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1.
Biochem Pharmacol ; : 116258, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38705533

ABSTRACT

Over the past decade, human genome-wide association and expression studies have strongly implicated dysregulation of the innate immune system in the pathogenesis of Alzheimer's disease (AD). Single cell mRNA sequencing studies have identified innate immune cell subtypes that are minimally present in normal healthy brain, but whose numbers greatly increase in association with AD pathology. These AD pathology-associated immune cells are putatively the locus for the immune-related AD risk. While the prevailing view is that these immune cells arise from transformation of resident brain microglia, studies across several decades and using multiple techniques and strategies suggest instead that the pathology-associated immune cells are bone-marrow derived hematopoietic cells that are recruited into brain. We critically review this translational literature, emphasizing the strengths and limitations of techniques used to address recruitment and the experimental designs employed. We conclude that the aggregate evidence points toward recruitment into brain of innate immune cells of the myeloid dendritic cell lineage. Recruitment of dendritic cells and their role in AD pathogenesis has broad implications for our understanding of the etiology and pathobiology of AD that impact the strategies to develop new, immune system-targeted therapeutics for this devastating disease.

2.
Neuron ; 101(6): 1099-1108.e6, 2019 03 20.
Article in English | MEDLINE | ID: mdl-30737131

ABSTRACT

Cerebrovascular alterations are a key feature of Alzheimer's disease (AD) pathogenesis. However, whether vascular damage contributes to synaptic dysfunction and how it synergizes with amyloid pathology to cause neuroinflammation and cognitive decline remain poorly understood. Here, we show that the blood protein fibrinogen induces spine elimination and promotes cognitive deficits mediated by CD11b-CD18 microglia activation. 3D molecular labeling in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. Fibrinogen-induced spine elimination was prevented by inhibiting reactive oxygen species (ROS) generation or genetic ablation of CD11b. Genetic elimination of the fibrinogen binding motif to CD11b reduced neuroinflammation, synaptic deficits, and cognitive decline in the 5XFAD mouse model of AD. Thus, fibrinogen-induced spine elimination and cognitive decline via CD11b link cerebrovascular damage with immune-mediated neurodegeneration and may have important implications in AD and related conditions.


Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , Cognitive Dysfunction/metabolism , Dendritic Spines/metabolism , Fibrinogen/metabolism , Microglia/metabolism , Plaque, Amyloid/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Animals , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Brain/physiology , Brain/physiopathology , CD11b Antigen/metabolism , CD18 Antigens/metabolism , Cognitive Dysfunction/pathology , Cognitive Dysfunction/physiopathology , Dendritic Spines/pathology , Disease Models, Animal , Humans , Imaging, Three-Dimensional , Mice , Plaque, Amyloid/pathology , Reactive Oxygen Species/metabolism
3.
Nat Immunol ; 19(11): 1212-1223, 2018 11.
Article in English | MEDLINE | ID: mdl-30323343

ABSTRACT

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.


Subject(s)
Antibodies, Monoclonal/immunology , Fibrinogen/antagonists & inhibitors , Neurodegenerative Diseases/immunology , Animals , Epitopes , Humans , Inflammation/immunology , Mice , Rats
4.
Bioorg Med Chem Lett ; 21(9): 2631-6, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21269825

ABSTRACT

The synthesis and structure-activity relationship (SAR) of a novel series of di-substituted imidazoles, derived from modification of DAPT, are described. Subsequent optimization led to identification of a highly potent series of inhibitors that contain a ß-amine in the imidazole side-chain resulting in a robust in vivo reduction of plasma and brain Aß in guinea pigs. The therapeutic index between Aß reductions and changes in B-cell populations were studied for compound 10 h.


Subject(s)
Alzheimer Disease , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Amination/drug effects , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/metabolism , Animals , Biological Assay , Diamide/chemical synthesis , Diamide/chemistry , Diamide/pharmacology , Enzyme Inhibitors/chemistry , Guinea Pigs , HeLa Cells , Humans , Imidazoles/chemistry , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 21(9): 2637-40, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21269827

ABSTRACT

A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aß in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aß EC(50) lead to the identification of compound 14f (PF-3084014) which was selected for clinical development.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Tetrahydronaphthalenes/chemical synthesis , Tetrahydronaphthalenes/pharmacology , Valine/analogs & derivatives , Animals , Biological Assay , Drug Design , Enzyme Inhibitors/chemistry , Guinea Pigs , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Valine/chemical synthesis , Valine/chemistry , Valine/pharmacology
6.
Curr Opin Investig Drugs ; 10(7): 672-80, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19579173

ABSTRACT

This review discusses current knowledge of the complex interactions between amyloid-beta (A beta) peptide, the receptor for advanced glycation endproducts (RAGE), and inflammatory mediators, focusing on the roles of such interactions in the pathogenesis of Alzheimer's disease. As a ubiquitous cell-surface receptor, RAGE demonstrates enhanced expression in an A beta-rich environment; the effects of RAGE on microglia, the blood-brain barrier and neurons are mediated through various signaling pathways. Relevant preclinical models illustrate that the A beta-RAGE interaction amplifies neuronal stress and the accumulation of A beta, impairs memory and learning, and exaggerates neuroinflammation. These findings suggest that RAGE may mediate a common proinflammatory pathway in neurodegenerative disorders.


Subject(s)
Alzheimer Disease/etiology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Brain/pathology , Inflammation/etiology , Receptors, Immunologic/physiology , Alzheimer Disease/pathology , Amyloid beta-Peptides/pharmacology , Animals , Brain/metabolism , Disease Models, Animal , Humans , Mice , Models, Biological , Neurodegenerative Diseases/metabolism , Receptor for Advanced Glycation End Products , Receptors, Immunologic/agonists
7.
J Cataract Refract Surg ; 34(4): 585-90, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18361979

ABSTRACT

PURPOSE: To present the findings of an outbreak of toxic anterior segment syndrome (TASS). SETTING: Six states, 7 ophthalmology surgical centers, United States. METHODS: Cases were identified through electronic communication networks and via reports to a national TASS referral center. Information on the procedure, details of instrument reprocessing, and products used during cataract surgery were also collected. Medications used during the procedures were tested for endotoxin using a kinetic assay. RESULTS: The search identified 112 case patients (median age 74 years) from 7 centers from July 19, 2005, through November 28, 2005. Common presenting clinical features included blurred vision (60%), anterior segment inflammation (49%), and cell deposition (56%). Of the patients, 100 (89%) had been exposed to a single brand of balanced salt solution manufactured by Cytosol Laboratories and distributed by Advanced Medical Optics as AMO Endosol. Two patients continued to have residual symptoms. There were no reports of significant breaches in sterile technique or instrument reprocessing. Of 14 balanced salt solution lots, 5 (35%) had levels exceeding the endotoxin limit (0.5 EU/mL). Based on these findings, the balanced salt solution product was withdrawn, resulting in a termination of the outbreak. CONCLUSIONS: This is the first known report of an outbreak of TASS caused by intrinsic contamination of a product with endotoxin. Ophthalmologists and epidemiologists should be aware of TASS and its common causes. To facilitate investigations of adverse outcomes such as TASS, those performing cataract surgeries should document the type and lot numbers of products used intraoperatively.


Subject(s)
Acetates , Anterior Eye Segment/pathology , Disease Outbreaks , Drug Contamination , Minerals , Shock, Septic/epidemiology , Sodium Chloride , Uveitis, Anterior/epidemiology , Adult , Aged , Aged, 80 and over , Drug Combinations , Female , Humans , Male , Middle Aged , Shock, Septic/diagnosis , Shock, Septic/etiology , Syndrome , United States/epidemiology , Uveitis, Anterior/diagnosis , Uveitis, Anterior/etiology , Vision Disorders/diagnosis , Vision Disorders/epidemiology , Vision Disorders/etiology
8.
J Neurosci ; 27(12): 3090-7, 2007 Mar 21.
Article in English | MEDLINE | ID: mdl-17376970

ABSTRACT

Postoperative cognitive dysfunction, confusion, and delirium are common after general anesthesia in the elderly, with symptoms persisting for months or years in some patients. Even middle-aged patients are likely to have postoperative cognitive dysfunction for months after surgery, and Alzheimer's disease (AD) patients appear to be particularly at risk of deterioration after anesthesia. Several investigators have thus examined whether general anesthesia is associated with AD, with some studies suggesting that exposure to anesthetics may increase the risk of AD. However, little is known on the biochemical consequences of anesthesia on pathogenic pathways in vivo. Here, we investigated the effect of anesthesia on tau phosphorylation and amyloid precursor protein (APP) metabolism in mouse brain. We found that, regardless of the anesthetic used, anesthesia induced rapid and massive hyperphosphorylation of tau, rapid and prolonged hypothermia, inhibition of Ser/Thr PP2A (protein phosphatase 2A), but no changes in APP metabolism or Abeta (beta-amyloid peptide) accumulation. Reestablishing normothermia during anesthesia completely rescued tau phosphorylation to normal levels. Our results indicate that changes in tau phosphorylation were not a result of anesthesia per se, but a consequence of anesthesia-induced hypothermia, which led to inhibition of phosphatase activity and subsequent hyperphosphorylation of tau. These findings call for careful monitoring of core temperature during anesthesia in laboratory animals to avoid artifactual elevation of protein phosphorylation. Furthermore, a thorough examination of the effect of anesthesia-induced hypothermia on the risk and progression of AD is warranted.


Subject(s)
Anesthesia/adverse effects , Hypothermia/metabolism , Phosphoprotein Phosphatases/antagonists & inhibitors , Phosphoprotein Phosphatases/metabolism , tau Proteins/metabolism , Anesthetics/administration & dosage , Anesthetics/adverse effects , Animals , Hippocampus/drug effects , Hippocampus/enzymology , Hippocampus/metabolism , Hypothermia/enzymology , Male , Mice , Phosphorylation/drug effects , Protein Phosphatase 2
9.
Curr Pharm Des ; 11(26): 3335-52, 2005.
Article in English | MEDLINE | ID: mdl-16250840

ABSTRACT

There is extensive evidence that changes in immune system activation accompany the pathological changes of Alzheimer's disease (AD), but a mechanistic understanding of how the immune system actually participates in disease pathogenesis is still largely lacking. Because of the complexity of the immunological response, and the difficulty in identifying the key molecular players that underlie any given immunological response, expanding our understanding of the immunological response in AD beyond its descriptive stages has not been a straightforward exercise. The development of transgenic animals that form deposits of Abeta peptide in their brains has provided an unexpected dividend to those interested in the immunological response characterizing AD. Several of these transgenic models develop structures greatly resembling neuritic plaques, a hallmark feature of AD brain that is also a focal point of the immunological response occurring in AD. Genetic and pharmacological manipulation of these Abeta-depositing transgenic mice is providing some intriguing and unexpected insights into the role of innate and adaptive immune mechanisms in the pathogenesis of AD. This review will discuss immunological perspectives that have arisen from research using Abeta-depositing transgenic mice, and place these perspectives in the context of epidemiological and genetic studies that have previously suggested a role for the immune system in AD. The emerging story affirms the likely role of innate and adaptive immune mechanisms in the pathogenesis of AD, but provides a cautionary note as to the difficulties that are likely to face potential immunomodulatory therapies due to the dualistic beneficial and detrimental roles that immune mechanisms appear to play in AD.


Subject(s)
Alzheimer Disease/immunology , Mice, Transgenic/immunology , Neuroimmunomodulation/physiology , Alzheimer Disease/genetics , Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/immunology , Animals , Humans , Mice , Mice, Transgenic/genetics
10.
Bioorg Med Chem Lett ; 14(17): 4511-4, 2004 Sep 06.
Article in English | MEDLINE | ID: mdl-15357982

ABSTRACT

The synthesis and nNOS and eNOS activity of 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-5-ethyl-2-methoxyphenyl)-pyridin-2-ylamines and 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-2,5-dimethoxyphenyl)-pyridin-2-ylamines 1-8 are described. These compounds are potent inhibitors of the human nNOS isoform.


Subject(s)
Amines/chemistry , Enzyme Inhibitors/chemistry , Nerve Tissue Proteins/antagonists & inhibitors , Nitric Oxide Synthase/antagonists & inhibitors , Pyridines/chemistry , Amines/pharmacology , Enzyme Inhibitors/pharmacology , Humans , Neural Inhibition/drug effects , Nitric Oxide Synthase Type I , Pyridines/pharmacology
11.
J Med Chem ; 47(6): 1575-86, 2004 Mar 11.
Article in English | MEDLINE | ID: mdl-14998342

ABSTRACT

The synthesis and structure-activity relationships of a series of 6-phenyl-2-aminopyridines that potently and selectively inhibit the neuronal isoform of nitric oxide synthase (nNOS) are described. Compound 14bi from this series exhibits potent in vivo activity in harmaline-induced cGMP formation in rat cerebellum, a functional model of nNOS inhibition, and in the PCP-induced hypermotility model in the rat. These results suggest that 14bi may be a useful reagent for evaluating potential therapeutic applications of nNOS inhibitors in the central nervous system.


Subject(s)
Aminopyridines/chemical synthesis , Nitric Oxide Synthase/antagonists & inhibitors , Tetrahydronaphthalenes/chemical synthesis , Aminopyridines/chemistry , Aminopyridines/pharmacology , Animals , Cerebellum/drug effects , Cerebellum/metabolism , Cyclic GMP/biosynthesis , Male , Motor Activity/drug effects , Nitric Oxide Synthase/chemistry , Nitric Oxide Synthase Type I , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology
12.
Peabody, Mass; EBSCO Publishing; 9 ed; 1994. 266 p. ilus.
Monography in English | PAHO | ID: pah-17097
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