scholarly journals Sustained Interleukin-1β overexpression exacerbates Tau pathology in a murine tauopathy model via cyclooxygenase-1

2021 ◽  
Author(s):  
Simantini Ghosh ◽  
Solomon S. Shaftel ◽  
Stephanos Kyrkanides ◽  
John A. Olschowka ◽  
M. Kerry O’Banion
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Interleukin 1Β ◽  
Tau Pathology ◽  
Cyclooxygenase 1 ◽  
The Central Nervous System ◽  
P301l Mutation ◽  
Cox 1

AbstractPathologic accumulation of abnormally phosphorylated tau in neurofibrillary tangles is a hallmark feature of Alzheimer’s disease and other tauopathies. Interleukin-1β ◻◻◻ −1β◻ is a major proinflammatory cytokine in the central nervous system that has been implicated in the pathogenesis of tauopathies as well as Alzheimer’s disease. To explore the role of chronic IL-1β overexpression in tauopathies in vivo we used an inducible model of IL-1β overexpression developed in our laboratory. The IL-1β (IL-1) mice bear a transcriptional stop flanked by LoxP elements upstream of a human IL-1β gene. Upon delivery of Cre, the IL-1 transgene is locally activated by excision of the stop sequence. The IL-1 mice were bred to JNPL3 (Tau) mice, which overexpress human tau with the P301L mutation. Expression of IL-1β was induced in the dentate gyrus of 8 to 8.5 month old progeny by stereotaxic injection of FIV-Cre. One and three months later, Tau/IL-1 mice demonstrated 2-4 fold increases in phospho-tau and glial activation. To attenuate IL-1β mediated inflammation, we reduced PGE2 production via pharmacological inhibition of cyclooxygenase-1 (COX-1) with SC560 in Tau/IL-1 mice, and observed significant reductions in phospho-tau pathology and microglial activation. Further, we found upregulation in active forms of p38MAPK, which was significantly reduced in mice receiving SC560 treatment. Our results demonstrate that IL-1β has a direct exacerbating effect on tau pathology in vivo, and inhibiting COX-1 can reverse this. COX-1 inhibition can therefore serve as a valuable therapeutic strategy for tauopathies with an advanced inflammatory component.

scholarly journals TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading

2018 ◽  
Vol 215 (9) ◽  
pp. 2355-2377 ◽  
Author(s):  
Heidi Martini-Stoica ◽  
Allysa L. Cole ◽  
Daniel B. Swartzlander ◽  
Fading Chen ◽  
Ying-Wooi Wan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Connections ◽  
Transgenic Mouse Models ◽  
Reverse Effect ◽  
Tau Pathology ◽  
Transcription Factor Eb ◽  
Human Brains

The progression of tau pathology in Alzheimer’s disease follows a stereotyped pattern, and recent evidence suggests a role of synaptic connections in this process. Astrocytes are well positioned at the neuronal synapse to capture and degrade extracellular tau as it transits the synapse and hence could potentially have the ability to inhibit tau spreading and delay disease progression. Our study shows increased expression and activity of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, in response to tau pathology in both human brains with dementia and transgenic mouse models. Exogenous TFEB expression in primary astrocytes enhances tau fibril uptake and lysosomal activity, while TFEB knockout has the reverse effect. In vivo, induced TFEB expression in astrocytes reduces pathology in the hippocampus of PS19 tauopathy mice, as well as prominently attenuates tau spreading from the ipsilateral to the contralateral hippocampus in a mouse model of tau spreading. Our study suggests that astrocytic TFEB plays a functional role in modulating extracellular tau and the propagation of neuronal tau pathology in tauopathies such as Alzheimer’s disease.

scholarly journals α-Synuclein modulates tau spreading in mouse brains

2020 ◽  
Vol 218 (1) ◽  
Author(s):  
Fares Bassil ◽  
Emily S. Meymand ◽  
Hannah J. Brown ◽  
Hong Xu ◽  
Timothy O. Cox ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Synergistic Effects ◽  
Tau Pathology ◽  
Vitro Data ◽  
In Vitro Data

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson’s disease (PD) and Alzheimer’s disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate–derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.

scholarly journals The Role of Eicosanoids in Alzheimer’s Disease

2019 ◽  
Vol 16 (14) ◽  
pp. 2560 ◽  
Author(s):  
Roger G. Biringer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Biological Functions ◽  
Tau Pathology ◽  
Cellular Processes ◽  
Eicosanoid Metabolism ◽  
Underlying Mechanisms

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders known. Estimates from the Alzheimer’s Association suggest that there are currently 5.8 million Americans living with the disease and that this will rise to 14 million by 2050. Research over the decades has revealed that AD pathology is complex and involves a number of cellular processes. In addition to the well-studied amyloid-β and tau pathology, oxidative damage to lipids and inflammation are also intimately involved. One aspect all these processes share is eicosanoid signaling. Eicosanoids are derived from polyunsaturated fatty acids by enzymatic or non-enzymatic means and serve as short-lived autocrine or paracrine agents. Some of these eicosanoids serve to exacerbate AD pathology while others serve to remediate AD pathology. A thorough understanding of eicosanoid signaling is paramount for understanding the underlying mechanisms and developing potential treatments for AD. In this review, eicosanoid metabolism is examined in terms of in vivo production, sites of production, receptor signaling, non-AD biological functions, and known participation in AD pathology.

scholarly journals Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Ding ◽  
Jin Wang ◽  
Miaoxin Huang ◽  
Zhangpeng Chen ◽  
Jing Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Knock Out ◽  
Classical Complement Pathway ◽  
Synaptic Remodeling ◽  
The Central Nervous System ◽  
System Activation ◽  
Knock Out Mice ◽  
Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

scholarly journals The Role of the Innate Immune System in Alzheimer’s Disease and Frontotemporal Lobar Degeneration: An Eye on Microglia

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Elisa Ridolfi ◽  
Cinzia Barone ◽  
Elio Scarpini ◽  
Daniela Galimberti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontotemporal Lobar Degeneration ◽  
Environmental Changes ◽  
Current Evidence ◽  
Neuronal Function ◽  
Immune Effector ◽  
Effector Cells ◽  
The Central Nervous System

In the last few years, genetic and biomolecular mechanisms at the basis of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) have been unraveled. A key role is played by microglia, which represent the immune effector cells in the central nervous system (CNS). They are extremely sensitive to the environmental changes in the brain and are activated in response to several pathologic events within the CNS, including altered neuronal function, infection, injury, and inflammation. While short-term microglial activity has generally a neuroprotective role, chronic activation has been implicated in the pathogenesis of neurodegenerative disorders, including AD and FTLD. In this framework, the purpose of this review is to give an overview of clinical features, genetics, and novel discoveries on biomolecular pathogenic mechanisms at the basis of these two neurodegenerative diseases and to outline current evidence regarding the role played by activated microglia in their pathogenesis.

P2-385: Binding and pharmacokinetic properties of novel 18 F-labeled agents for in vivo imaging of tau pathology in Alzheimer's disease

2010 ◽  
Vol 6 ◽  
pp. S429-S430
Author(s):  
Nobuyuki Okamura ◽  
Shozo Furumoto ◽  
Katsutoshi Furukawa ◽  
Hiroyuki Arai ◽  
Kazuhiko Yanai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vivo Imaging ◽  
Tau Pathology ◽  
Pharmacokinetic Properties

scholarly journals Conformation-selective tau monoclonal antibodies inhibit tau pathology in primary neurons and a mouse model of Alzheimer’s disease

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Garrett S. Gibbons ◽  
Soo-Jung Kim ◽  
Qihui Wu ◽  
Dawn M. Riddle ◽  
Susan N. Leight ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoclonal Antibodies ◽  
Statistical Significance ◽  
Neuritic Plaque ◽  
Plaque Burden ◽  
Primary Neurons ◽  
Tau Pathology ◽  
Model Of Alzheimer’S Disease

Abstract Background The spread of tau pathology in Alzheimer’s disease (AD) is mediated by cell-to-cell transmission of pathological tau seeds released from neurons that, upon internalization by recipient neurons, template the misfolding of naïve cellular tau, thereby propagating fibrillization. We hypothesize that anti-tau monoclonal antibodies (mAbs) that selectively bind to pathological tau seeds will inhibit propagation of tau aggregates and reduce the spread of tau pathology in vivo. Methods We inoculated mice with human AD brain-derived extracts containing tau paired helical filaments (AD-tau) and identified two novel mAbs, DMR7 and SKT82, that selectively bind to a misfolded pathological conformation of tau relative to recombinant tau monomer. To evaluate the effects of these mAbs on the spread of pathological tau in vivo, 5xFAD mice harboring significant brain Aβ plaque burden were unilaterally injected with AD-tau in the hippocampus, to initiate the formation of neuritic plaque (NP) tau pathology, and were treated weekly with intraperitoneal (i.p.) injections of DMR7, SKT82, or IgG isotype control mAbs. Results DMR7 and SKT82 bind epitopes comprised of the proline-rich domain and c-terminal region of tau and binding is reduced upon disruption of the pathological conformation of AD-tau by chemical and thermal denaturation. We found that both DMR7 and SKT82 immunoprecipitate pathological tau and significantly reduce the seeding of cellular tau aggregates induced by AD-tau in primary neurons by 60.5 + 13.8% and 82.2 + 8.3%, respectively, compared to IgG control. To investigate the mechanism of mAb inhibition, we generated pH-sensitive fluorophore-labeled recombinant tau fibrils seeded by AD-tau to track internalization of tau seeds and demonstrate that the conformation-selective tau mAbs inhibit the internalization of tau seeds. DMR7 and SKT82 treatment reduced hyperphosphorylated NP tau as measured with AT8 immunohistochemistry (IHC) staining, but did not achieve statistical significance in the contralateral cortex and SKT82 significantly reduced tau pathology in the ipsilateral hippocampus by 24.2%; p = 0.044. Conclusions These findings demonstrate that conformation-selective tau mAbs, DMR7 and SKT82, inhibit tau pathology in primary neurons by preventing the uptake of tau seeds and reduce tau pathology in vivo, providing potential novel therapeutic candidates for the treatment of AD.

P4-307: IN VIVO 18 F-FLORTAUCIPIR CORRELATES STRONGLY WITH POSTMORTEM ALZHEIMER'S DISEASE TAU PATHOLOGY

2006 ◽  
Vol 14 (7S_Part_30) ◽  
pp. P1573-P1573
Author(s):  
Ruben Smith ◽  
Moa Wibom ◽  
Daria Pawlik ◽  
Elisabet Englund ◽  
Oskar Hansson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Pathology
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