, prevention and treatment of neurodegeneration). In addition, Neuro‐Bio has a published international patent application with 12 corresponding national phases at different stages of prosecution based on each of WO2016/083809 (Novel linear peptides for treating neurodegeneration); WO2018/033724 (Peptidomimetics for treating Alzheimer's disease); and WO2016/156803 (Antibody that recognizes the T14 peptide of AChE). Neuro‐Bio also has published international patent application based on WO2018/178665 (Quantitative predictive biomarker for predicting cognitive decline) with national phases proceeding in the USA and EP. Neuro‐Bio additionally has an unpublished UK patent application drawn to Braak staging and positron emision tomography (PET) scanning for diagnosing Alzheimer's disease, and an unpublished international patent cooperation treaty (PCT) application protecting an in vivo animal model of Alzheimer's disease for testing novel therapies. In addition to Neuro‐Bio's core focus of detection and therapy of neurodegenerative disorders (in particular, Alzheimer's disease), it has two patent families concerning cancer and metastasis, that is, WO2017/130003 (diagnosing cancer) and WO2015/054068 (treating cancer with cyclic peptides), both of which have 12 national phases currently pending. All are owned by Neuro‐Bio with no encumbrance. Recent inventions have led to patent applications relating to various skin conditions. Neuro‐Bio has also recently filed a United Kingdom (UK) patent application for the treatment of Down's syndrome. Susan Greenfield is a member of the House of Lords in the United Kingdom's Parliament; this is a non‐stipendiary appointment. Clive Coen holds shares in the company and sits on the Neuro‐Bio Science Advisory Board (non‐stipendiary). He is Editor of Neuroendocrinology and the Chair of the Rationalist Association [UK]; neither of these entities has made payments to him or his institution. His research has been supported by the Biotechnology and Biological Sciences Research Council. Sara Garcia‐Ratés, Paul Morrill, Owen Hollings, Matthew Passmore, and Sibah Hasan are employees of Neuro‐Bio. Gregory Cole and his colleagues at University of California, Los Angeles (UCLA) (Sally Fraustchy, Ram P Singh, and Marisa Mekkittikul), have received partial support for consumables from Neuro‐Bio. Nikisha Carty, Silvia Bison, Laura Piccoli, Renzo Carletti, Stephano Tacconi, Anna Chalidou, Matthew Pedercini, Tim Kroecher, Hubert Astner, and Philip Gerrard are employees of Evotec. Evotec, a provider of scientific expertise to the global health care industry and academia, was contracted by Neuro‐Bio to undertake the behavioral part of the project and the immunohistochemical studies on amyloid. In the past 36 months, Gregory Cole has received grants and contracts: Veterans administration (VA) Merit BX004332, 2019‐2023 (Cole Principal Investigator (PI)): Tauopathy in mice and humans: surrogate plasma biomarkers for brain trauma‐initiated neurodegenerative disease. Akros/Japan Tobacco Contract, 2018‐2020 (Cole PI): Enhancing pyruvate dehydrogenase activity. NIH NIA R01AG057658, 2017‐2022 (Cole Co‐PI): Treating Alzheimer's disease by reducing brain insulin resistance with incretin receptor agonists. AstraZeneca NCR‐19‐14517, 2019‐2020 (Ajit Divakaruni PI; Cole Co‐I): Determining the role of brain nutrient preference in cognitive impairment and AD. National Neurological Aids Bank 3U24MH100929‐08S1, 2021‐2023 (Elyse Singer PI; Cole Co‐I): Alzheimer's related biomarker neuropathology in HIV post‐mortem brains. NIH/NIA R21 AG069100‐01, 2020 (Qiulan Ma PI; Cole Co‐I): Modulation of TGF‐beta signaling by omega‐6 polyunsaturated fatty acids for treating Alzheimer's disease. NIH NINR R01NR017190‐03, 2020‐2021 (Sarah Choi & Rajesh Kumar MPI; Cole Co‐I): Relationships between brain tissue integrity and self‐care abilities in adults with type 2 diabetes administrative supplement. Michael J Fox Foundation, 2021 (David Eisenberg PI; Cole Co‐I): Completion of pre‐clinical study of a safe and effective image‐based biomarker for Parkinson's disease. Michael J Fox Foundation, 2021‐2022 (Sally Frautschy PI; Cole Co‐I): Liganded nanoparticles to inhibit alpha‐synuclein aggregate deficits in endosomal/lysosomal/autophagy. In the past 36 months, Gregory Cole has received royalties or licenses from a curcumin formulation patent and Ram Singh has received consulting fees from UCLA., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Retinal imaging is a non-invasive tool to study both retinal vasculature and neurodegeneration. In this exploratory retinal curcumin-fluorescence imaging (RFI) study, we sought to determine whether retinal vascular features combined with retinal amyloid burden correlate with the neurocognitive status., Methods: We used quantitative RFI in a cohort of patients with cognitive impairment to automatically compute retinal amyloid burden. Retinal blood vessels were segmented, and the vessel tortuosity index (VTI), inflection index, and branching angle were quantified. We assessed the correlations between retinal vascular and amyloid parameters, and cognitive domain Z-scores using linear regression models., Results: Thirty-four subjects were enrolled and twenty-nine (55% female, mean age 64 ± 6 years) were included in the combined retinal amyloid and vascular analysis. Eleven subjects had normal cognition and 18 had impaired cognition. Retinal VTI was discriminated among cognitive scores. The combined proximal mid-periphery amyloid count and venous VTI index exhibited significant differences between cognitively impaired and cognitively normal subjects (0.49 ± 1.1 vs. 0.91 ± 1.4, p = 0.006), and correlated with both the Wechsler Memory Scale-IV and SF-36 mental component score Z-scores ( p < 0.05)., Conclusion: This pilot study showed that retinal venular VTI combined with the proximal mid-periphery amyloid count could predict verbal memory loss. Future research is needed to finesse the clinical application of this retinal imaging-based technology.

Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap in individuals with Alzheimer's disease (AD). The interaction of white matter ischemic lesions with amyloid pathology seen in AD is poorly characterized. We designed a novel mouse model of subcortical white matter ischemic stroke and AD that can inform our understanding of the cellular and molecular mechanisms of mixed vascular and AD dementia. Subcortical white matter ischemic stroke underlying forelimb motor cortex was induced by local stereotactic injection of an irreversible eNOS inhibitor. Subcortical white matter ischemic stroke or sham procedures were performed on human ApoE4-targeted-replacement (TR):5XFAD mice at 8 weeks of age. Behavioral tests were done at 7, 10, 15, and 20 weeks. A subset of animals underwent 18 FDG-PET/CT. At 20 weeks of age, brain tissue was examined for amyloid plaque accumulation and cellular changes. Compared with sham E4-TR:5XFAD mice, those with an early subcortical ischemic stroke showed a significant reduction in amyloid plaque burden in the region of cortex overlying the subcortical stroke. Cognitive performance was improved in E4-TR:5XFAD mice with stroke compared with sham E4-TR:5XFAD animals. Iba-1+ microglial cells in the region of cortex overlying the subcortical stroke were increased in number and morphologic complexity compared with sham E4-TR:5XFAD mice, suggesting that amyloid clearance may be promoted by an interaction between activated microglia and cortical neurons in response to subcortical stroke. This novel approach to modeling mixed vascular and AD dementia provides a valuable tool for dissecting the molecular interactions between these two common pathologies.

Introduction: Despite advances in imaging retinal amyloidosis, a quantitative and topographical investigation of retinal amyloid beta burden in patients with cognitive decline has never been reported., Methods: We used the specific amyloid-binding fluorophore curcumin and laser ophthalmoscopy to assess retinal amyloid imaging (RAI) in 34 patients with cognitive decline. We automatically quantified retinal amyloid count (RAC) and area in the superotemporal retinal sub-regions and performed correlation analyses with cognitive and brain volumetric parameters., Results: RAC significantly and inversely correlated with hippocampal volume (HV; r = -0.39, P  = .04). The proximal mid-periphery (PMP) RAC and RA areas were significantly greater in patients with Montreal Cognitive Assessment (MOCA) score < 26 ( P  = .01; Cohen d = 0.83 and 0.81, respectively). PMP showed significantly more RAC and area in subjects with amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to cognitively normal ( P  = .04; Cohen d = 0.83)., Conclusion: Quantitative RAI is a feasible technique and PMP RAC may predict HV. Future larger studies should determine RAI's potential as a biomarker of early AD., Competing Interests: Keith L. Black, Steven Verdooner, Yosef Koronyo, and Maya Koronyo‐Hamaoui are co‐founding members of NeuroVision Imaging Inc. Keith L. Black, Steven Verdooner, and Czeszynski Alan D are in leading roles in NeuroVision Imaging Inc. Keith L. Black, Steven Verdooner, Yosef Koronyo, and Maya Koronyo‐Hamaoui are co‐inventors of US patents related to retinal imaging and Alzheimer's disease. Sally Frautschy is co‐inventor on US patent US9192644B2 for a curcumin formulation and is a co‐founding member of Optimized Curcumin Longvida. Other authors declare no conflict., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Phagocytosis plays diverse roles in biology, but our understanding of the purpose, interplay, and cell signaling mechanisms associated with different modes of phagocytosis is limited, without being able to capture and visualize each step in this rapid process from the beginning to end. A new study by Walbaum et al. uses stunning time-lapse 3D imaging of the engulfment of erythrocytes by macrophages via sinking, ruffling, and cup formation, unequivocally confirming a visionary 44-year-old theory derived from still electron microscopy photos that phagocytosis mediated by complement receptor CR3 occurs via a sinking mechanism and antibodymediated phagocytosis occurs via phagocytic cup formation. The article also challenges the dogma, showing that phagocytic cup formation is not unique to antibody receptor phagocytosis, rather CR3 plays a complex role in different modes of phagocytosis. For example, inhibition of antibody-mediated phagocytosis leads to a compensatory upregulation of CR3-mediated sinking phagocytosis. These findings animate, in vivid colors, processes previously only captured as stills, exposing interactions between different phagocytic mechanisms and altering our basic understanding of this important process. [ABSTRACT FROM AUTHOR]

Gene therapy has made substantial progress in the treatment of the genetic diseases, focussing on the reduction of characteristics of recessive/dominant disorders, as well as various cancers. Extensive research has been conducted in the past few decades to investigate the application of nanotechnology and CRISPR/Cas technology in gene therapy. Nanotechnology due to attributes such has targeted drug delivery, controlled release, scalability and low toxicity has gained attention of the medical world. CRISPR/Cas9 system is considered as an impactful genome editing tool in the area of next-generation therapeutics and molecular diagnostics. CRISPR technology emphasises on gene editing, gene regulation modulation, and formulation of defined genetic changes. Its applications in treatment of the genetic disorders are extended beyond traditional therapies. These techniques are being explored as treatment of several genetic disorders including Duchenne muscular dystrophy, cystic fibrosis, Alzheimer's disease, Parkinson's disease, and Huntington disease. Despite considerable therapeutic potential of gene therapy, several obstacles must be addressed before it can be widely adopted in clinical practice, particularly in terms of ensuring safety and effectiveness. As research advances in this captivating field, these therapies will become the primary treatments and will have significant beneficial effects on the lives of patients with genetic disorders., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Psychiatric disorders cause long-lasting disabilities across different age groups. While various medications are available for mental disorders, some patients do not fully benefit from them or experience treatment resistance. The pathogenesis of psychiatric disorders involves multiple mechanisms, including an increase in the inflammatory response. Targeting inflammatory mechanisms has shown promise as a therapeutic approach for these disorders. Curcumin, known for its anti-inflammatory properties and potential neuroprotective effects, has been the subject of studies investigating its potential as a treatment option for psychiatric disorders. This review comprehensively examines the potential therapeutic role of curcumin and its nanoformulations in psychiatric conditions, including major depressive disorder (MDD), bipolar disorder, schizophrenia, and anxiety disorders. There is lack of robust clinical trials across all the studied psychiatric disorders, particularly bipolar disorder and schizophrenia. More studies have focused on MDD. Studies on depression indicate that curcumin may be effective as an antidepressant agent, either alone or as an adjunct therapy. However, inconsistencies exist among study findings, highlighting the need for further research with improved blinding, optimized dosages, and treatment durations. Limited evidence supports the use of curcumin for bipolar disorder, making its therapeutic application challenging. Well-designed clinical trials are warranted to explore its potential therapeutic benefits. Exploring various formulations and delivery strategies, such as utilizing liposomes and nanoparticles, presents intriguing avenues for future research. More extensive clinical trials are needed to assess the efficacy of curcumin as a standalone or adjunctive treatment for psychiatric disorders, focusing on optimal dosages, formulations, and treatment durations., (© 2024 John Wiley & Sons Ltd.)

Apolipoprotein J (apoJ; also known as clusterin and sulfated glycoprotein (SGP)-2) is associated with senile plaques in degenerating regions of Alzheimer's disease brains, where activated microglia are also prominent. We show a functional link between apoJ and activated microglia by demonstrating that exogenous apoJ activates rodent microgliain vivoandin vitro. Intracerebroventricular infusion of purified human plasma apoJ (∼4 µg over 28 days) activated parenchymal microglia to a phenotype characterized by enlarged cell bodies and processes (phosphotyrosine immunostaining).In vitro, primary rat microglia were also activated by apoJ, with changes in morphology and induction of major histocompatibility complex class II (MHCII) antigen. ApoJ increased the secretion of reactive nitrogen intermediates in a dose-dependent manner (EC50 112 nm), which was completely blocked by aminoguanidine (AG), a nitric oxide synthase inhibitor. However, AG did not block the increased secretion of tumor necrosis factor-α by apoJ (EC50 55 nm). Microglial activation by apoJ was also blocked by an anti-apoJ monoclonal antibody (G7), and by chemical cleavage of apoJ with 2-nitro-5-thiocyanobenzoate. The mitogen-activated protein kinase kinase and protein kinase C inhibitors PD98059 and H7 inhibited apoJ-mediated induction of reactive nitrogen intermediate secretion from cultured microglia. As a functional measure, apoJ-activated microglia secreted neurotoxic agents in a microglia–neuron co-culture model. We hypothesize that ApoJ contributes to chronic inflammation and neurotoxicity through direct effects on microglia. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta plaques and neurofibrillary tangles, leading to neuronal loss. Curcumin, a polyphenolic compound derived from Curcuma longa, has shown potential neuroprotective effects due to its anti-inflammatory and antioxidant properties. This review aims to synthesize current preclinical data on the anti-neuroinflammatory mechanisms of curcumin in the context of AD, addressing its pharmacokinetics, bioavailability, and potential as a therapeutic adjunct. An exhaustive literature search was conducted, focusing on recent studies within the last 10 years related to curcumin's impact on neuroinflammation and its neuroprotective role in AD. The review methodology included sourcing articles from specialized databases using specific medical subject headings terms to ensure precision and relevance. Curcumin demonstrates significant neuroprotective properties by modulating neuroinflammatory pathways, scavenging reactive oxygen species, and inhibiting the production of pro-inflammatory cytokines. Despite its potential, challenges remain regarding its limited bioavailability and the scarcity of comprehensive human clinical trials. Curcumin emerges as a promising therapeutic adjunct in AD due to its multimodal neuroprotective benefits. However, further research is required to overcome challenges related to bioavailability and to establish effective dosing regimens in human subjects. Developing novel delivery systems and formulations may enhance curcumin's therapeutic potential in AD treatment., (© 2024 John Wiley & Sons Ltd.)

Background: Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits., Methods: Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients., Results: Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031)., Conclusion: The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring., Funding: National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.

Alzheimer's disease (AD) is a form of brain degeneration that gradually impairs a person's memory and cognitive skills, eventually making it harder for them to perform everyday activities. Its pathophysiology has been attributed to the deposition of amyloid β (Aβ), neurofibrillary tangles (NFT), and α-synuclein (A-s) in some cases. Presently, 4 drugs have been approved for the treatment. They are Donepezil, Rivastigmine, Galantamine and Memantine. The first three are acetylcholinesterase inhibitors, while memantine is an NMDA receptor antagonist. Even though these medications are successful in treating mild to moderate Alzheimer's disease, they have not been able to reverse the disease or even slow its progression completely. Hence, natural products are gaining more popularity due to the advantage of the multitarget intervention effect. The most investigated spice, Curcuma longa 's bioactive component, curcumin, has demonstrated anti-amyloid, anti-NFT, and anti-Lewy body properties and substantial antiinflammatory, antioxidant, and antiapoptotic properties. However, its proven neuroprotective activity is hampered by many factors, such as poor water solubility and bioavailability. Therefore, many novel formulations have been designed to improve its bioavailability with methods such as 1) Micellar Solubilization, 2) Cyclodextrin Complexation, 3) Crystal Modification, and 4) Particle Size Reduction, etc. The current chapter aims to summarize various novel formulations of curcumin and their effectiveness in treating AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimer's disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-beta protein (Abeta). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Abeta from the amyloid precursor protein (APP) have led to two proposed mechanisms by which NSAIDs may protect against Alzheimer's disease: one, the selective lowering of Abeta42 by a subset of NSAIDs; and two, the reduction of inflammation. Although Alzheimer's disease is a disorder of brain and synaptic function, the effects of NSAIDs on Abeta-mediated suppression of synaptic plasticity and memory function have never been reported. We therefore investigated how three different NSAIDs, chosen for their distinct effects on Abeta42 production and the inhibition of the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, affect memory function and synaptic plasticity. By focusing upon brain and synapse function, we made novel observations about the effects of NSAIDs on Abeta-mediated neural processes. Here we report that the selective inhibition of COX-2, but not COX-1, acutely prevented the suppression of hippocampal long-term plasticity (LTP) by Abeta. The non-selective NSAIDs, ibuprofen and naproxen, and a selective COX-2 inhibitor, MF-tricyclic, each restored memory function in Tg2576 mice over-expressing APP, and also blocked Abeta-mediated inhibition of LTP. There was no advantage of ibuprofen, a selective Abeta42-lowering agent (SALA), over the non-SALAs, naproxen and MF-tricyclic. The beneficial effects on memory did not depend upon lowered levels of Abeta42 or the inflammatory cytokines, tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Intriguingly, improved memory function was inversely related to prostaglandin E2 (PGE2) levels. Conversely, exogenous PGE2 prevented the restorative effects of COX-2 inhibitors on LTP. The data indicate that the inhibition of COX-2 blocks Abeta-mediated suppression of LTP and memory function, and that this block occurs independently of reductions in Abeta42 or decreases in inflammation. The results lead us to propose a third possible mechanism by which NSAIDs may protect against Alzheimer's disease, involving the blockade of a COX-2-mediated PGE2 response at synapses. [ABSTRACT FROM AUTHOR]

High-density lipoprotein (HDL) is protective against cardiovascular disease. Exercise can increase HDL concentration, and some evidence suggests that this effect occurs more strongly in women than in men. Both HDL and exercise are associated with inflammation. We hypothesized a sex-by-exercise interaction on HDL level, whereby women would benefit from exercise more strongly than men, and tumor necrosis factor alpha and serum soluble tumor necrosis factor receptor-2 would mediate this relationship. This study included 2,957 older adult participants (1,520 women; 41% Black, 59% White; 73.6-years-old) from the Health, Aging, and Body Composition study. Regression models revealed a positive exercise-HDL relationship in women only (sex-by-exercise interaction: β = 0.09, p =.013; exercise on HDL in women: β = 0.07, p =.015), mediated by TNFα (axb = 0.15; CI: 0.01, 0.30), suggesting that exercise may increase HDL levels in women through reduced inflammation. Given that vascular risk contributes to Alzheimer's disease risk, findings have implications for sex differences in AD risk factors. [ABSTRACT FROM AUTHOR]

Recent years have seen significant advances in diagnostic testing of central nervous system (CNS) function and disease. However, there remain challenges in developing a comprehensive suite of non- or minimally invasive assays of neural health and disease progression. Due to the direct connection with the CNS, structural changes in the neural retina, retinal vasculature and morphological changes in retinal immune cells can occur in parallel with disease conditions in the brain. The retina can also, uniquely, be assessed directly and non-invasively. For these reasons, the retina may prove to be an important "window" for revealing and understanding brain disease. In this review, we discuss the gross anatomy of the eye, focusing on the sensory and non-sensory cells of the retina, especially microglia, that lend themselves to diagnosing brain disease by imaging the retina. We include a history of ocular imaging to describe the different imaging approaches undertaken in the past and outline current and emerging technologies including retinal autofluorescence imaging, Raman spectroscopy, and artificial intelligence image analysis. These new technologies show promising potential for retinal imaging to be used as a tool for the diagnosis of brain disorders such as Alzheimer's disease and others and the assessment of treatment success. [ABSTRACT FROM AUTHOR]

In recent years, researchers have highly observed that neurological disorders (NSDs) with the aging of the population are a global health burden whose prevalence is increasing every year. Previous evidence suggested that the occurrence of neurological disorders is correlated with predisposing factors such as inflammation, aging, and injury. Particularly, the neuronal cells are susceptible to oxidative stress, leading to lesions caused by high oxygen-consuming properties. Oxidative stress (OS) is a state of peroxidation, which occurs as a result of the disruption of the balance between oxidizing and antioxidizing substances. The oxidative intermediates such as free radicals, hydrogen peroxide (H2O2), and superoxide anion (O2-) produced by OS promote disease progression. Curcumin, a natural diketone derived from turmeric, is a natural antioxidant with a wide range of neuroprotective, anti-inflammatory, anti-tumor, anti-aging, and antioxidant effects. Fortunately, curcumin is recognized for its potent antioxidant properties and is considered a promising candidate for the prevention and treatment of neurological diseases. Consequently, this review elucidates the mechanisms by which curcumin mitigates oxidative stress and emphasizes the potential in treating nervous system disorders, including depression, Alzheimer's disease, Parkinson's disease, epilepsy, subarachnoid hemorrhage, and glioblastoma. We aim to provide a new therapeutic option for the management of neurological diseases. [ABSTRACT FROM AUTHOR]

As current treatments for Alzheimer's disease (AD) lack disease‐modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti‐inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)‐derived neural stem cells (NSCs) hold promise as a disease‐modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC‐NSC‐EVs in 3‐month‐old 5xFAD mice. IN administered hiPSC‐NSC‐EVs incorporated into microglia, including plaque‐associated microglia, and encountered astrocyte soma and processes in the brain. Single‐cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease‐associated microglia, NOD‐, LRR‐, and pyrin domain‐containing protein 3 (NLRP3)‐inflammasome and interferon‐1 (IFN‐1) signalling displayed reduced expression in microglia. Adding hiPSC‐NSC‐EVs to cultured human microglia challenged with amyloid‐beta oligomers resulted in similar effects. Astrocytes also displayed reduced expression of genes linked to IFN‐1 and interleukin‐6 signalling. Furthermore, the modulatory effects of hiPSC‐NSC‐EVs on microglia in the hippocampus persisted 2 months post‐EV treatment without impacting their phagocytosis function. Such effects were evidenced by reductions in microglial clusters and inflammasome complexes, concentrations of mediators, and end products of NLRP3 inflammasome activation, the expression of genes and/or proteins involved in the activation of p38/mitogen‐activated protein kinase and IFN‐1 signalling, and unaltered phagocytosis function. The extent of astrocyte hypertrophy, amyloid‐beta plaques, and p‐tau were also reduced in the hippocampus. Such modulatory effects of hiPSC‐NSC‐EVs also led to better cognitive and mood function. Thus, early hiPSC‐NSC‐EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid‐beta plaque load, and p‐tau. These results reflect the first demonstration of the efficacy of hiPSC‐NSC‐EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes. [ABSTRACT FROM AUTHOR]

Xenorhabdus and Photorhabdus bacteria, which live in mutualistic symbiosis with entomopathogenic nematodes, are currently recognised as an important source of bioactive compounds. During their extraordinary life cycle, these bacteria are capable of fine regulation of mutualism and pathogenesis towards two different hosts, a nematode and a wide range of insect species, respectively. Consequently, survival in a specific ecological niche favours the richness of biosynthetic gene clusters and respective metabolites with a specific structure and function, providing templates for uncovering new agrochemicals and therapeutics. To date, numerous studies have been published on the genetic ability of Xenorhabdus and Photorhabdus bacteria to produce biosynthetic novelty as well as distinctive classes of their metabolites with their activity and mechanism of action. Research shows diverse techniques and approaches that can lead to the discovery of new natural products, such as extract-based analysis, genetic engineering, and genomics linked with metabolomics. Importantly, the exploration of members of the Xenorhabdus and Photorhabdus genera has led to encouraging developments in compounds that exhibit pharmaceutically important properties, including antibiotics that act against Gram- bacteria, which are extremely difficult to find. This article focuses on recent advances in the discovery of natural products derived from these nematophilic bacteria, with special attention paid to new valuable leads for therapeutics. [ABSTRACT FROM AUTHOR]

The total number of Japanese populations is 124.34 million in 2023, and the population of older than 100 years old is 92,139 (about 0.07% of total population). Japan is called as the super aging society. Possibly, it is easily understood that the aging society is widely spread in the world. We have to work out countermeasures for preventing onset of several severe diseases, e.g., dementia, cerebrovascular disease, frailty, etc., seen in the elderly persons. In this review, we focused on the effects of oroxylin A and curcumin on the age-related memory impairment and frailty. Oroxylin A is an extract of Oroxylum indicum and is a natural flavone with anti-inflammatory, neuroprotective and anti-oxidant properties. It has been reported that oroxylin A increases the brain derived neurotrophic factor expression and significantly increased the Complex-I activity in the cortex and other regions. Moreover, it has been documented that oroxylin A dose-dependently inhibited the beta-secretase expressions and activities in PS-70 cells. These results suggest that oroxylin A is a proper supplement to use to reduce the severity of Alzheimer !s disease. Moreover, Curcuma longa has been well documented in the 细 urveda India as for the treatment of diabetes, respiratory disorders, liver disease, inflammatory conditions. Curcumin C3 complex® is a standardized extract from Curcuma longa for 95% curcuminoids. The effects of Curcumin C3 complex® on dementia and osteoarthritis have been well estimated. In conclusion, co-administration of oroxylin A and curcumin is for the prevention of specific diseases in elderly persons. And such novel supplement can contribute the development of acting health in the super aging society. [ABSTRACT FROM AUTHOR]

While Alzheimer's disease and other neurodegenerative diseases have traditionally been viewed as brain disorders, there is growing evidence indicating their manifestation in the eyes as well. The retina, being a developmental extension of the brain, represents the only part of the central nervous system that can be noninvasively imaged at a high spatial resolution. The discovery of the specific pathological hallmarks of Alzheimer's disease in the retina of patients holds great promise for disease diagnosis and monitoring, particularly in the early stages where disease progression can potentially be slowed. Among various retinal imaging methods, hyperspectral imaging has garnered significant attention in this field. It offers a label-free approach to detect disease biomarkers, making it especially valuable for large-scale population screening efforts. In this review, we discuss recent advances in the field and outline the current bottlenecks and enabling technologies that could propel this field toward clinical translation. [ABSTRACT FROM AUTHOR]

Microglia, the resident immune cells of the central nervous system, play a crucial role in regulating adult neurogenesis and contribute significantly to the pathogenesis of Alzheimer's disease (AD). Under physiological conditions, microglia support and modulate neurogenesis through the secretion of neurotrophic factors, phagocytosis of apoptotic cells, and synaptic pruning, thereby promoting the proliferation, differentiation, and survival of neural progenitor cells (NPCs). However, in AD, microglial function becomes dysregulated, leading to chronic neuroinflammation and impaired neurogenesis. This review explores the intricate interplay between microglia and adult neurogenesis in health and AD, synthesizing recent findings to provide a comprehensive overview of the current understanding of microglia-mediated regulation of adult neurogenesis. Furthermore, it highlights the potential of microglia-targeted therapies to modulate neurogenesis and offers insights into potential avenues for developing novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer's disease, tauopathies, and Huntington's diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell.

Leading neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the impairment of memory and motor functions, respectively. Despite several breakthroughs, there exists a lack of disease-modifying treatment strategies for these diseases, as the available drugs provide symptomatic relief and bring along side effects. Bioactive compounds are reported to bear neuroprotective properties with minimal toxicity, however, a detailed elucidation of their modes of neuroprotection is lacking. The review elucidates the neuroprotective mechanism(s) of some of the major phyto-compounds in pre-clinical and clinical studies of AD and PD to understand their potential in combating these diseases. Curcumin, eugenol, resveratrol, baicalein, sesamol and so on have proved efficient in countering the pathological hallmarks of AD and PD. Curcumin, resveratrol, caffeine and so on have reached the clinical phases of these diseases, while aromadendrin, delphinidin, cyanidin and xanthohumol are yet to be extensively explored in pre-clinical phases. The review highlights the need for extensive investigation of these compounds in the clinical stages of these diseases so as to utilize their disease-modifying abilities in the real field of treatment. Moreover, poor pharmacokinetic properties of natural compounds are constraints to their therapeutic yields and this review suggests a plausible contribution of nanotechnology in overcoming these limitations., (© 2023 John Wiley & Sons Ltd.)

Oligomerization of the amyloid β-protein (Aβ) is a seminal event in Alzheimer's disease. Aβ42, which is only two amino acids longer than Aβ40, is particularly pathogenic. Why this is so has not been elucidated fully. We report here results of computational and experimental studies revealing a C-terminal turn at Val36-Gly37 in Aβ42 that is not present in Aβ40. The dihedral angles of residues 36 and 37 in an Ile31-Ala42 peptide were consistent with β-turns, and a β-hairpin-like structure was indeed observed that was stabilized by hydrogen bonds and by hydrophobic interactions between residues 31-35 and residues 38-42. In contrast, Aβ(31-40) mainly existed as a statistical coil. To study the system experimentally, we chemically synthesized Aβ peptides containing amino acid substitutions designed to stabilize or destabilize the hairpin. The triple substitution Gly33Val-Val36Pro-Gly38Val ("VPV") facilitated Aβ42 hexamer and nonamer formation, while inhibiting formation of classical amyloid-type fibrils. These assemblies were as toxic as were assemblies from wild-type Aβ42. When substituted into Aβ40, the VPV substitution caused the peptide to oligomerize similarly to Aβ42. The modified Aβ40 was significantly more toxic than Aβ40. The double substitution d-Pro36-l-Pro37 abolished hexamer and dodecamer formation by Aβ42 and produced an oligomer size distribution similar to that of Aβ40. Our data suggest that the Val36-Gly37 turn could be the sine qua non of Aβ42. If true, this structure would be an exceptionally important therapeutic target., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Limonoids are important constituents of citrus that have a significant impact on promoting human health. Therefore, the primary focus of this research was to assess the overall limonoid content and isolate limonoids from Adalia lemon (Citrus limon L.) peels for their potential use as antioxidants and anti-diabetic agents. The levels of limonoid aglycones in the C. limon peel extract were quantified through a colorimetric assay, revealing a concentration of 16.53 ± 0.93 mg/L limonin equivalent. Furthermore, the total concentration of limonoid glucosides was determined to be 54.38 ± 1.02 mg/L. The study successfully identified five isolated limonoids, namely limonin, deacetylnomilin, nomilin, obacunone 17-O-β-D-glucopyranoside, and limonin 17-O-β-D-glucopyranoside, along with their respective yields. The efficacy of the limonoids-rich extract and the five isolated compounds was evaluated at three different concentrations (50, 100, and 200 µg/mL). It was found that both obacunone 17-O-β-D-glucopyranoside and limonin 17-O-β-D-glucopyranoside possessed the highest antioxidant, free radical scavenging, and anti-diabetic activities, followed by deacetylnomilin, and then the limonoids-rich extract. The molecular dynamic simulations were conducted to predict the behavior of the isolated compounds upon binding to the protein's active site, as well as their interaction and stability. The results revealed that limonin 17-O-β-D-glucopyranoside bound to the protein complex system exhibited a relatively more stable conformation than the Apo system. The analysis of Solvent Accessible Surface Area (SASA), in conjunction with the data obtained from Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), and Radius of Gyration (ROG) computations, provided further evidence that the limonin 17-O-β-D-glucopyranoside complex system remained stable within the catalytic domain binding site of the human pancreatic alpha-amylase (HPA)-receptor. The research findings suggest that the limonoids found in Adalia lemon peels have the potential to be used as effective natural substances in creating innovative therapeutic treatments for conditions related to oxidative stress and disorders in carbohydrate metabolism. [ABSTRACT FROM AUTHOR]