L’article Publication: “Aging alters the vulnerability pattern to amyloid-beta oligomers in wild-type mice: a behavioral and neurobiological study” est apparu en premier sur ETAP-LAB.

Sci Rep 15, 29738 (2025).

Authors: Miny, L., Rontard, J., Allouche, A. et al.

Affiliated:

• NETRI (Lyon, France)
• Hospices Civils de Lyon – Department of Biochemistry and Molecular Biology, Neurodegenerative Pathologies (Bron, France)
• Lyon Neurosciences Research Center (CNRS UMR 5292 / INSERM U1028)
• ETAP-Lab – Preclinical Efficacy CRO (Vandoeuvre-Lès-Nancy, France)

Abstract:

Neurodegenerative diseases, including Alzheimer’s disease (AD), present significant diagnostic challenges due to overlapping symptoms and the invasive, time-consuming, and costly nature of current diagnostic methods. While AD remains the only neurodegenerative disorder for which biomarkers in cerebrospinal fluid (CSF), such as amyloid beta peptide (Aβ), are available for clinical diagnosis, similar tools are lacking for other neurodegenerative conditions. This diagnostic gap hinders timely and accurate differential diagnoses, limiting patient access to appropriate clinical trials and therapeutic interventions. In this study, we developed a compartmentalized microfluidic platform to facilitate differential diagnosis of neurodegenerative diseases by providing an initial screening tool to guide patients toward targeted clinical pathways. Using CSF samples from AD patients with confirmed diagnoses, we showed a proof of concept to distinguish between non neurodegenerative (NN) and Alzheimer’s samples. Human glutamatergic neurons derived from induced pluripotent stem cells (iPSCs) were exposed to synthetic Aβ oligomers (AβO) and patient CSF to assess their effects on neuronal network activity. Neuronal responses were recorded via microelectrode array (MEA) before and after treatments, with tetrodotoxin (TTX) serving as a control for validating modulation of the neuronal network. Our findings demonstrated that key electrophysiological metrics extracted from MEA recordings can tend to differentiate AD from non-neurodegenerative CSF samples. This standardized platform not only provides a robust approach for AD biomarker validation but also offers a foundation for broader differential diagnosis of neurodegenerative diseases. By enabling more accurate patient stratification, this tool could have the potential to direct patients toward appropriate clinical trials, enabling the diagnosis of a broader range of neurodegenerative diseases. This approach has the potential to expand the patient population included in research and accelerate the development of new therapeutic strategies.

Keywords: Proteinopathy, Protein Aggregation,Neurodegenerative Diseases, Oligomers, Brain On Chip, diagnosis of neurodegenerative disorders, preclinical biomedical research.

L’article Publication on Functional discrimination of CSF from Alzheimer’s patients in a brain on chip platform est apparu en premier sur ETAP-LAB.

Keywords: Alzheimer’s disease, Mechanisms of disease, Parkinson’s disease

L’article Publication on NDD’s cellular models – Scientific Reports (Nature) est apparu en premier sur ETAP-LAB.

Learn more about our high-thoughput capacitites for neurogenerative diseases in the poster!

Until the poster is available here, don’t wait any longer and ask for the poster in PDF!

Authors: Valentin TALLANDIER, Ahmad ALLOUCHE, Julie COLIN, Léane Dier, Sonia KRIDI, Nicolas VIOLLE

Abstract:

Synaptic plasticity alterations are a hallmark of cognitive decline in neurodegenerative diseases (NDD). Synaptic loss occurs at early stages of the disease, highlighting its potential as a critical therapeutic target. Despite extensive research, most therapeutic candidates for NDD have failed in clinical trials, primarily due to the late stage targeting of current therapeutic strategies. Therefore, there is an urgent need to develop predictive and reliable preclinical models that replicate the early neuropathological features of NDD within the synaptic environment. Additionally, the implementation of high-throughput methodologies could significantly accelerate drug discovery efforts for this challenging disease.

Here, we report progress in developing high-throughput in vitro systems that model NDD characteristics to study the synaptic environment in standard 2D culture and compartmentalized microfluidic devices.

Synapse density was assessed using a fluorescent high-content imaging system in primary cortical neurons from embryonic rodents. Initially, in standard 2D culture, neurons were exposed to a synaptotoxic environment, including glutamate and oligomeric species of amyloid-beta (AβO) and tau (TauO) which are implicated in NDD. Secondly, we employed a three-chamber microfluidic device to independently study pre- and post-synaptic neurons, isolated from the synaptic environment, to specifically target synaptic connexions. By separating the neuronal compartments, this model provided insights into the specific effects of synaptotoxic agents on each side of the synapse, thereby advancing our understanding of synapse-specific vulnerability in NDD.

Our data show that: 1) using glutamate treatment as proof of concept, high-content imaging allows quantification of synaptic density modulation, 2) exposure to AβO and TauO significantly induces synaptic degeneration, and 3) specifically targeting the synapse using a compartmentalised microfluidic device represents a screening tool of interest for the development of drugs for NDD.

In conclusion, our findings mark a significant advancement in developing relevant, automated, and reproducible NDD models for specifically studying synaptic connections, with the potential to uncover new pathological mechanisms and screen for effective treatments.

Keywords: Alzheimer’s disease; Synapses; oligomers; High-throughput; pharmacology.

L’article POSTER: High-throughput Brain-on-Chip for neurogenerative diseases est apparu en premier sur ETAP-LAB.

Learn more about our cutting-edge platform for target identification & drug discovery in the poster!

Until the poster is available here, don’t wait any longer and ask for the poster in PDF!

*Ahmad ALLOUCHE, Valentin TALLANDIER, Léane DIER, Sonia KRIDI, Julie COLIN, Nicolas VIOLLE.

L’article POSTER: “NEUROINFLAMMATION MODELS OF NEURODEGENERATIVE DISEASES” est apparu en premier sur ETAP-LAB.

Learn more about our cutting-edge platform for target identification & drug discovery in the poster!

Until the poster is available here, don’t wait any longer and ask for the poster in PDF!

*Ahmad ALLOUCHE, Valentin TALLANDIER, Sonia KRIDI, Léane DIER, Julie COLIN, Nicolas VIOLLE

L’article POSTER: “ADVANCING ALZHEIMER’S DISEASE MODELS FOR PRECLINICAL DRUG TESTING” est apparu en premier sur ETAP-LAB.

• How to automate image acquisition of microfluidic devices
• How to set up a pre-scan re-scan routine for selected relevant channels within brain-on- chip devices
• How to increase throughput for quantitative microscopy-based screening of brain-on-chip models

Contact our team if you would like proof-of-concept on your therapeutics using a compartmentalized microfluidic device with our protocols and expertise.

Download the Technical Note: https://www.revvity.com/fr-en/content/high-content-imaging-brain-chip-microfluidic-devices-using-preciscan-intelligent

L’article Technical Note: High-content imaging of brain-on-chip microfluidic devices using PreciScan intelligent acquisition. est apparu en premier sur ETAP-LAB.

A tryptic hydrolysate of bovine αs1-casein (CH) exerts anxiolytic-like properties in many species, including humans. This is mainly related to the presence of α-casozepine (α-CZP), which yields these properties in rodents. This study evaluates, in a rat model, the roles of the vagus nerve and the benzodiazepine binding site of GABAA receptors in the mode of action of CH.

Methods

The conditioned defensive burying test was used to evaluate anxiety.

Results

Participation of the vagus nerve in the mode of action of CH was excluded, as the global anxiety score in vagotomised rats was not significantly different from that of non-vagotomised animals. The blocking of the binding sites of benzodiazepines with flumazenil antagonised CH anxiolytic-like properties.

Conclusions

The vagus nerve does not play a role in the anxiolytic-like properties of CH. On the other hand, this anxiolytic-like activity relies on the benzodiazepine binding site of the GABAA receptors. This result is consistent with previous in vitro studies and, more specifically with the discovery of α-CZP, the peptide responsible for the anxiolytic-like properties of CH.

Keywords

GABAA; anxiolysis; casein tryptic hydrolysate; vagotomy; α-casozepine.

Link to Pubmed

L’article The Anxiolytic-like Properties of a Tryptic Hydrolysate of Bovine αs1 Casein Containing α-Casozepine Rely on GABAA Receptor Benzodiazepine Binding Sites but Not the Vagus Nerve est apparu en premier sur ETAP-LAB.

Building on strong neurosurgery and behavioural analysis expertise, ETAP-Lab has developed a new model of Alzheimer’s disease, using human beta-amyloid peptide oligomers (hABO). Derived from a unique know-how, hABOs induce reproducible memory deficits in the elderly mouse, correlated with alterations in neurobiological markers characteristic of AD. In comparison with young mice, aged mice show increased susceptibility to the neurotoxic effects of hABO. This model is a new translational tool for preclinical pharmacology.

>> Read more about our in vivo model

We’ve been working on developing new preclinical models  for several years now, focusing on new
concepts such as hABO neurotoxicity and tau proteins. Our cellular models have allowed us to evaluate the efficacy of neuroprotective compounds and immunotherapy.

>> Read more about our in vitro models

In partnership with Netri (Lyon, France), a company specialised in the manufacture of microfluidic devices, we were able to demonstrate that our oligomers, used in non-cytotoxic doses, strongly disrupted electrical activity and connectivity (MEA technology)

within neuronal networks in culture. This approach is an initial step towards an Alzheimer’s disease model that is both more physiological and more representative.

>> Download the application note

The results of our in vitro and in vivo work were presented at the last AAIC conference:
“New Alzheimer models for drug screening based on improved human amyloid beta (1-42) oligomer preparations”

>> Download the poster

ETAP-Lab is also a partner in the Bioprolor2 research programme, co-financed by the ERDF and the Grand Est Region, as leader of the Alzheimer working group. This programme has allowed us to both develop new experimental models and identify and select new therapeutic compounds produced by French biotech company PAT (Nancy).

ETAP-Lab’s core mission is to support the development of new therapeutics for the benefit of human and animal health.

Our team of experts care deeply about their work, and are available to answer any questions you may have.

L’article Newsletter #11: World Alzheimer’s Day: review of the ETAP-Lab preclinical models est apparu en premier sur ETAP-LAB.

ETAP-Lab has been producing A-beta_1-42 peptide oligomers since 2019, and offers an in vitro testing service for the screening of new therapeutic agents in neurodegenerative diseases (Find out more about our in vitro models >>).

We have now been able to show that intracerebroventricular administration of these same A-beta_1-42 oligomers (AβO) to 18-month-old mice leads to highly reproducible short- and long-term memory deficits (Fig. 1). These observed cognitive alterations are statistically correlated with decreased expression of synaptic markers (PSD-95) and increased apoptotic signalling (Bax/Bcl2 ratio) in the hippocampus (Fig. 2). Used as a reference molecule, Donepezil significantly improved cognitive performance in these mice in both of the tests used (Fig.  3), confirming the model’s translational value.

This research was carried out as part of the Bioprolor2 programme. Bioprolor2 is co-inanced by the “Region Grand-Est” and the European Union through the “FEDER-FSE Lorraine et Massif des Vosges 2014-2020” operational programme.

The AβO, together with the associated models now on offer from ETAP-Lab make it possible to evaluate both the efficacy and the therapeutic potential of molecules against Alzheimer’s disease, both in vitro and in vivo.

For more information, please contact our team of neuroscientists >>

L’article Newsletter #9 : ETAP-Lab launches its new model, associating beta-amyloid oligomers and aged mice est apparu en premier sur ETAP-LAB.

AD currently represents the most common form of dementia in elderly people, and with rising life expectancy the number of patients suffering from AD is expected to increase over the coming years, reaching 132 million by 2050 (World Alzheimer Report).

The causes of AD are poorly understood. However, the involvement of both amyloid beta and tau abnormalities has been largely documented. These abnormalities appear concomitantly, in association with mitochondrial and vascular dysfunction, neuroinflammation and oxidative stress that eventually leads to neurodegeneration.

Disease-modifying treatment strategies for AD continue to be extensively researched. To date, there are only symptomatic treatments for this disorder (i.e. cholinesterase inhibitors, memantine or the combination of these two agents.).

It is widely accepted that a series of pathophysiological changes begins decades before the appearance of AD symptoms, progressing in a predictable manner during the asymptomatic and symptomatic phases of disease. A wide range of molecular and cellular processes play a critical role in the development of AD, including those involving amyloid precursor protein (APP), tau, inflammation, lipid transport, autophagy and lysosome function, mitochondrial function, synaptic function, cytoskeletal function, and axonal transport.

Considering both Aβ and tau prime targets for disease-modifying treatment, multiple biopharmaceutical companies have attempted to find therapeutic agents capable of targeting these classic hallmarks of AD. Nearly all monotherapy trials conducted to date have resulted in a failure to halt the progression of cognitive decline in Phase III of clinical trials. The complex nature of AD is considered one of the main reasons for the high failure rate of these treatments; another reason is our incomplete understanding of the numerous mechanisms involved in the development of AD and the later neurodegeneration.

Many factors support the development of combination disease‐modifying therapies for AD (Salloway et al., 2020):

• Multiple complex biological pathways contribute to the disease
• A wide range of druggable targets exist within these pathways
• To achieve a clinically meaningful benefit, it may be necessary to target multiple pathways, or a single pathway at two (or more) different points
• Monotherapies whose clinical effects when used alone are modest, may, when combined, produce additive or synergistic effects
• The use of two or more disease‐modifying agents may allow for smaller (and potentially safer) doses of each agent
• As biological mechanisms evolve, a sequence or combination of agents may be required across the continuum of disease
• Regulators (the Food and Drug Administration) have both endorsed the concept of combination therapies and issued guidance for the co‐development of two or more new investigational drugs for use together
• Clinicians are accustomed to combining therapies in the treatment of many diseases

It is reasonable to assume that drugs designed to reduce Aβ and tau aggregation may have additive or synergistic effects when combined with each other, with other pathophysiological pathways (i.e. drugs designed to reduce inflammation, autophagy and lysosome dysfunction, mitochondrial dysfunction, etc.), or with non‐pharmacological interventions (i.e. exercise, nutrition and diet, cognitive training, social interaction, etc.).

Therefore, though recent developments suggest that an anti‐amyloid therapy such as aducanumab – a high-affinity human monoclonal antibody that binds aggregated (but not monomer) forms of Aβ – delivered during an earlier stage of AD, may limit cognitive decline to some extent, and such an agent might prove more effective when coupled with another agent that targets a process having a more direct bearing on cognitive decline.  Aducanumab was discovered by scientists at Neurimmune, together with a team of researchers at the University of Zurich. Neurimmune is currently collaborating with Biogen on aducanumab, who are co-developing it with Eisai.

Complementary articles about Tau and Tau oligomers

More information about our neurodegenerative diseases models

References

Salloway, S.P., Sevingy, J., Budur, K., Pederson, J.T., DeMattos, R.B., Rosenstiel, P.V., Paez, A., Evans, R., Weber, C.J., Hendrix, J.A., Worley, S., Bain, L.J., & Carrillo, M.C. (2020) Advancing combination therapy for Alzheimer’s disease. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 6, e12073.

World Alzheimer Report 2015, The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends (n.d.) 87.

L’article New hope for Alzheimer’s disease: what’s combining therapeutic strategies all about? est apparu en premier sur ETAP-LAB.

Figure 1: Current clinical trials targeting tau (Adapted from Congdon and Sirgudsson, 2018)

Contents

1. Targetable pathological events
   1.1. Targeting post-translational modifications of tau
   1.2. Targeting tau aggregation
   1.3. Targeting microtubule stabilizers
   1.4. Targeting tau expression
   1.5. Immunotherapy (tau clearance)
   1.6. Disease-modifying therapies using other mechanisms
2. What can be learned from clinical trial failure in tauopathies?

1.Targetable pathological events

1.1. Targeting post-translational modifications of tau

This aspect of tau-targeted therapies presented a major potential treatment strategy. It focused on post-translational tau modifications by:

• inhibiting tau hyper-phosphorylation kinases (e.g. GSK3β, CDK 5 and Fyn kinase)
• promoting the activity of tau dephosphorylation enzyme protein phosphate 2A (PP2A activators)
• inhibiting tau acetylation and tau deglycosylation

Unfortunately, no clinical benefits were observed. Since these processes begin long before symptoms of dementia become evident, clinical benefits might be observed if treatment could be administered earlier (Congdon & Sigurdsson, 2018).

1.2. Targeting tau aggregation

Despite promising preclinical results, both methylene blue and its derivative (TRx0237) have failed in clinical trials(Congdon & Sigurdsson, 2018). To gain insight into this failure, a recent study has shown that methylene blue actions are limited to inhibition of tau fibril formation, but do not have the same effect on tau oligomers (Soeda et al., 2019).

Curcumin, a natural polyphenolic molecule which can bind to proteins in β-sheet conformation and prevent aggregation, had no effect on either cognition or CSF biomarkers in two phase II trials in AD patients. Other clinical trials evaluating methylene blue’s derivative and curcumin are ongoing (Congdon & Sigurdsson, 2018).

1.3.Targeting microtubule stabilizers

Though microtubule-stabilizing drugs such as Epithilone D and abeotaxane (TPI 287) had shown preclinical promise, clinical trials of these stabilizers have been discontinued because of adverse effects (Varidaki et al., 2018). Davunetide (AL-108, NAP) is an eight amino acid peptide that has promoted microtubule stability and decreases tau phosphorylation in preclinical studies. MCI patients administered this peptide showed a trend towards improvements in working memory and attention in a phase II trial, but unfortunately, no significant differences relative to placebo were seen (Jarskog et al., 2013).

1.4. Targeting tau expression

Down-regulation of tau expression via antisense oligonucleotide technology has shown promising preclinical results. The phase II clinical trial on candidate therapeutics is ongoing in patients with Mild Alzheimer’s Disease (Jadhav et al., 2019).

1.5. Immunotherapy (tau clearance)

Emerging evidence in various preclinical models suggests that both active and passive immunotherapies are a practical approach to inducing antibody responses that are able to promote tau clearance. Many clinical trials evaluating immunotherapies are either ongoing, or set to enter, clinical trials in the near future (Congdon & Sigurdsson, 2018).

The anti-tau antibodies that have reached clinical trials target:

• Single or multiple phospho-epitopes
• Tau’s amino terminus
• Full-length normal and mutant tau
• Oligomeric tau
• Misfolded tau

Tau oligomers (TauO) are new therapeutic targets in AD. The targeting of TauO demands closer consideration than that of amyloid beta oligomers with regard to the variety of splicing isoforms, truncations, and post-translational modifications occurring naturally in the brain. Most clinical studies are currently in phase I or early phase II trials, and little data on efficacy is available (Vander Zanden & Chi, 2020).

1.6. Disease-modifying therapies using other mechanisms

A range of other approaches not specifically targeting tau are also under investigation (Huang et al., 2020). Some groups have turned their attention to protecting neurons from degeneration through the use of various methods, such as:

• Modulating components of the ubiquitin proteasome system or endoplasmic reticulum stress responses
• Neuroprotection
• Anti-inflammatory effects
• Growth factor promotion
• Metabolic effects (modifying physical activity, blood pressure and lipidemia)
• Stem cell therapies

Despite disappointing clinical trial outcomes, the therapeutic capacity of the drugs mentioned above is still far from being fully explored. To move the field forward, it is essential to learn from the failures of the past and use this knowledge to improve the clinical efficacy of these drugs (e.g. TRx0237, a derivative of methylene blue, will be studied at low doses. This trial is currently underway to confirm whether low-dose monotherapy is effective. Results are expected by the end of 2021).

2. What can be learned from clinical trial failure in tauopathies?

If it is true that we learn more from failure than from success, then we should accept, after a long series of failed trials for drugs targeting amyloid or tau deposits, that we lack understanding of certain critical aspects of disease biology that may affect the success of development programmes. The absence of an adequate understanding of the complex pathophysiology of AD seems to be mainly responsible for the failure of clinical trials (Kosik et al., 2016).

Removal of insoluble aggregates may be necessary, while not sufficient for therapeutic benefit. It is therefore reasonable to suggest that other, or additional, pathophysiological substrates need to be targeted (e.g. oligomeric forms that are considered the primary neurotoxic entity in AD, neuroinflammations and glial activation, autophagy/proteasome/unfolded protein response, oxidation, excitoxicity, iron deregulation, cholesterol metabolism, blood–brain barrier dysfunction, etc.) (Lo et al., 2014; Kosik et al., 2016; Galzitskaya, 2020).

Most tau-targeting therapies in clinical trials are immunotherapies (Congdon & Sigurdsson, 2018). Many factors govern the efficacy of anti-tau therapeutic antibodies, such as the epitope (normal or primarily pathological) and the site of action (extra- and intra-cellular, or extracellular only).

The lack of success of AD studies has also raised the question of whether the stage of disease generally targeted (mild-to-moderate dementia stages) may be too late. Aggregate deposition begins 10 years or more prior to the onset of cognitive symptoms. Earlier diagnosis and treatment of the disease might be more effective (Lasagna-Reeves et al., 2012; Combs et al., 2016).

Biomarkers play a critical role in the success of drug development programmes. The use of various types of biomarkers is associated with higher success rates in trials, in comparison with trials having no or few biomarkers (Green et al., 2018). AD clinical trials have commonly used cognitive and function improvement as co-primary endpoints (Sabbagh et al., 2019). In addition to these biomarkers, others must be further investigated in the trial process, such as biomarkers for neuroinflammation and glial activation, axonal degeneration, synaptic dysfunction, iron metabolism and excessive oxidation. The combination of these biomarkers allows more precise staging of AD (Anoop et al., 2010; Blennow et al., 2010).

New clinical trial designs (including adequate trial and appropriate population sizes, dosage of study drug and biomarker selection) will need to be further optimised to detect the effects of disease-modifying drugs (Romero et al., 2015; Das & Lo, 2017). Furthermore, tools used in AD studies having enough sensitivity to detect differences between study drug and placebo must be further developed.

Animal models are important gateways in the drug development process. The use of transgenic mice as a model system in preclinical testing may be a contributing factor to the high failure rate of AD trials. The reproducibility and translatability of preclinical models are urgently needed to improve both predictability and efficiency along the critical path (Seyhan, 2019). Better translational models of AD, which accurately portray the complexity of sporadic forms, can contribute to greater success in AD drug development (approaches include the use of human induced pluripotent stem cells, wild-type animals, etc.).

It remains possible that targeting a single pathologic pathway is inadequate, due to both the complex pathophysiology of AD and to the fact that combination therapy targeting multiple pathological proteins (such as amyloid beta or tau) or multiple compounds having different mechanisms of action, is necessary to success (Art 4). It remains possible that, given the great complexity of Alzheimer’s disease, targeting a single pathological pathway is inadequate. The use of therapies acting on several pathological pathways, via the combination of treatments (targeting, for example, amyloid beta and tau) may be necessary to success (see Article 4 for more information).

Complementary articles about Tau and Tau oligomers:

More information about our neurodegenerative diseases models:

References

Anoop, A., Singh, P.K., Jacob, R.S., & Maji, S.K. (2010) CSF Biomarkers for Alzheimer’s Disease Diagnosis. Int J Alzheimers Dis, 2010.

Blennow, K., Hampel, H., Weiner, M., & Zetterberg, H. (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol, 6, 131–144.

Combs, B., Hamel, C., & Kanaan, N.M. (2016) Pathological conformations involving the amino terminus of tau occur early in Alzheimer’s disease and are differentially detected by monoclonal antibodies. Neurobiol Dis, 94, 18–31.

Congdon, E.E. & Sigurdsson, E.M. (2018) Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol, 14, 399–415.

Das, S. & Lo, A.W. (2017) Re-inventing drug development: A case study of the I-SPY 2 breast cancer clinical trials program. Contemp Clin Trials, 62, 168–174.

Galzitskaya, O.V. (2020) Oligomers Are Promising Targets for Drug Development in the Treatment of Proteinopathies. Front Mol Neurosci, 12.

Green, D.J., Liu, X.I., Hua, T., Burnham, J.M., Schuck, R., Pacanowski, M., Yao, L., McCune, S.K., Burckart, G.J., & Zineh, I. (2018) Enrichment Strategies in Pediatric Drug Development: An Analysis of Trials Submitted to the US Food and Drug Administration. Clin Pharmacol Ther, 104, 983–988.

Huang, L.-K., Chao, S.-P., & Hu, C.-J. (2020) Clinical trials of new drugs for Alzheimer disease. J Biomed Sci, 27, 18.

Jadhav, S., Avila, J., Schöll, M., Kovacs, G.G., Kövari, E., Skrabana, R., Evans, L.D., Kontsekova, E., Malawska, B., de Silva, R., Buee, L., & Zilka, N. (2019) A walk through tau therapeutic strategies. Acta Neuropathologica Communications, 7, 22.

Jarskog, L.F., Dong, Z., Kangarlu, A., Colibazzi, T., Girgis, R.R., Kegeles, L.S., Barch, D.M., Buchanan, R.W., Csernansky, J.G., Goff, D.C., Harms, M.P., Javitt, D.C., Keefe, R.S., McEvoy, J.P., McMahon, R.P., Marder, S.R., Peterson, B.S., & Lieberman, J.A. (2013) Effects of Davunetide on N -acetylaspartate and Choline in Dorsolateral Prefrontal Cortex in Patients with Schizophrenia. Neuropsychopharmacology, 38, 1245–1252.

Kosik, K.S., Sejnowski, T.J., Raichle, M.E., Ciechanover, A., & Baltimore, D. (2016) A path toward understanding neurodegeneration. Science, 353, 872–873.

Lasagna-Reeves, C.A., Castillo-Carranza, D.L., Sengupta, U., Sarmiento, J., Troncoso, J., Jackson, G.R., & Kayed, R. (2012) Identification of oligomers at early stages of tau aggregation in Alzheimer’s disease. FASEB J, 26, 1946–1959.

Lo, A.W., Ho, C., Cummings, J., & Kosik, K.S. (2014) Parallel Discovery of Alzheimer’s Therapeutics. Science Translational Medicine, 6, 241cm5-241cm5.

Romero, K., Ito, K., Rogers, J.A., Polhamus, D., Qiu, R., Stephenson, D., Mohs, R., Lalonde, R., Sinha, V., Wang, Y., Brown, D., Isaac, M., Vamvakas, S., Hemmings, R., Pani, L., Bain, L.J., Corrigan, B., Alzheimer’s Disease Neuroimaging Initiative, & Coalition Against Major Diseases (2015) The future is now: model-based clinical trial design for Alzheimer’s disease. Clin Pharmacol Ther, 97, 210–214.

Sabbagh, M.N., Hendrix, S., & Harrison, J.E. (2019) FDA position statement “Early Alzheimer’s disease: Developing drugs for treatment, Guidance for Industry.” Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 5, 13–19.

Seyhan, A.A. (2019) Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles. Translational Medicine Communications, 4, 18.

Soeda, Y., Saito, M., Maeda, S., Ishida, K., Nakamura, A., Kojima, S., & Takashima, A. (2019) Methylene Blue Inhibits Formation of Tau Fibrils but not of Granular Tau Oligomers: A Plausible Key to Understanding Failure of a Clinical Trial for Alzheimer’s Disease. J Alzheimers Dis, 68, 1677–1686.

Vander Zanden, C.M. & Chi, E.Y. (2020) Passive Immunotherapies Targeting Amyloid Beta and Tau Oligomers in Alzheimer’s Disease. Journal of Pharmaceutical Sciences, 109, 68–73.

Varidaki, A., Hong, Y., & Coffey, E.T. (2018) Repositioning Microtubule Stabilizing Drugs for Brain Disorders. Front Cell Neurosci, 12.

L’article Tau Clinical Trials – What can be learned from failure? est apparu en premier sur ETAP-LAB.

Contents

1. TauO is present in AD patients
2. TauO leads to memory impairment
3. TauO participates in the intracellular accumulation of tau
4. TauO takes part in tau’s prion-like mechanisms
5. TauO is the seed for the aggregates
6. TauO destabilises nucleic acids

1. TauO is present in AD patients

Significant quantities of tau oligomers are present in patients with Alzheimer’s Disease (AD). TauO are found in the patients’ brains very early on (McInnes et al., 2018). From the early stages of Braak, TauO is detected in the frontal cortex, where neurofibrillary degeneration will occur at later stages of the disease (Maeda et al., 2006; Lasagna-Reeves et al., 2012). Moreover, the amount of TauO found in patients’ brains is predictive of the degree of cognitive impairment in AD patients (Lowe et al., 2018). TauO thus represents a potential new biomarker that could be used in the early diagnosis of AD (Sengupta et al., 2017). The presence of significant quantities of TauO in key areas from an early stage therefore makes it a prime target for new translational R&D research strategies.

2. TauO leads to memory impairment

Clinical data also show a correlation between the presence of tau and the intensity of cognitive deficits in patients. What impact does TauO have on the mechanisms underlying memory? Isolated from patient brains, TauO can cause a decrease in long term potentiation (LTP) in hippocampal cell cultures and slices of adult rat hippocampus (Lasagna-Reeves et al., 2011, 2012; Fá et al., 2016). TauO reduces phosphorilation of CREB, which in turn limits the acetylation of histones H3 and H4, necessary for LTP and spatial memory (Acquarone et al., 2019). Other mechanisms are also in play, since the effects of TauO also seem intimately linked to another actor in AD: the Amyloid Precursor Protein (APP). As the APP is involved in synapse stabilisation, its interaction with TauO could block APP activity, ultimately leading to the appearance of memory deficits in mice (Puzzo et al., 2017). These authors were able to show that only those wild-type mice expressing APP are sensitive to TauO, reporting alterations in LTP and memory functions.

Other TauO-induced cerebral dysfunctions have also been observed, particularly in relation to mitochondrial dysfunction and memory deficits. (Lasagna-Reeves et al., 2011; Shafiei et al., 2017; Zheng et al., 2020).

3. TauO participates in the intracellular accumulation of tau

One of the two historical biomarkers of AD is the presence of neurofibrillary degeneration linked to the accumulation of tau in the intracellular compartment. Here again, TauO seems to play a key role. Tau acetylation, favouring its oligomerisation, is enough to induce both cognitive disorders and a reduction in the number of synapses in mice(Maeda et al., 2006; Lasagna-Reeves et al., 2011, 2012). By limiting interactions between tau lysine residues and the ubiquitin/proteasome system, this acetylation also favours the accumulation of tau at intracellular level (Min et al., 2010).

In the same way, TauO is also able to limit the activity of the endosome-lysosome/autophagy system (Chen et al., 2020).

4. TauO takes part in tau’s prion-like mechanisms

TauO could also support tau’s prion-like behaviour. Several in vitro studies have shown that the use of human TauO is capable of gradually contaminating neurons.

Further, in vivo studies have shown that intracerebral administration of purified tau protein from the brains of AD patients leads to the formation of numerous tau inclusions in non-transgenic mice (Guo et al., 2016). The results of this study are complemented by other studies showing that TauO is essential to the propagation of tau in vivo (Lasagna-Reeves et al., 2012; Usenovic et al., 2015).

The cell types and mechanisms involved have yet to be clearly identified. Nevertheless, recent work has investigated various possible mechanisms supporting the spread of tau. The acetylation of tau seems to contribute to cell-to-cell propagation in the brain (Tai et al., 2014). A 2020 study has shown that Heparan Sulphate Proteoglycan (HSPG) is involved in the internalisation of TauO. Moreover, this mechanism is reversible through the use of HSPG antagonists, which reduce TauO internalisation, limit translocation in the endosome-lysosome/autophagy system and ultimately reduce the appearance of tau in fibrillar form at intracellular level (Puangmalai et al., 2020).

5. TauO is the seed for the aggregates

Tau aggregate formation is clearly related to a change in monomer conformation.

Monomeric tau has a core (microtubule binding domaine (MBD)) that is positively charged, thus allowing interaction with the negatively charged tubulin and preventing it from interacting with other tau monomers. In pathological conditions (for example, when tau is strongly phosphorylated) positive charges are neutralised by the phosphorus groups, which has a two-fold effect: tau monomer can no longer interact with the tubulin and becomes detached – that is, the protein loses its microtubule stabilising function, and the change in configuration of tau monomer allows it to assemble with other monomers to form oligomers (Morris et al., 2011).

This same phenomenon of change in the configuration of the tau monomer can be observed in the presence of other charged compounds such as RNA, heparin or micelles (Goedert et al., 1996; Kampers et al., 1996; Chirita et al., 2003).

Figure 1: Change to tau monomer configuration and formation of TauO

The precise mechanisms of tau toxicity are not yet known, but seem to be linked to tau’s three-dimensional conformation. In « paper-clip » physiological condition of tau, the N-terminal end will be close to the MBD. In pathological conditions, the « paper-clip » would be open, allowing activation of the phosphatase-activating domain, and thus causing intracellular disturbances (Kanaan et al., 2016).

6. TauO destabilises nucleic acids

One lesser-known role of tau is the one it plays at cell nucleus level, which is equally crucial to the survival of neurons. Yet tau aggregates have been found in the cell nucleus of brain tissue of AD patients.

In both animals and humans, in vitro and in vivo studies show that non-pathological forms of the tau protein participate in the protection of DNA integrity and in the metabolism of nuclear and cytoplasmic RNA (Violet et al., 2015; Mansuroglu et al., 2016; Sotiropoulos et al., 2017). The interaction of tau and DDX6 favours increased activity among the mi-RNAs participating in the regulation of mRNAs. (Chauderlier et al., 2018). Conversely, the presence of pathological forms such as TauO disrupts these core protection mechanisms (Mansuroglu et al., 2016; Sotiropoulos et al., 2017; Montalbano et al., 2020). In addition to the loss of protective and regulatory functions, TauO also gains toxic biological functions by disrupting trafficking through nuclear pores via interaction with Nup98 (Eftekharzadeh et al., 2018). An interaction with a protein called TIA1, which belongs to the family of RNA binding proteins, increases TauO stability and thus builds their toxicity.

This has been a quick overview of some of the abundant current literature on Tau, which is unanimous: TauO could be key to understanding AD and seems a relevant target. If you’d like to integrate TauO to your research projects, please get in touch!

More information about our neurodegenerative diseases models

Complementary articles about tau and tau oligomers

References

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Lasagna-Reeves, C.A., Castillo-Carranza, D.L., Sengupta, U., Clos, A.L., Jackson, G.R., & Kayed, R. (2011) Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Molecular Neurodegeneration, 6, 39.

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L’article 6 reasons to include tau oligomers in your R&D strategy for the treatment of Alzheimer’s Disease est apparu en premier sur ETAP-LAB.

Contents

1. Characterization of TauO preparation
2. Neurotoxicity of TauO preparation
3. TauO induce neurotoxicity in a dose-dependent manner

1. Characterization of TauO preparation

ETAP-Lab has developed a method of producing stable misfolded TauO from recombinant full-length human tau protein (2N4R, 441 aa) without chemical modification or helper proteins. This preparation contains a mixture of trimers and low-molecular-weight oligomers, as well as remaining monomeric forms of the protein (Fig. 1).

Fig.1: Characterization of TauO preparation by SDS-PAGE/Coomassie staining: SDS-page gel profile, revealed by Coomassie blue staining, demonstrating that the produced oligomers are a mixture of trimers and low-molecular-weight oligomers.

2. Neurotoxicity of TauO preparation

TauO-induced neurotoxicity was evaluated in primary rat cortical neurons. Incubation of cortical neurons with TauO decreases cell viability quite significantly (*; p<0.0001), while neuron incubation with the same concentration of monomers showed no neurotoxic effect (Fig. 2). Moreover, neuron treatment with Brain Derived Neurotrophic Factor (BDNF) significantly reversed TauO-induced neurotoxicity (#; p<0.0001).

Fig.2: Neuron incubation with Tau monomers, TauO and TauO+BDNF: Incubation of neurons with TauO quite significantly decreases cell viability, while monomers showed no neurotoxic effect. TauO-induced neurotoxicity is reduced by BDNF, used as a positive control. Data are expressed as percent of vehicle (set at 100%) and represent the mean ± SD (n=12, N=3). * P<0.0001 vs. vehicle-treated cells, # P<0.0001 vs. TauO-treated cells (Scheffe’s test)

3. Dose-dependant neurotoxicity induced by TauO preparation

Primary cortical neurons, challenged with TauO over the concentration range of 0.5 to 10 μM, showed clear and biphasic dose-dependent neurotoxicity, with a clear cut-off around 9 µM (Fig. 3).

Fig.3: TauO induce dose-dependent neurotoxicity in primary cortical neurons: Neuron incubation with increasing doses of TauO showed dose-dependent neurotoxicity. Data are expressed as percent of vehicle (set at 100%) and represent the mean ± SD (n=12, N=3). * P<0.0001 vs. vehicle-treated cells (Scheffe’s test).

Primary cortical neurons were challenged with 4 independent batches of TauO to evaluate the reproducibility of the pharmacological assay. Results of cell viability showed very low batch-to-batch variabilities (Fig. 4).

Fig.4: Alzheimer’s disease model reproducibility

Neuron incubation with different TauO batches induced a highly reproducible and significant neurotoxicity. Data are expressed as percent of vehicle (set at 100%) and represent the mean ± SD (n=3, N=1). * P<0.0001 vs. vehicle-treated cells (Scheffe’s test)

More information about our neurodegenerative diseases models

https://www.etap-lab.com/neurodegenerative-diseases

 Complementary articles about tau and Tau oligomers

L’article Tau oligomers: a new tool for drug discovery in AD est apparu en premier sur ETAP-LAB.

In late January, ETAP-Lab created ETAP-Cell, a new in vitro pharmacological service in the field of evaluating proteopathic neurodegenerative diseases using our unique know-how in the solubilization and stabilization of oligomeric proteins (AβO, αSO and TauO).

Three weeks ago, we successfully produced our first batch of soluble Aβ oligomers. This preparation contains a mixture of stable dimers, trimers and tetramers of human Aβ _1-42, as well as some remaining monomeric forms of the peptides (Fig. 1).

 AβO-induced neurotoxicity was evaluated in cultured rat cortical neurons by MTT cell viability assay. As expected, ETAP-Cell’s AβO preparation induced a clear dose-dependent neurotoxicity. Neurotoxic effects were increased in a time dependent manner and attenuated by brain-derived neurotrophic factor (BDNF), used as a positive control (Fig. 2).

The coming weeks will be devoted to full validation of the AβO, αSO and TauO in vitro models, using 3 independent replicas for each model to ensure batch-to-batch reproducibility (new batch of each neurotoxin / replica). In vitro services will be available for sale from August.

Alongside this, ETAP-Lab will begin validation of the corresponding in vivo models in mice.

The ETAP-Lab team is very open to hearing about your needs and expectations, the better to integrate these into the solutions being developed over the next few months.

Please do not hesitate to contact us, should you have any questions or suggestions.

L’article ETAP-Cell: a new in vitro pharmacology service for drug research in neurodegenerative diseases – Newsletter #5 est apparu en premier sur ETAP-LAB.

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Numerous studies have indicated the value of music therapy in the management of patients with Alzheimer’s disease. A recent pilot study demonstrated the feasibility and usefulness of a new music therapy technique. The aim of this controlled, randomised study was to assess the effects of this new music therapy technique on anxiety and depression in patients with mild to moderate Alzheimer-type dementia.

METHODS:

This was a single-centre, comparative, controlled, randomised study, with blinded assessment of its results. The duration of follow-up was 24 weeks. The treated group (n = 15) participated in weekly sessions of individual, receptive music therapy. The musical style of the session was chosen by the patient. The validated ‘U’ technique was employed. The control group (n = 15) participated under the same conditions in reading sessions. The principal endpoint, measured at weeks 1, 4, 8, 16 and 24, was the level of anxiety (Hamilton Scale). Changes in the depression score (Geriatric Depression Scale) were also analyzed as a secondary endpoint.

RESULTS:

Significant improvements in anxiety (p < 0.01) and depression (p < 0.01) were observed in the music therapy group as from week 4 and until week 16. The effect of music therapy was sustained for up to 8 weeks after the discontinuation of sessions between weeks 16 and 24 (p < 0.01).

CONCLUSION:

These results confirm the valuable effect of music therapy on anxiety and depression in patients with mild to moderate Alzheimer’s disease. This new music therapy technique is simple to implement and can easily be integrated in a multidisciplinary programme for the management of Alzheimer’s disease.

L’article Effect of music therapy on anxiety and depression in patients with Alzheimer’s type dementia: randomised, controlled study est apparu en premier sur ETAP-LAB.

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L’article A tryptic hydrolysate from bovine milk alphaS1-casein improves sleep in rats subjected to chronic mild stress est apparu en premier sur ETAP-LAB.

Preclinical results in rats have demonstrated anxiolytic-like effects of a tryptic bovine alphaS1-casein hydrolysate.

AIM OF THE STUDY:

We investigated the putative effects of this tryptic hydrolysate on systolic (SBP), diastolic (DBP) blood pressures, heart rate (HR) values and plasma cortisol concentrations (CC) in human healthy volunteers facing successive stress situations.

METHODS:

The subjects were (double blind) randomly allocated to ingest three times, 12 hours apart, two capsules containing either 200 mg of alphaS1-casein hydrolysate (TS) or bovine skimmed milk powder as a placebo (CS). On the morning of the test day, a first blood sample for baseline measurement of CC was taken before the subjects were submitted to the Stroop test (ST) and, after a 30-min rest, to a Cold Pressor test (CPT). SBP, DBP, and HR were continuously recorded for 5 min before the ST and during each stress situation. A second blood sample was taken 15 min after the end of the CPT condition.

RESULTS:

ST and ST + CPT combined test situations increased SBP, DBP and HR. The significant “Treatment x SBP” and “Treatment x DBP” interactions indicated the lower percentage changes in SBP and DBP of the TS. In addition, the results showed a significant decrease of the CC in the TS but not in the CS throughout the ST + CPT combined stress tests. HR remained stable in TS between the initial rest period and the CPT unlike what happened in CS.

CONCLUSION:

On the basis of blood pressure and cortisol changes, these results suggest an antistress profile of this alphaS1-casein hydrolysate in human subjects.

L’article Effects of a tryptic hydrolysate from bovine milk alphaS1-casein on hemodynamic responses in healthy human volunteers facing successive mental and physical stress situations est apparu en premier sur ETAP-LAB.

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L’article Effects of ING-911, a tryptic hydrolysate from bovine Milk alpha S1-Casein on anxiety of Wistar male rats measured in the conditioned defensive burying paradigm and the elevated-plus maze test est apparu en premier sur ETAP-LAB.