Metal Ion Dyshomeostasis Research Articles

ZIP8 A391T Crohn’s Disease-Linked Risk Variant Induces Colonic Metal Ion Dyshomeostasis, Microbiome Compositional Shifts, and Inflammation

BackgroundThe pathogenesis of Crohn’s disease involves genetic and environmental factors, with the gut microbiome playing a crucial role. The Crohn’s disease-associated variant rs13107325 in the SLC39A8 gene results in an A391T substitution in the ZIP8 metal ion transporter and has previously been linked to alterations in the colonic microbiome in variant carriers. We hypothesized that the A391T substitution alters metal ion homeostasis in the colonic mucosal–luminal interface, thereby inducing dysbiosis which may promote intestinal inflammation.MethodsTo evaluate this hypothesis, we generated a SLC39A8 A393T mouse model (matching human A391T). We first examined trace element abundance in the colonic mucosal epithelium and lumen of homozygous A393T and wild-type (WT) mice to determine if the variant affected metal distribution. We also performed 16S rRNA gene sequencing on colon samples at 2 months, 3–4 months, and 12 months of age, and conducted histological scoring of colon tissue collected from 5-month and 10-month old mice.ResultsConsistent with an effect of the variant on ZIP8 function, homozygous A393T mice exhibited increased cobalt in the colonic mucosa, but reduced iron, zinc, manganese, cobalt, copper, and cadmium in the colonic lumen. 16S rRNA gene sequencing of colon samples revealed variant-linked effects on microbiome beta diversity in 2-month-, 3–4-month-, and 12-month-old mice. Histological scoring showed spontaneous intestinal inflammation in 10-month but not in 5-month-old mice. Lastly, predicted pathway analysis of the microbiome samples revealed differential enrichment of iron-, zinc-, and cobalt-dependent pathways in A393T mice compared to wild-type controls.ConclusionThese results suggest that the variant in SLC39A8 primarily restricts metal availability to the microbiota, resulting in compositions that can adapt to the environment and that A393T-linked dysbiosis occurs prior to the onset of inflammation. This study paves the way for future studies investigating risk variants as microbiome-disease modifiers.Graphical

Recent Advances in Targeting Transition Metals (Copper, Iron, and Zinc) in Alzheimer's Disease.

Changes in the transition metal homeostasis in the brain are closely linked with Alzheimer's disease (AD), including intraneuronal iron accumulation and extracellular copper and zinc pooling in the amyloid plague. The brain copper, zinc, and iron surplus are commonly acknowledged characteristics of AD, despite disagreements among some. This has led to the theory that oxidative stress resulting from abnormal homeostasis of these transition metals may be a causative explanation behind AD. In the nervous system, the interaction of metals with proteins appears to be an essential variable in the development or suppression of neurodegeneration. Chelation treatment may be an option for treating neurodegeneration induced by transition metal ion dyshomeostasis. Some clinicians even recommend using chelating agents as an adjunct therapy for AD. The current review also looks at the therapeutic strategies that have been attempted, primarily with metal-chelating drugs. Metal buildup in the nervous system, as reported in the AD, could be the result of compensatory mechanisms designed to improve metal availability for physiological functions.

Cascade-targeting multifunctional nanochaperone remodels brain microenvironment for synergistic therapy of Alzheimer’s disease

The development of a cure for Alzheimer’s disease (AD) has been hindered by complicated pathologies in brain microenvironment, including β-amyloid protein (Aβ) deposition, metal ion dyshomeostasis and excessive oxidative stress. Moreover, the low blood-brain barrier (BBB) penetration and lack AD locus selectivity further limited disease-modifying efficacy of current AD drugs. Herein, we report the design of cascade-targeting multifunctional nanochaperone to remodel brain microenvironment for synergistic treatment of AD. With the cascade mediation of BBB-targeting and AD lesion-targeting peptides modified on surface, the nanochaperone can efficiently penetrate the BBB and selectively accumulate in the AD nidus with abundant Aβ deposits after intravenous administration. More importantly, the brain-arrived nanochaperone can simultaneously promote Aβ aggregates clearance, modulate metal ion homeostasis and scavenge reactive oxygen species (ROS) through the synergic effect of chaperone-mimicking microdomains on surface and functional small-molecule drugs encapsulated in core, thereby achieving multi-target therapy to deal with the complex pathologies in AD microenvironment. After treatment with this multifunctional nanochaperone, the neuron damages and cognitive deficits of APP/PS1 transgenic AD mice are significantly relieved in the brain. Therefore, this work represents a promising candidate for comprehensive treatment of AD and provides new perspectives in the development of drugs for other neurodegenerative disorders.

Effect of cycloastragenol and punicalagin on Prp(106–126) and Aβ(25–35) oligomerization and fibrillizaton

Numerous neurological disorders, including prion, Parkinson's, and Alzheimer's disease (AD), are identified as being caused by alterations in protein conformation, aggregation, and metal ion dyshomeostasis. Recent years have seen a significant increase in the exploration and study of natural products (NPs) from plant and microbial sources for their therapeutic potential against several diseases, including cancer, diabetes, cardiovascular disease, and neurodegenerative diseases. In this study, we have examined the effect of two NPs, cycloastragenol (CAG) and punicalagin (PCG), on the metal-induced oligomerization and aggregation of Aβ25–35 and PrP106–126 peptides. The peptide aggregation and inhibitory properties of both NPs were examined by the thioflavin-T (ThT) assay, MALDI-TOF, circular dichroism (CD) spectroscopy, and transmission electron microscopy (TEM). Among the two NPs, PCG significantly binds to the peptides, chelates metal ions (Cu2+ and Zn2+), inhibits peptide aggregation, substantially reduces oxidative stress, and controls the production of reactive oxygen species (ROS). Both NPs exhibited low cytotoxicity and prominently mitigated peptide-mediated cell cytotoxicity in hippocampal neuronal HT-22 cells by covalent bonding and hydrophobic interactions.

Parkinson's Disease: Current Status, Diagnosis, and Treatment Using Nanomedicines

AbstractParkinson's disease (PD) is a chronic, and highly neurodegenerative disorder with complex pathological processes. The features for neuropathological identification of PD include α‐synuclein (α‐syn) protein aggregates, oxidative stress, metal ion dyshomeostasis, neurotransmitter deficiencies, and mitochondrial dysfunction. Currently, no definite treatment paradigm can completely cure PD patients, which is increasing globally over the past few decades. The existence of the blood‐brain barrier (BBB) restricts the conventional treatment processes and makes the therapeutic delivery to the brain a bit more challenging. Therefore, developing new useful medicines for improving brain distribution is vital to overcome BBB and helping the early diagnosis and treatment of PD. In this review, the current limitations of conventional drugs are highlighted and the development of new medicines to overcome such limitations is covered. This work will provide insight into the direction for designing novel efficient nanomedicines for the early diagnosis and treatment of PD.

Design, synthesis, and evaluation of 2,2'-bipyridyl derivatives as bifunctional agents against Alzheimer's disease.

Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease. Metal ion dyshomeostasis and Aβ aggregation have been proposed to contribute to AD progression.Metal ions can bind to Aβ and promote Aβ aggregation, and ultimately lead to neuronal death.Bifunctional (metal chelation and Aβ interaction) compounds are showing promise againstAD. In this work, eleven new 3,3'-diamino-2,2'-bipyridine derivatives 4a-4k were synthesized, and evaluated as bifunctional agents for AD treatment. In vitro Aβ aggregation inhibition assay confirmed that most of the synthesized compounds exhibited significant self-induced Aβ1-42 aggregation inhibition. Among them, compound 4d displayed the best inhibitory potency of self-induced Aβ1-42 aggregation with IC50 value of 9.4 µM, and it could selectively chelate with Cu2+ and exhibited 66.2% inhibition of Cu2+-induced Aβ1-42 aggregation. Meanwhile, compound 4d showed strong neuroprotective activity against Aβ1-42 and Cu2+-treated Aβ1-42 induced cell damage. Moreover, compound 4d in high dose significantly reversed Aβ-induced memory impairment in mice.

Discovery of novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones as balanced multifunctional agents against Alzheimer's disease

Based on previous work, a series of novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones derivatives were identified as potential multifunctional therapeutic agents for Alzheimer's disease. Biological evaluation exhibited that these derivatives had great performance against MAO-B, Aβ1-42 aggregation, oxidative stress and metal ion dyshomeostasis. Among them, 10x was selected as the optimal agent for its excellent MAO-B inhibitory activity (IC50 = 0.41 μM, SI > 24.4), good antioxidant activity (1.16 Trolox equivalent) and anti-Aβ aggregation activity (56.03% and 57.51% for inhibition of self- and Cu2+-induced Aβ1-42 aggregation; 81.91% and 82.40% for disaggregation of self- and Cu2+-induced Aβ1-42 fibrils at 25.0 μM). Besides, 10x also exhibited obvious metal-ion chelating ability, anti-neuroinflammation (NO, TNF-α), neuroprotective activity and BBB permeability. More importantly, in vivo behavioral assessment demonstrated 10x could remarkably improve the memory and cognitive impairment in Aβ1-42 induced AD mice model. Overall, these test results indicated 10x could serve as a balanced multifunctional anti-AD agent and deserved further research.

The effect of metal ions on the Spf1p P5A-ATPase. High sensitivity to irreversible inhibition by zinc

The Spf1p protein from Saccharomyces cerevisiae belongs to the family of P5A-ATPases that have recently been shown to protect the endoplasmic reticulum by dislocating misinserted membrane proteins. The loss of function of P5A-ATPases leads to endoplasmic reticulum stress with a pleiotropic phenotype including protein, sterol and metal ion dyshomeostasis. Like other P-ATPases, Spf1p requires Mg2+. We found that free Mg2+ stimulated the Spf1p ATPase activity along a double hyperbolic curve with two components of K1/2 = 14 and 800 μM Ca2+, Mn2+ and Co2+ lowered about 50% of the Spf1p ATPase with relatively low affinity (Ki ∼75 μM) and the activity was fully recovered after metal ion chelation with EGTA. In contrast, low concentrations of Zn2+ and Cd2+decreased the activity to less than 20% and lead to slow irreversible inactivation of the enzyme. After the treatment with Zn2+, Spf1p exhibited a reduced apparent affinity for ATP and formed lower levels of the catalytic phosphoenzyme. The inactivation by Zn2+ occurred preferentially at a pH > 6 and could be prevented by adding either ATP or ADP to the inactivation media. These results suggest that Zn2+ inactivated Spf1p by binding to amino acid residues from the nucleotide binding-phosphorylation domains that are protonated at lower pH. Alternatively the binding of nucleotides may indirectly compete with a conformational change leading to the Zn2+-inactive form of the enzyme. Exposure of yeast cells to high concentrations of Zn2+ led to changes similar to the phenotype characteristic of the Spf1Δ cells. Altogether, our data, point out a possible mechanism by which the inhibition of P5A-ATPases could potentiate metal ion–induced ER stress and proteotoxicity.

Novel melatonin-trientine conjugate as potential therapeutic agents for Alzheimer’s disease

Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aβ deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aβ levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.

Rationally Designed Molecules Synergistically Modulate Multifaceted Aβ Toxicity, Microglial Activation, and Neuroinflammation.

Synergistic modulation of multifaceted toxicity is the key to tackle multifactorial Alzheimer's disease (AD). The etiology of AD includes amyloid β (Aβ) amyloidosis, metal ion dyshomeostasis, reactive oxygen species (ROS), oxidative stress, mitochondrial damage, and neuroinflammation. We rationally designed multifunctional modulators by integrating pharmacophores for metal chelation, antioxidant and anti-inflammatory properties, and modulation of Aβ42 aggregation on the naphthalene monoimide (NMI) scaffold. The in vitro and cellular studies of NMIs revealed that M3 synergistically modulates metal-independent and -dependent amyloid toxicity, scavenges ROS, alleviates oxidative stress, and emulates Nrf2-mediated stress response in neuronal cells. M3 effectively reduced structural and functional damage of mitochondria, reduced Cyt c levels, and rescued cells from apoptosis. The biological atomic force microscopy and Western blot analysis revealed the ability of M3 to suppress microglial activation and neuroinflammation through inhibition of the NF-κβ pathway. The synergistic action of M3 is in agreement with our design strategy to develop a multifunctional therapeutic candidate by integrating multiple pharmacophores with distinct structural and functional elements to ameliorate the multifaceted toxicity of AD.

A Metallomic Approach to Assess Associations of Plasma Metal Levels with Amnestic Mild Cognitive Impairment and Alzheimer's Disease: An Exploratory Study.

Alzheimer’s disease (AD) involves the abnormal activity of transition metals and metal ion dyshomeostasis; however, the potential of trace metal biomarkers in predicting cognitive decline has not been evaluated. This study aimed to assess the potential of 36 trace elements in predicting cognitive decline in patients with amnestic mild cognitive impairment (aMCI) or AD. Participants (9 controls, 23 aMCI due to AD, and 8 AD dementia) underwent comprehensive cognitive tests, including the Mini-Mental State Examination (MMSE) and trace metal analysis. The correlations between the plasma trace element levels and annual MMSE changes during follow-up were analyzed. We found that an increase in disease severity was linked to lower plasma levels of boron (B), bismuth (Bi), thorium (Th), and uranium (U) (adjusted p < 0.05). Higher baseline calcium levels (r = 0.50, p = 0.026) were associated with less annual cognitive decline; those of B (r = −0.70, p = 0.001), zirconium (r = −0.58, p = 0.007), and Th (r = −0.52, p = 0.020) with rapid annual cognitive decline in the aMCI group; and those of manganese (r = −0.91, p = 0.035) with rapid annual cognitive decline in the AD group. Overall, our exploratory study suggests that plasma metal levels have great potential as in vivo biomarkers for aMCI and AD. Larger sample studies are necessary to confirm these results.

Metal Complexation Mechanisms of Polyphenols Associated to Alzheimer's Disease.

Polyphenols are a class of compounds, produced by plants, which share the ability to act as potent antioxidants. First investigations on polyphenols' antioxidant activity are dated almost twenty years ago when their relationship and implication with the prevention and treatment of cancer was proposed for the first time. Later, in the early 2000s, the neuroprotective effects of several polyphenols were demonstrated. Nowadays, the benefits of a plethora of polyphenols have been studied and their ameliorating effects in several disease conditions, like cancer, cardiac and neuronal diseases are widely recognised. More than 1000 papers dealing with polyphenols and Alzheimer's disease have been published so far, describing the antioxidant properties, the metal chelating features and the anti-aggregating behavior of these compounds. The aim of this review is to rationalize, from a chemical point of view, the metal complexation mechanisms of polyphenols related to two significant events of Alzheimer's disease: oxidative stress and metal ion dyshomeostasis. In order to address this issue, we have herein discussed several aspects implicated in Alzheimer's disease and polyphenols involved in the treatment of the disease.

Electrochemical characterization of Cu(II) complexes of brain-related tau peptides

Metal ion dyshomeostasis plays an important role in diseases, including neurodegeneration. Tau protein is a known neurodegeneration biomarker, but its interactions with biologically relevant metal ions, such as Cu(II), are not fully understood. Herein, the Cu(II) complexes of four tau R peptides, based on the tau repeat domains, R1, R2, R3, and R4, were characterized by electrochemical methods, including cyclic voltammetry, square-wave voltammetry, and differential pulse voltammetry in solution under aerobic conditions. The current and potential associated with Cu(II)/(I) redox couple was modulated as a function of R peptide sequence and concentration. All R peptides coordinated Cu(II) resulting in a dramatic decrease in the current associated with free Cu(II), and the appearance of a new redox couple due to metallo–peptide complex. The metallo–peptide complexes were characterized by the irreversible redox couple at more positive potentials and slower electron-transfer rates compared with the free Cu(II). The competition binding studies between R peptides with Cu(II) indicated that the strongest binding affinity was observed for the R3 peptide, which contained 2 His and 1 Cys residues. The formation of complexes was also evaluated as a function of peptide concentration and in the presence of competing Zn(II) ions. Data indicate that all metallo–peptides remain redox active pointing to the potential importance of the interactions between tau protein with metal ions in a biological setting.

Bis(8‐hydroxyquinoline) Ligands: Exploring their Potential as Selective Copper‐Binding Agents for Alzheimer's Disease

AbstractAmyloid‐β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress are pathological features of Alzheimer's disease (AD). Aβ and metal ions form metal‐Aβ complex species that influence the aggregation of Aβ and, in particular, redox metal ions such as Cu lead to the production of reactive oxygen species (ROS). To target metal coordination to Aβ and the reactivities of Cu−Aβ, metal chelating agents must extract Cu2+ from Aβ in AD pathological conditions. Bis(8‐hydroxyquinoline) ligands can extract Cu2+ from Aβ and therefore inhibit the Cu‐induced Aβ aggregation and the aerobic oxidation of ascorbate. In particular, N‐butyl‐2,2‐imino‐bis(8‐hydroxyquinoline) can selectively target Cu−Aβ reactivities in the presence of Zn2+ such as in AD brain patients. The ligands can release Cu in intracellular environments in the presence of a large excess of glutathione, contributing to restore Cu homeostasis.

Evaluation of Zn, Cu, and Se Levels in the North American Autism Spectrum Disorder Population

Metal ion dyshomeostasis and disparate levels of biometals like zinc (Zn), copper (Cu), and selenium (Se) have been implicated as a potential causative factor for Autism Spectrum Disorder (ASD). In this study, we have enrolled 129 children (aged 2–4 years) in North America, of which 64 children had a diagnosis of ASD and 65 were controls. Hair, nail, and blood samples were collected and quantitatively analyzed for Zn, Cu and Se using inductively coupled plasma mass spectrometry (ICP-MS). Of the analyzed biometals, serum Se (116.83 ± 14.84 ng/mL) was found to be significantly lower in male ASD cases compared to male healthy controls (128.21 ± 9.11 ng/mL; p < 0.005). A similar trend was found for nail Se levels in ASD (1.01 ± 0.15 mcg/g) versus that of controls (1.11 ± 0.17 mcg/g) with a p-value of 0.0132 using a stratified Wilcoxon rank sum testing. The level of Se in ASD cohort was co-analyzed for psychometric correlation and found a negative correlation between total ADOS score and serum Se levels. However, we did not observe any significant difference in Zn, Cu, and Zn/Cu ratio in ASD cases versus controls in this cohort of North American children. Further studies are recommended to better understand the biology of the relationship between Se and ASD status.

Zn2+ modulates in vitro phase separation of TDP-432C and mutant TDP-432C-A315T C-terminal fragments of TDP-43 protein implicated in ALS and FTLD-TDP diseases

TDP-43 proteinopathy is implicated in the neurodegenerative diseases, ALS and FTLD-TDP. Metal ion dyshomeostasis is observed in neurodegenerative diseases including ALS. Previously, mice expressing A315T familial ALS TDP-43 mutant showed elevated spinal cord Zn2+ levels. Recently, Zn2+ was observed to modulate the in vitro amyloid-like aggregation of the TDP-43's RRM12 domains. As a systematic knowledge of the TDP-43's interaction with Zn2+ is lacking, we in silico predicted potential Zn2+ binding sites in TDP-43 and estimated their relative solvent accessibilities. Zn2+ binding sites were predicted in the TDP-43's N-terminal domain, in the linker region between RRM1 and RRM2 domain, within RRM2 domain and at the junction of the RRM2 and C-terminal domain (CTD), but none in the 311–360 region of CTD. Furthermore, we found that Zn2+ promotes the in vitro thioflavin-T-positive aggregations of C-terminal fragments (CTFs) termed TDP-432C and TDP-432C-A315T that encompass the RRM2 and CTD domains. Also, while the Alexa-fluor fluorescently labelled TDP-432C and TDP-432C-A315T proteins manifested liquid-like spherical droplets, Zn2+ caused a solid-like phase separation that was not ameliorated even by carboxymethylation of the free cysteines thereby implicating the other Zn2+-binding residues. The observed Zn2+-promoted TDP-43 CTF's solid-like phase separation can be relevant to the Zn2+ dyshomeostasis in ALS and FTLD-TDP.

Fluorescent probes for bioimaging of potential biomarkers in Parkinson's disease.

Parkinson's disease (PD), as the second most common neurodegenerative disease, is caused by complex pathological processes and currently remains very difficult to treat. PD brings great distress to patients and imposes a heavy economic burden on society. The number of PD patients is growing as the aging population increases worldwide. Therefore, it is crucial to develop new tools for aiding the early diagnosis and treatment of PD. The significant pathological features involved in PD include the abnormal accumulation of α-synuclein, metal ion dyshomeostasis, oxidative stress, mitochondrial dysfunction and neurotransmitter deficiencies. In recent years, fluorescent probes have emerged as a powerful bioimaging tool with potential to help understand the pathological processes of PD via the detection and monitoring of pathological features. In this review, we comprehensively summarize the design and working mechanisms of fluorescent probes along with their applications in the detection of various PD biomarkers. We also discuss the current limitations of fluorescent probes and provide perspectives on how these limitations can be overcome to develop better fluorescent probes suitable for application in clinical trials in the future. We hope that this review provides valuable information and guidance for the development of new fluorescent probes that can be used clinically in the early diagnosis of PD and contributes to the development of efficient PD drugs in the future.

Single-cell transcriptome analysis of the Akimba mouse retina reveals cell-type-specific insights into the pathobiology of diabetic retinopathy.

Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Despite recent advances, our understanding of its pathophysiology remains incomplete. The aim of this study was to provide deeper insight into the complex network of molecular and cellular changes that underlie diabetic retinopathy by systematically mapping the transcriptional changes that occur in the different cellular compartments of the degenerating diabetic mouse retina. Single-cell RNA sequencing was performed on retinal tissue from 12-week-old wild-type and Akimba (Ins2Akita×Vegfa+/-) mice, which are known to replicate features of clinical diabetic retinopathy. This resulted in transcriptome data for 9474 retinal cells, which could be annotated to eight distinct retinal cell types. Using STRING analysis, we studied differentially expressed gene networks in neuronal, glial and immune cell compartments to create a comprehensive view on the pathological changes that occur in the Akimba retina. Using subclustering analysis, we further characterised macroglial and inflammatory cell subpopulations. Prominent findings were confirmed at the protein level using immunohistochemistry, western blotting and ELISA. At 12weeks, the Akimba retina was found to display degeneration of rod photoreceptors and presence of inflammatory cells, identified by subclustering analysis as monocyte, macrophage and microglial populations. Analysis of differentially expressed genes in the rod, cone, bipolar cell and macroglial compartments indicated changes in cell metabolism and ribosomal gene expression, gliosis, activation of immune system pathways and redox and metal ion dyshomeostasis. Experiments at the protein level supported a metabolic shift from glycolysis to oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase), activation of microglia/macrophages (isolectin-B4), metal ion and oxidative stress response (metallothionein and haem oxygenase-1) and reactive macroglia (glial fibrillary acidic protein and S100) in the Akimba retina, compared with wild-type mice. Our single-cell approach also indicates macroglial subpopulations with distinct fibrotic, inflammatory and gliotic profiles. Our study identifies molecular pathways underlying inflammatory, metabolic and oxidative stress-mediated changes in the Akimba mouse model of diabetic retinopathy and distinguishes distinct functional subtypes of inflammatory and macroglial cells. RNA-seq data have been deposited in the ArrayExpress database at EMBL-EBI ( www.ebi.ac.uk/arrayexpress ) under accession number E-MTAB-9061. Graphical abstract.

Multiple reactivities of flavonoids towards pathological elements in Alzheimer's disease: structure-activity relationship.

Amyloid-β (Aβ) accumulation, metal ion dyshomeostasis, oxidative stress, and cholinergic deficit are four major characteristics of Alzheimer's disease (AD). Herein, we report the reactivities of 12 flavonoids against four pathogenic elements of AD: metal-free and metal-bound Aβ, free radicals, and acetylcholinesterase. A series of 12 flavonoids was selected based on the molecular structures that are responsible for multiple reactivities including hydroxyl substitution and transfer of the B ring from C2 to C3. Our experimental and computational studies reveal that the catechol moiety, the hydroxyl groups at C3 and C7, and the position of the B ring are important for instilling multiple functions in flavonoids. We establish a structure–activity relationship of flavonoids that should be useful for designing chemical reagents with multiple reactivities against the pathological factors of AD.

Characterising the brain metalloproteome in Down syndrome patients with concomitant Alzheimer's pathology.

Down syndrome (DS) is a common intellectual disability, with an incidence of 1 in 700 and is caused by trisomy 21. People with DS develop Alzheimer's disease (AD)-like neuropathology by the age of 40. As metal ion dyshomeostasis (particularly zinc, iron and copper) is one of the characteristics of AD and is believed to be involved in the pathogenesis of disease, we reasoned that it may also be altered in DS. Thus, we used inductively coupled plasma mass spectrometry to examine metal levels in post-mortem brain tissue from DS individuals with concomitant AD pathology. Size exclusion-ICPMS was also utilised to characterise the metalloproteome in these cases. We report here for the first time that iron levels were higher in a number of regions in the DS brain, including the hippocampus (40%), frontal cortex (100%) and temporal cortex (34%), compared to controls. Zinc and copper were also elevated (both 29%) in the DS frontal cortex, but zinc was decreased (23%) in the DS temporal cortex. Other elements were also examined, a number of which also showed disease-specific changes. The metalloproteomic profile in the DS brain was also different to that in the controls. These data suggest that metals and metal:protein interactions are dysregulated in the DS brain which, given the known role of metals in neurodegeneration and AD, is likely to contribute to the pathogenesis of disease. Interrogation of the underlying cellular mechanisms and consequences of this failure in metal ion homeostasis, and the specific contributions of the individual DS and AD phenotypes to these changes, should be explored.