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 Targeting MicroRNA-485-3p Blocks Alzheimer’s Disease Progression

2021 ◽  
Vol 22 (23) ◽  
pp. 13136
Author(s):  
Han Seok Koh ◽  
SangJoon Lee ◽  
Hyo Jin Lee ◽  
Jae-Woong Min ◽  
Takeshi Iwatsubo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Treatment Strategies ◽  
Tau Pathology ◽  
Memory Decline ◽  
Tnf Α ◽  
The Brain

Alzheimer’s disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction. With only one FDA-approved therapy, effective treatment strategies for AD are urgently needed. In this study, we found that microRNA-485-3p (miR-485-3p) was overexpressed in the brain tissues, cerebrospinal fluid, and plasma of patients with AD, and its antisense oligonucleotide (ASO) reduced Aβ plaque accumulation, tau pathology development, neuroinflammation, and cognitive decline in a transgenic mouse model of AD. Mechanistically, miR-485-3p ASO enhanced Aβ clearance via CD36-mediated phagocytosis of Aβ in vitro and in vivo. Furthermore, miR-485-3p ASO administration reduced apoptosis, thereby effectively decreasing truncated tau levels. Moreover, miR-485-3p ASO treatment reduced secretion of proinflammatory cytokines, including IL-1β and TNF-α, and eventually relieved cognitive impairment. Collectively, our findings suggest that miR-485-3p is a useful biomarker of the inflammatory pathophysiology of AD and that miR-485-3p ASO represents a potential therapeutic candidate for managing AD pathology and cognitive decline.

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.

Toll-Like Receptors 2 and 4 Are Involved in the Induction of Graft-Versus-Host-Disease in Mice.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5175-5175
Author(s):  
Axel Nogai ◽  
Markus M. Heimesaat ◽  
Marc Thiele ◽  
Stefan Bereswill ◽  
Eckhard Thiel ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Lipid A ◽  
Host Disease ◽  
Graft Versus Host ◽  
Vitro Data ◽  
In Vitro Data

Abstract BACKGROUND: Intestinal Graft-versus-Host disease is a frequent and often lethal complication after allogenic stem cell transplantation. Since NOD2 polymorphisms have been recognized as potential triggers of severe intestinal GvHD in humans, we have developed murine transplantation models to investigate the role of different pattern recognition receptors (PRR) in GvHD and GvL. Here we report our results on the role of TLR2 and TLR4 for the induction of GvHD. METHODS: Severity of GvHD in wildtype (wt) C57B/10 (H-2Db), TLR2−/−, TLR4−/−, and combined TLR2−/−TLR4−/− C57B/10 mice was investigated. Mice received treosulfan 2000 mg/kg from day -3 to -1 and cyclophosphamide 200 mg/kg day -1 prior to injection of 10×10^6 H-2Dd BM cells and 5×10^6 splenocytes (SC). Survival and GvHD score were assessed daily. Engraftment was determined every 2 weeks in pB and at the end of the experiments in bone marrow by flow cytometry. T cell alloreactivity in GvH direction was assessed by MLR using splenocytes as stimulators from PRR-deficient mice or wt as control and CFSE-staining as read-out. The relevance of PRR ligands for the enhancement of GvH alloreactivity was determined by addition of lipid A, lipopetides, or CpG. RESULTS: in vivo data: The transfer of 10×10^6 BMC + 5×10^6 SC induced a severe GvHD in all wt recipients, leading to death of 90% of the animals within 20 days. Recipient mice lacking either TLR2 or TLR4 showed only a slightly and not significantly decreased GvHD lethality. In recipients lacking both PPRs, i.e. TLR2 and TLR4, GvHD was generally milder and the majority (60%) of the animals survived until day 20 (p<0.05). However, the long term survival was not significantly improved. Differences in clinical severity of GvHD were confirmed histologically. In vitro data: Stimulation with cells from TLR2−/− and TLR4−/− mice resulted in a decreased alloreactivity in MLR. A median of 2% of Balb/c CD4+ T cells proliferated in response to C57B/10 stimulators. The addition of the TLR2 and TLR4 ligands lipopeptide, Lipid A and CpG significantly (p<0.05) increased the proliferation of CD4+ T cells in a specific manner more than twofold. CONCLUSION: Our in vivo and in vitro data consistantly show that bacterial components are involved in triggering GvH alloreactivity via different types of PPRs. Binding of bacterial substances to TLR2 and TLR4 leads to activation of the immune system and subsequent induction of GvHD. Our data provide an experimental basis for the development of strategies for modulation of the intestinal gut flora by selective gut decontamination and/or probiotic regimens to prevent GvHD in humans.

scholarly journals Copper Modulation as a Therapy for Alzheimer's Disease?

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Yasmina Manso ◽  
Gemma Comes ◽  
Juan Hidalgo ◽  
Ashley I. Bush ◽  
Paul A. Adlard
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Ion ◽  
Amyloid A ◽  
Animal Data ◽  
Clinical Literature ◽  
Behavioural Performance

The role of metals in the pathophysiology of Alzheimer's disease (AD) has gained considerable support in recent years, with both in vitro and in vivo data demonstrating that a mis-metabolism of metal ions, such as copper and zinc, may affect various cellular cascades that ultimately leads to the development and/or potentiation of AD. In this paper, we will provide an overview of the preclinical and clinical literature that specifically relates to attempts to affect the AD cascade by the modulation of brain copper levels. We will also detail our own novel animal data, where we treated APP/PS1 (7-8 months old) mice with either high copper (20 ppm in the drinking water), high cholesterol (2% supplement in the food) or a combination of both and then assessedβ-amyloid (Aβ) burden (soluble and insoluble Aβ), APP levels and behavioural performance in the Morris water maze. These data support an interaction between copper/cholesterol and both Aβand APP and further highlight the potential role of metal ion dyshomeostasis in AD.

scholarly journals Hormonal treatment, mild cognitive impairment and Alzheimer's disease

2008 ◽  
Vol 20 (1) ◽  
pp. 47-56 ◽  
Author(s):  
Joanne Ryan ◽  
Jaqueline Scali ◽  
Isabelle Carriere ◽  
Karen Ritchie ◽  
Marie-Laure Ancelin
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Verbal Memory ◽  
Late Onset ◽  
Controlled Trial ◽  
Hormonal Changes

ABSTRACTA plethora of in vitro and in vivo studies have supported the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented postmenopausal women suggest a temporary positive effect (notably on verbal memory), and four meta-analyses converge to suggest a possible protective effect in relation to Alzheimer's disease (reducing risk by 29 to 44%). However, data from the only large randomized controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Apart from methodological differences, one key shortcoming of this trial has probably been the focus on late-onset (postmenopausal) hormonal changes, i.e. at a time when the neurodegenerative process has already begun and without taking into account individual lifetime exposure to hormone variability. Multifactorial models based on an exhaustive view of all hormonal events throughout the reproductive life (rather than on a specific exposure to a given steroid) together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.

scholarly journals LBD Dimerization of the Androgen Receptor but Not N/C Interaction Is Crucial for Normal Male Development in Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A822-A822
Author(s):  
Sarah El Kharraz ◽  
Christine Helsen ◽  
Vanessa Dubois ◽  
Claude Libert ◽  
Matti Poutanen ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Binding Domain ◽  
Bone Homeostasis ◽  
Bone Phenotype ◽  
Male Development ◽  
Vitro Data ◽  
In Vitro Data

Abstract The androgen receptor (AR) is a nuclear receptor with a main role in the development and maintenance of the male phenotype. To execute its role as transcription factor, the AR forms homodimers. Three dimerization modes have been described for the AR: one via the DNA binding domain, a second via the ligand binding domain (LBD) and a third via interactions between the LBD and the aminoterminus of the AR (N/C). Based exclusively on in vitro data, all three dimerization modes seem to contribute to full AR activity, albeit to a different extent. The in vivo role of the dimerization modes, however, remains unknown. To study the physiological relevance, we generated two mouse models using a CRISPR/Cas9 approach, in which either the N/C interaction (ARNoC) or LBD dimerization (ARLmon) was disrupted. Surprisingly, the male ARNoC mice have a normal phenotype, indicating that the N/C interaction is not crucial for male development. In contrast, ARLmon males have an external female phenotype with cryptorchid testes and high levels of circulating testosterone (T), androstenedione and luteinizing hormone (LH) (6-, 13- and 45-fold higher, respectively). They have no prostate, seminal vesicles or epididymis, illustrating the importance of LBD dimerization during male development. Phenotyping the ARLmon model furthermore provided evidence of a crucial role for the AR in bone homeostasis as well as steroidogenesis. The ARLmon males display a severe bone phenotype, similar to that of complete AR knockout (ARKO) mice. The bone phenotype of ARKO was postulated to be mainly due to lower estrogen levels. However, in contrast to ARKO mice, ARLmon mice have high circulating levels of T, which can still function as prohormone for estradiol and support bone function via the ERα. Immunohistological analysis of ARLmon testes showed hyperplasia of the Leydig cells and residual spermatogenesis. Analysis of the steroidogenic pathway revealed that while the expression of most genes is increased, the expression of Hsd17b3, encoding the enzyme responsible for conversion of androstenedione into T, is low in ARLmon testis. Reporter assays confirmed that the promotor of this gene is indeed upregulated by the AR itself. In conclusion, our work uncovers the physiological role of the N/C interaction and LBD dimerization of the AR. It furthermore demonstrates a direct role for AR in male bone development independent of T aromatization into estrogens. Finally, we show that the AR controls the final step in the synthesis of its own ligand. In contrast to the in vitro data, N/C interaction is not crucial for male development in vivo. The ARLmon model illustrates that LBD dimerization could be an excellent new therapeutic target for inhibiting AR activity for example in advanced prostate cancer that has developed resistance to the current AR-targeting therapies.

scholarly journals Study on the Multitarget Synergistic Effects of Kai-Xin-San against Alzheimer’s Disease Based on Systems Biology

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Sirui Guo ◽  
Jiahong Wang ◽  
Yunjia Wang ◽  
Ying Zhang ◽  
Kaishun Bi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Systems Biology ◽  
Synergistic Effects ◽  
Medicine Research ◽  
Related Proteins ◽  
Functional Mechanisms ◽  
The Brain

Kai-Xin-San (KXS), a classical Chinese traditional prescription, was widely applied in the treatment of Alzheimer’s disease (AD), while its functional mechanisms still remain unclear. By using systems biology approaches at animal, cellular, and molecular levels, the improvement of KXS on cognitive impairment was achieved by inhibiting abnormal acetylcholinesterase. The function on the nerve skeleton was performed by regulating the Tau phosphorylation pathway. Its antioxidant, anti-inflammatory, and antiapoptotic effects by modulating the aberrant upregulation of ROS, proinflammatory factors, and apoptosis-related proteins in the brain were studied to reveal the synergistic therapeutic efficacy of KXS. Then, formula dismantling in vitro indicated that ginseng was the principal herb, whereas three other herbs served adjuvant roles to achieve the best effect. After that, the in vivo analysis of components into plasma and brain of AD rats showed that 8 of 23 components in blood and 4 of 10 components in brain were from ginseng, respectively, further verifying the principal status of ginseng and the synergistic effects of the formula. Thus, the anti-AD effects of KXS were achieved by multitargets and multichannels. The systems biology approaches presented here provide a novel way in traditional herbal medicine research.

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 Molecular mechanism of the repressive phase of the mammalian circadian clock

2020 ◽  
Vol 118 (2) ◽  
pp. e2021174118
Author(s):  
Xuemei Cao ◽  
Yanyan Yang ◽  
Christopher P. Selby ◽  
Zhenxing Liu ◽  
Aziz Sancar
Keyword(s):  
Circadian Clock ◽  
Local Concentration ◽  
Transcriptional Repressors ◽  
In Vivo Experiments ◽  
E Box ◽  
Vitro Data ◽  
In Vitro Data

The mammalian circadian clock consists of a transcription–translation feedback loop (TTFL) composed of CLOCK–BMAL1 transcriptional activators and CRY–PER transcriptional repressors. Previous work showed that CRY inhibits CLOCK–BMAL1-activated transcription by a “blocking”-type mechanism and that CRY–PER inhibits CLOCK–BMAL1 by a “displacement”-type mechanism. While the mechanism of CRY-mediated repression was explained by both in vitro and in vivo experiments, the CRY–PER-mediated repression in vivo seemed in conflict with the in vitro data demonstrating PER removes CRY from the CLOCK–BMAL1–E-box complex. Here, we show that CRY–PER participates in the displacement-type repression by recruiting CK1δ to the nucleus and mediating an increased local concentration of CK1δ at CLOCK–BMAL1-bound promoters/enhancers and thus promoting the phosphorylation of CLOCK and dissociation of CLOCK–BMAL1 along with CRY from the E-box. Our findings bring clarity to the role of PER in the dynamic nature of the repressive phase of the TTFL.

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.

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