Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

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Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(4), P. 1912 - 1930

Published: Jan. 9, 2020

Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we demonstrated potent IFN immunogenicity of nucleic acid–containing (NA-containing) amyloid fibrils in the periphery. Here, investigated whether associated with β-amyloidosis inside brain contributes to neuropathology. An IFN-stimulated gene (ISG) signature was detected brains multiple murine Alzheimer disease (AD) models, phenomenon also observed WT mouse challenged generic NA-containing fibrils. In vitro, microglia innately responded AD activated ISG-expressing exclusively surrounded NA+ β plaques, which accumulated an age-dependent manner. Brain administration rIFN-β resulted microglial activation complement C3-dependent synapse elimination vivo. Conversely, selective receptor blockade effectively diminished ongoing microgliosis loss models. Moreover, enveloping neuritic plaques postmortem patients AD. Gene expression interrogation revealed pathway grossly upregulated clinical significantly correlated severity activation. Therefore, constitutes pivotal element within neuroinflammatory network critically neuropathogenic processes.

Language: Английский

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Alzheimer’s Disease: Treatment Strategies and Their Limitations

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(22), P. 13954 - 13954

Published: Nov. 12, 2022

Alzheimer’s disease (AD) is the most frequent case of neurodegenerative and becoming a major public health problem all over world. Many therapeutic strategies have been explored for several decades; however, there still no curative treatment, priority remains prevention. In this review, we present an update on clinical physiological phase AD spectrum, modifiable non-modifiable risk factors treatment with focus prevention strategies, then research models used in AD, followed by discussion limitations. The methods can significantly slow evolution are currently best strategy possible before advanced stages disease. Indeed, current drug treatments only symptomatic effects, disease-modifying not yet available. Drug delivery to central nervous system complex process represents challenge developing preventive strategies. Studies underway test new techniques facilitate bioavailability molecules brain. After deep study literature, find use soft nanoparticles, particular nanoliposomes exosomes, as innovative approach reducing solving problems brain bioavailability. show promising role exosomes smart systems able penetrate blood–brain barrier target tissues. Finally, different administration neurological disorders discussed. One intranasal which should be preclinical studies diseases.

Language: Английский

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Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models

Cell Reports, Journal Year: 2020, Volume and Issue: 32(2), P. 107908 - 107908

Published: July 1, 2020

We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis differential gene expression 2,114 postmortem samples. discover 30 coexpression modules from seven regions as major source AD transcriptional perturbations. next examine overlap with 251 differentially expressed sets mouse models and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology reveal age- sex-dependent signatures for progression. Human enriched neuronal and/or microglial genes broadly AD, Huntington's disease, amyotrophic lateral sclerosis, aging. Other modules, including those implicated proteostasis, are not activated but rather following other, unexpected genetic manipulations. Our results comprise cross-species resource, highlighting networks altered by pathophysiology identifying correspondences preclinical studies.

Language: Английский

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Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study

Frontiers in Aging Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: July 23, 2021

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization the model(s) being used. There are numerous that have been generated study Alzheimer's disease (AD) and underlying pathogenesis disease. While transgenic instrumental understanding AD mechanisms risk factors, they limited degree characteristics displayed comparison with humans, full spectrum effects has yet be recapitulated a single mouse model. Model Organism Development Evaluation for Late-Onset Disease (MODEL-AD) consortium was assembled by National Institute Aging (NIA) develop more robust increased relevance human disease, standardize models, improve preclinical testing animals, establish clinically relevant biomarkers, among other aims toward enhancing translational value clinical drug design treatment development. Here we conducted detailed 5XFAD mouse, including transcriptomics, electroencephalogram, vivo imaging, biochemical characterization, behavioral assessments. data from this is publicly available through Knowledge Portal.

Language: Английский

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Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies

Science, Journal Year: 2021, Volume and Issue: 371(6532)

Published: Feb. 25, 2021

The many faces of tau protein is implicated in several brain disorders, including Alzheimer's disease, suggesting that it could be a target therapeutics. However, because unclear how the pleiotropic roles lead to neural pathology different diseases, drug development remains challenging. Chang et al. review possible mechanisms diseases and paths forward improving research development. Science , this issue p. eabb8255

Language: Английский

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Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation

Journal of Biological Chemistry, Journal Year: 2019, Volume and Issue: 294(34), P. 12754 - 12765

Published: July 5, 2019

In cortical regions of brains from individuals with preclinical or clinical Alzheimer's disease (AD), extracellular β-amyloid (Aβ) deposition precedes the aggregation pathological intracellular tau (the product gene microtubule-associated protein (MAPT)). To our knowledge, current mouse models tauopathy reconstitute pathology by overexpressing mutant human protein. Here, through a homologous recombination approach that replaced entire murine Mapt ortholog, we developed knock-in mice humanized to create an in vivo platform for studying tauopathy. Of note, expressed all six isoforms present humans. We next cross-bred MAPT single amyloid precursor (App) investigate Aβ–tau axis AD etiology. The double-knock-in exhibited higher phosphorylation than did but initially lacked apparent and neurodegeneration, as observed App mice. further humanization significantly accelerates cell-to-cell propagation brain-derived both absence presence Aβ-amyloidosis. Aβ-amyloidosis, accumulation was intensified closely associated dystrophic neurites, consistently showing Aβ-amyloidosis affects pathology. Our results also indicated interacts better tau, suggesting species-specific differences between these orthologous pathogenic proteins. propose will make it feasible behaviors characteristics animal model.

Language: Английский

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APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2020, Volume and Issue: 15(1)

Published: Nov. 4, 2020

Abstract Investigations of apolipoprotein E ( APOE ) gene, the major genetic risk modifier for Alzheimer’s disease (AD), have yielded significant insights into pathogenic mechanism. Among three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases late-onset AD compared with APOE*ε3 . Despite increased understanding detrimental effect , it remains unclear how confers protection against AD. Accumulating evidence suggests that protects through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition, has been identified as a longevity suggesting systemic on aging process. However, is not entirely benign; carriers exhibit certain cerebrovascular diseases neurological disorders. Here, we review from human animal studies demonstrating protective propose working model depicting potential underlying Finally, discuss therapeutic strategies designed to leverage APOE2 treat

Language: Английский

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Microglia in Brain Development, Homeostasis, and Neurodegeneration

Annual Review of Genetics, Journal Year: 2019, Volume and Issue: 53(1), P. 263 - 288

Published: Sept. 13, 2019

Advances in human genetics have implicated a growing number of genes neurodegenerative diseases, providing insight into pathological processes. For Alzheimer disease particular, genome-wide association studies and gene expression emphasized the pathogenic contributions from microglial cells motivated function/dysfunction. Here, we summarize recent genetic evidence for involvement with focus on disease, which is most compelling. To provide context these discoveries, discuss how microglia influence brain development homeostasis, characteristics change activities likely course neurodegeneration. In all, aim to synthesize varied aspects biology highlight as possible targets therapeutic interventions disease.

Language: Английский

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Traumatic Brain Injury Induces Tau Aggregation and Spreading

Journal of Neurotrauma, Journal Year: 2019, Volume and Issue: 37(1), P. 80 - 92

Published: July 18, 2019

The misfolding and aggregation of tau protein into neurofibrillary tangles is the main underlying hallmark tauopathies. Most tauopathies have a sporadic origin can be associated with multiple risk factors. Traumatic brain injury (TBI) has been suggested as factor for by triggering disease onset facilitating its progression. Several studies indicate that TBI seems to development Alzheimer chronic traumatic encephalopathy, because there relationship severity propensity these illnesses. In this study, we evaluated whether moderate severe trigger initial formation pathological would induce pathology throughout brain. To end, subjected transgenic mice assessed phosphorylation pattern create spatial heat map deposition spreading in Our results suggest injured an accelerated different regions increases over time compared sham mice. appearance occurs distant area are connected synaptically, suggesting dissemination aggregates. Overall, work posits through induction hyperphosphorylation aggregation.

Language: Английский

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