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1.
Blood ; 2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38598841

ABSTRACT

Intrinsic molecular programs and extrinsic factors including pro-inflammatory molecules are understood to regulate hematopoietic aging. This is based on foundational studies using genetic perturbation to evaluate causality. However, individual organisms exhibit natural variation in hematopoietic aging phenotypes and the molecular basis of this heterogeneity is poorly understood. Here, we generated individual single cell transcriptomic profiles of hematopoietic and non-hematopoietic cell types in five young adult and nine middle-aged C57BL/6J female mice, providing a web-accessible transcriptomic resource for the field. Among all assessed cell types, hematopoietic stem cells (HSCs) exhibited the greatest phenotypic variation in expansion among individual middle-aged mice. We computationally pooled samples to define modules representing the molecular signatures of middle-aged HSCs and interrogated which extrinsic regulatory cell types and factors would predict variance in these signatures between individual middle-aged mice. Decline in signaling mediated by ADIPOQ, KITL and IGF1 from mesenchymal stromal cells (MSCs) was predicted to have the greatest transcriptional impact on middle-aged HSCs, as opposed to signaling mediated by endothelial cells or mature hematopoietic cell types. In individual middle-aged mice, lower expression of Kitl and Igf1 in MSCs highly correlated with reduced lymphoid lineage commitment of HSCs and increased signatures of differentiation-inactive HSCs. These signatures were independent of expression of aging-associated pro-inflammatory cytokines including IL1, IL6, TNF and RANTES. In sum, we find that Kitl and Igf1 expression are co-regulated and variable between individual mice at middle age and expression of these factors is predictive of HSC activation and lymphoid commitment independently of inflammation.

2.
Alzheimers Dement (N Y) ; 10(1): e12458, 2024.
Article in English | MEDLINE | ID: mdl-38469553

ABSTRACT

INTRODUCTION: In September 2022, The Jackson Laboratory Center for Alzheimer's and Dementia Research (JAX CADR) hosted a workshop with leading researchers in the Alzheimer's disease and related dementias (ADRD) field. METHODS: During the workshop, the participants brainstormed new directions to overcome current barriers to providing patients with effective ADRD therapeutics. The participants outlined specific areas of focus. Following the workshop, each group used standard literature search methods to provide background for each topic. RESULTS: The team of invited experts identified four key areas that can be collectively addressed to make a significant impact in the field: (1) Prioritize the diversification of disease targets, (2) enhance factors promoting resilience, (3) de-risk clinical pipeline, and (4) centralize data management. DISCUSSION: In this report, we review these four objectives and propose innovations to expedite ADRD therapeutic pipelines.

3.
Front Behav Neurosci ; 16: 1033975, 2022.
Article in English | MEDLINE | ID: mdl-36703722

ABSTRACT

In human Alzheimer's disease (AD) patients and AD mouse models, both differential pre-disease brain features and differential disease-associated memory decline are observed, suggesting that certain neurological features may protect against AD-related cognitive decline. The combination of these features is known as brain reserve, and understanding the genetic underpinnings of brain reserve may advance AD treatment in genetically diverse human populations. One potential source of brain reserve is brain microstructure, which is genetically influenced and can be measured with diffusion MRI (dMRI). To investigate variation of dMRI metrics in pre-disease-onset, genetically diverse AD mouse models, we utilized a population of genetically distinct AD mice produced by crossing the 5XFAD transgenic mouse model of AD to 3 inbred strains (C57BL/6J, DBA/2J, FVB/NJ) and two wild-derived strains (CAST/EiJ, WSB/EiJ). At 3 months of age, these mice underwent diffusion magnetic resonance imaging (dMRI) to probe neural microanatomy in 83 regions of interest (ROIs). At 5 months of age, these mice underwent contextual fear conditioning (CFC). Strain had a significant effect on dMRI measures in most ROIs tested, while far fewer effects of sex, sex*strain interactions, or strain*sex*5XFAD genotype interactions were observed. A main effect of 5XFAD genotype was observed in only 1 ROI, suggesting that the 5XFAD transgene does not strongly disrupt neural development or microstructure of mice in early adulthood. Strain also explained the most variance in mouse baseline motor activity and long-term fear memory. Additionally, significant effects of sex and strain*sex interaction were observed on baseline motor activity, and significant strain*sex and sex*5XFAD genotype interactions were observed on long-term memory. We are the first to study the genetic influences of brain microanatomy in genetically diverse AD mice. Thus, we demonstrated that strain is the primary factor influencing brain microstructure in young adult AD mice and that neural development and early adult microstructure are not strongly altered by the 5XFAD transgene. We also demonstrated that strain, sex, and 5XFAD genotype interact to influence memory in genetically diverse adult mice. Our results support the usefulness of the 5XFAD mouse model and convey strong relationships between natural genetic variation, brain microstructure, and memory.

4.
Sci Rep ; 10(1): 13688, 2020 08 13.
Article in English | MEDLINE | ID: mdl-32792571

ABSTRACT

Patients with frontotemporal dementia (FTD) resulting from granulin (GRN) haploinsufficiency have reduced levels of progranulin and exhibit dysregulation in inflammatory and lysosomal networks. Microglia produce high levels of progranulin, and reduction of progranulin in microglia alone is sufficient to recapitulate inflammation, lysosomal dysfunction, and hyperproliferation in a cell-autonomous manner. Therefore, targeting microglial dysfunction caused by progranulin insufficiency represents a potential therapeutic strategy to manage neurodegeneration in FTD. Limitations of current progranulin-enhancing strategies necessitate the discovery of new targets. To identify compounds that can reverse microglial defects in Grn-deficient mouse microglia, we performed a compound screen coupled with high throughput sequencing to assess key transcriptional changes in inflammatory and lysosomal pathways. Positive hits from this initial screen were then further narrowed down based on their ability to rescue cathepsin activity, a critical biochemical readout of lysosomal capacity. The screen identified nor-binaltorphimine dihydrochloride (nor-BNI) and dibutyryl-cAMP, sodium salt (DB-cAMP) as two phenotypic modulators of progranulin deficiency. In addition, nor-BNI and DB-cAMP also rescued cell cycle abnormalities in progranulin-deficient cells. These data highlight the potential of a transcription-based platform for drug screening, and advance two novel lead compounds for FTD.


Subject(s)
Bucladesine/pharmacology , Cysteine Proteases/metabolism , Frontotemporal Dementia/genetics , Gene Expression Profiling/methods , Microglia/cytology , Naltrexone/analogs & derivatives , Progranulins/deficiency , Animals , Cell Cycle/drug effects , Cells, Cultured , Disease Models, Animal , Frontotemporal Dementia/drug therapy , Frontotemporal Dementia/metabolism , Gene Expression Regulation/drug effects , Gene Knockout Techniques , High-Throughput Nucleotide Sequencing , Humans , Lysosomes/genetics , Lysosomes/metabolism , Mice , Microglia/drug effects , Microglia/metabolism , Models, Biological , Naltrexone/pharmacology , Sequence Analysis, RNA , Small Molecule Libraries/pharmacology
5.
Curr Opin Neurobiol ; 48: 52-58, 2018 02.
Article in English | MEDLINE | ID: mdl-29028540

ABSTRACT

Endo-lysosomal pathways are essential in maintaining protein homeostasis in the cell. Numerous genes in the endo-lysosomal pathways have been found to associate with neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and frontotemporal dementia (FTD). Mutations of these genes lead to dysfunction in multiple steps of the endo-lysosomal network: autophagy, endocytic trafficking and lysosomal degradation, resulting in accumulation of pathogenic proteins. Although the exact pathogenic mechanism varies for different disease-associated genes, dysfunction of the endo-lysosomal pathways represents a converging mechanism shared by these diseases. Therefore, strategies that correct or compensate for endo-lysosomal dysfunction may be promising therapeutic approaches to treat neurodegenerative diseases.


Subject(s)
Lysosomes/genetics , Lysosomes/metabolism , Neurodegenerative Diseases/genetics , Animals , Humans , Neurodegenerative Diseases/metabolism , Signal Transduction/physiology
6.
Bioorg Med Chem Lett ; 26(6): 1624-1628, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26869193

ABSTRACT

We have previously shown the improved acetylcholinesterase inhibitory activity of a model hydroxypyridinone compound transforming the hydroxyl group on the main ring into an N,N-dimethylcarbamate group; in the course of that study we developed a computational model to screen compounds for enzymatic activity. Herein we report development of second generation libraries. Candidates that adhere to drug-like criteria from a virtual library of compounds were tested using computational docking studies. Synthesis and characterization of chosen test compounds and their acetylcholinesterase inhibitory activity are presented.


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Molecular Docking Simulation , Pyridones/chemistry , Pyridones/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , In Vitro Techniques , Molecular Structure , Pyridones/chemical synthesis , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 25(17): 3654-7, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-26141772

ABSTRACT

Finding a cure for Alzheimer's disease is an urgent goal. Multifunctional metal binders are used to elucidate its pathological features and investigated as potential therapeutics. The use of physicochemical and TD-DFT calculations constituted successful strategy in the design of 1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL21) and 1-(4-(benzo[d]thiazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL22). We report the synthesis and full characterization of these compounds, including X-ray crystallography. Using fluorescent signal as the readout, it was determined that HL22 interacts with amyloid-beta protein fibrils, and permeates into bEnd.3 cells used as a mimic of the blood-brain barrier. This provides the first example of direct investigation of our hydroxypyridinone compounds within a biological setting.


Subject(s)
Amyloid beta-Peptides/metabolism , Pyridones/chemistry , Animals , Blood-Brain Barrier/drug effects , Cell Line/drug effects , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Fluorescence , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Molecular Structure , Permeability , Pyridones/pharmacology
8.
J Inorg Biochem ; 132: 59-66, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24393377

ABSTRACT

The deleterious role of metal ions in Alzheimer's disease has inspired the study of various metal chelators. We previously showed the synthesis and in vitro activity of several bidentate hydroxypyridinone compounds, including 3-hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (1), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (2), and 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (3). While the focus has been on the Cu(II) ion, the other biorelevant metals, Zn(II) and Fe(III) have been largely neglected. Herein, we report the synthesis of Zn(II) and Fe(III) complexes of ligands 1, 2, and 3, and their characterization by infrared (IR) spectroscopy, high resolution mass spectrometry (HR-MS), elemental analysis, and NMR, where applicable. Solid state structures of Zn(1)2, Fe(1)3, and Cu(3)2 are analyzed with X-ray crystallography. The cytotoxicity of pro-ligands 1, 2, and 3, and the three metal complexes of 2 are examined in a neuronal cell line to determine the effect of metal chelation on toxicity of the compounds.


Subject(s)
Coordination Complexes/chemical synthesis , Copper/chemistry , Iron/chemistry , Pyridones/chemistry , Pyridones/toxicity , Zinc/chemistry , Animals , Brain/cytology , Cell Line , Chelating Agents/chemistry , Chelating Agents/toxicity , Coordination Complexes/chemistry , Coordination Complexes/toxicity , Ligands , Mice , Models, Molecular , Neurons/drug effects , Nitrogen/chemistry
9.
Metallomics ; 6(2): 249-62, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23999879

ABSTRACT

Metal ions have been implicated in several neurodegenerative diseases, including Alzheimer's disease, as their dyshomeostasis may lead to production of reactive oxygen species as well as increased toxicity of amyloid protein aggregates. In this work, we present design and synthesis of three novel multifunctional hydroxypyridinone ligands, HL11, HL12, and HL13, bearing benzothiazole and benzoxazole functionalities. We study the ability of these compounds to bind metal ions Cu(II), Zn(II), and Fe(III), as well as their antioxidant activity and cytotoxicity. Additionally, we determine the pro-ligands' (compounds prior to chelation) propensity to target amyloid protein. Through these studies we determine the effect of combining amyloid- and metal-binding functionalities within the HPO scaffold on different aspects of AD pathology.


Subject(s)
Amyloid/metabolism , Metals/metabolism , Pyridones/metabolism , Amyloid/ultrastructure , Amyloid beta-Peptides/chemistry , Animals , Antioxidants/metabolism , Cell Line , Chromans/metabolism , Ions , Ligands , Mice , Models, Molecular , Nephelometry and Turbidimetry , Protein Structure, Quaternary , Quantum Theory , Solutions , Spectrum Analysis , Static Electricity
10.
Mol Biosyst ; 9(4): 792-805, 2013 Apr 05.
Article in English | MEDLINE | ID: mdl-23435553

ABSTRACT

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of people worldwide. With no prevention or cure available, this progressive disease has a significant impact on society - dementia patients and their caretakers, healthcare systems, and the economy. Previously, we have reported initial developments of multifunctional drug candidates for AD based on two scaffolds - thioflavin-T and deferiprone. Individually, these molecules have shown several favorable functionalities, including dissociation of toxic amyloid-ß aggregates, antioxidant and/or metal chelating ability that can pacify reactive oxygen species, plaque targeting, and blood-brain barrier penetration. In this work, the two scaffolds are augmented with a new functionality - acetylcholinesterase inhibition. This functionality is incorporated by derivatization with a carbamate group, which is the active group in some AD drugs currently in the market. We present the rationale for designing three novel compounds, their synthesis and characterization, including X-ray crystallographic data, and encouraging results from in vitro and computational acetylcholinesterase inhibition studies. Also, we evaluate the compounds as potential drug candidates by Lipinski's rules and cytotoxicity studies in a neuronal cell line. Overall, we demonstrate the feasibility of improving on two well established scaffolds, as well as show in vitro efficacy plus initial mode of action and biological compatibility data.


Subject(s)
Alzheimer Disease/enzymology , Cholinesterase Inhibitors/pharmacology , Pyridones/pharmacology , Thiazoles/pharmacology , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Benzothiazoles , Binding, Competitive , Blood-Brain Barrier/metabolism , Catalytic Domain , Cell Survival/drug effects , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/toxicity , Deferiprone , Humans , Kinetics , Ligands , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Permeability , Prodrugs/chemistry , Protein Binding , Pyridones/chemistry , Pyridones/toxicity , Thiazoles/chemistry , Thiazoles/toxicity
11.
Chem Soc Rev ; 42(4): 1836-46, 2013 Feb 21.
Article in English | MEDLINE | ID: mdl-22952002

ABSTRACT

Neurodegenerative diseases are capturing the world's attention as being the next set of diseases we must tackle collectively. Not only are the patients experiencing gradual cognitive and physical decline in most cases, but these diseases are fatal with no prevention currently available. As these diseases are progressive, providing care and symptom treatment for the ageing population is becoming both a medical and a financial challenge. This review discusses how Werner coordination chemistry plays a role in three diseases - those of Alzheimer's, Parkinson's, and prions. Metal ions are considered to be involved in these diseases in part via their propensity to cause toxic aggregation of proteins. First, the coordination of metal ions, with emphasis on copper(II), to metalloproteins that are hallmarks of these diseases - amyloid ß, α-synuclein, and prion, respectively - will be discussed. We will present the current understanding of the metal coordination environments created by the amino acids of these proteins, as well as metal binding affinity. Second, a diverse set of examples of rationally designed metal chelators to outcompete this deleterious binding will be examined based on coordination mode and affinity toward bio-relevant metal ions. Overall, this review will give a general overview of protein and metal chelator coordination environments in neurodegenerative diseases.


Subject(s)
Chelating Agents/chemistry , Coordination Complexes/chemistry , Copper/chemistry , Neurodegenerative Diseases , Amyloid beta-Peptides/chemistry , Humans , alpha-Synuclein/chemistry
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