Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

Cell, Год журнала: 2019, Номер 179(2), С. 312 - 339

Опубликована: Сен. 26, 2019

Язык: Английский

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Hallmarks of neurodegenerative diseases

Cell, Год журнала: 2023, Номер 186(4), С. 693 - 714

Опубликована: Фев. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Язык: Английский

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A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk

Nature, Год журнала: 2022, Номер 603(7903), С. 885 - 892

Опубликована: Фев. 14, 2022

Язык: Английский

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

Journal of Clinical Investigation, Год журнала: 2020, Номер 130(4), С. 1912 - 1930

Опубликована: Янв. 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.

Язык: Английский

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Microglia use TAM receptors to detect and engulf amyloid β plaques

Nature Immunology, Год журнала: 2021, Номер 22(5), С. 586 - 594

Опубликована: Апрель 15, 2021

Язык: Английский

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Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer’s disease

Scientific Data, Год журнала: 2021, Номер 8(1)

Опубликована: Окт. 15, 2021

Abstract Mouse models of human diseases are invaluable tools for studying pathogenic mechanisms and testing interventions therapeutics. For disorders such as Alzheimer’s disease in which numerous being generated, a challenging first step is to identify the most appropriate model age effectively evaluate new therapeutic approaches. Here we conducted detailed phenotypic characterization 5xFAD on congenic C57BL/6 J strain background, across its lifespan – including seldomly analyzed 18-month old time point provide temporally correlated phenotyping this template LOAD they generated. This comprehensive analysis included quantification plaque burden, Aβ biochemical levels, neuropathology, neurophysiological measurements behavioral cognitive assessments, evaluation microglia, astrocytes, neurons. Analysis transcriptional changes was using bulk-tissue generated RNA-seq data from microdissected cortices hippocampi function aging, can be explored at MODEL-AD Explorer AD Knowledge Portal. deep-phenotyping pipeline identified novel aspects age-related pathology model.

Язык: Английский

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Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits

Journal of Neuroscience, Год журнала: 2020, Номер 40(14), С. 2960 - 2974

Опубликована: Фев. 24, 2020

Chronic neuroinflammation with sustained microglial activation occurs following severe traumatic brain injury (TBI) and is believed to contribute subsequent neurodegeneration neurological deficits. Microglia, the primary innate immune cells in brain, are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for their survival. In this preclinical study, we examined effects of delayed depletion chronically activated microglia functional recovery up 3 months postinjury. A CSF1R inhibitor, Plexxikon (PLX) 5622, was administered adult male C57BL/6J mice at month after controlled cortical impact remove microglia, inhibitor withdrawn 1-week later allow repopulation. Following TBI, repopulated displayed a ramified morphology similar that Sham uninjured mice, whereas vehicle-treated TBI showed typical chronic posttraumatic hypertrophic morphology. PLX5622 treatment limited TBI-associated neuropathological changes postinjury; these included smaller lesion, reduced hippocampal neuron cell death, decreased NOX2- NLRP3 inflammasome-associated neuroinflammation. Furthermore, led widespread transcriptome altered gene pathways involved neuroinflammation, oxidative stress, neuroplasticity. Using variety complementary neurobehavioral tests, PLX5622-treated also had improved long-term motor cognitive function through Together, studies demonstrate phase removal neurotoxic using inhibitors markedly reduce associated neurodegeneration, as well related SIGNIFICANCE STATEMENT Traumatic debilitating disorder can seriously patient's quality life. Microglial-mediated induced contributes deficits on-going neurodegenerative processes. Here, investigated effect breaking neuroinflammatory loop 1-month by pharmacological 5622. Overall, show short-term elimination during followed repopulation results improvements function, suppression stress pathways, reduction persistent These clinically relevant support new concepts therapeutic window may be far longer than traditionally if evolving microglial-mediated inhibited or regulated precise manner.

Язык: Английский

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Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?

The Journal of Experimental Medicine, Год журнала: 2021, Номер 218(9)

Опубликована: Июль 22, 2021

Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation microglia. Because variants genes expressed in microglia correlate with AD risk, microglial response to plausibly impacts course. In mouse models, single-cell RNA sequencing (scRNA-seq) analyses delineated this as progressive conversion homeostatic into disease-associated (DAM); additional reactive populations have been reported other models neurodegeneration neuroinflammation. We review all these signatures, highlighting four fundamental patterns: DAM, IFN-microglia, MHC-II microglia, proliferating propose that are either just one or a combination, depending on the clustering strategy applied model. further single-nucleus (snRNA-seq) data from human specimens discuss reasons for parallels discrepancies between transcriptional profiles. Finally, we outline future directions delineating impact pathogenesis.

Язык: Английский

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Adapting with Microbial Help: Microbiome Flexibility Facilitates Rapid Responses to Environmental Change

BioEssays, Год журнала: 2020, Номер 42(7)

Опубликована: Июнь 16, 2020

Abstract Animals and plants are metaorganisms associate with microbes that affect their physiology, stress tolerance, fitness. Here the hypothesis alteration of microbiome may constitute a fast‐response mechanism to environmental change is examined. This supported by recent reciprocal transplant experiments reef corals, which have shown adapts thermally variable habitats changes over time when transplanted into different environments. Further, inoculation corals beneficial bacteria increases tolerance. But differ in ability flexibly bacteria. How scales flexibility reflect metaorganism adaptation mechanisms discussed future directions for research pinpointed. It posited broad phenomenon contributes organisms respond change. Importantly, adapting microbial help provide an alternate route organismal facilitates rapid responses.

Язык: Английский

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Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition

eLife, Год журнала: 2021, Номер 10

Опубликована: Апрель 13, 2021

Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer’s disease (AD) progression. However, mechanisms microbiome–brain interaction AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aβ deposition. Germ-free (GF) mice exhibit substantially reduced plaque load and markedly SCFA plasma concentrations; conversely, supplementation to GF increased levels conventionally colonized (specific pathogen-free [SPF]) animals SPF even further exacerbated load. This was accompanied by pronounced alterations microglial transcriptomic profile, including upregulation ApoE. Despite recruitment plaques upon supplementation, microglia contained less intracellular Aβ. Taken together, our results demonstrate that are critical mediators along gut-brain axis deposition likely via modulation phenotype.

Язык: Английский

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