Tauopathies:
a hallmark of alzheimer's
Mechanisms of Tau Pathogenicity
Among the rare disorders classed as neurodegenerative conditions, tauopathies play a significant role in Alzheimer’s disease and related dementias. Alzheimer’s disease is characterized by two pathological hallmarks: parenchymal amyloid deposition and intraneuronal neurofibrillary tangles, known to be composed of hyperphosphorylated tau. Tau is a microtubule-associated protein that is crucial for regulating microtubules and axonal transport. Disruption of its degradation pathway leads to its detachment from microtubules and subsequent aggregation. This aggregation is a key factor in the pathogenesis of Alzheimer’s disease.
Ahead of clinical trials, a deeper understanding of the association between these pathologies is essential, particularly because these mechanisms are linked to cognitive deficits, a neglected burden hindering the development of effective therapeutic strategies.
SynapCell's EEG Solution to Better Address Tau Pathologies
To respond to the high attrition rate among drug candidates and to overcome the lack of translatable and pharmacodynamic biomarkers, we took advantage of SynapCell’s Cue platform to investigate the P301L tauopathy mouse model and study changes to EEG features over time.
P301L Model: a Relevant Model in the Field
The P301L model exhibits progressive tau aggregation, neurofibrillary tangles, and neuronal loss. It is thus invaluable for studying disease mechanisms, and testing therapeutic strategies to counteract tau-driven neurodegeneration. Its translational potential has made it a cornerstone of tauopathy research.
Bridging the Preclinical-to-clinical gap with EEG
On our platform, we analyzed resting EEG traces and identified qEEG differences in cortical structures between the P301L and WT mice.
Our results demonstrate that EEG is a sensitive technology, suitable for the study of differences in synaptic efficacy induced by tau over-expression.
EEG Phenotyping: Paving the way for New Predictive Models
Focusing our efforts on resting-state quantitative EEG, we strive to provide a powerful drug discovery tool, bringing our predictive approach to another level and allowing us to expand our pipeline of efficacy programs. The P301L mouse emerges as a model of choice to study treatments targeting neurodegenerative conditions, including Alzheimer’s disease (in the context of tau tangles) and Frontotemporal Dementia (FTD).
“I am very pleased with our collaboration with SynapCell for the investigation of EEG phenotypes in a tauopathy mouse. The work at SynapCell was very high quality, the results were delivered on time, and the people at SynapCell were a pleasure to work with.”
Frank Menniti, CSO of MindImmune Therapeutics
Key Features
of the P301L Mouse Model
The qEEG signatures measured in a resting state in the P301L mouse are significantly different to those in Wild-type mice. These differences will be used as biomarkers to measure potential efficacy of therapeutic strategies.
Immunohistochemistry in mice revealed immunoreactivity for AT-8 and SMI-312, markers of abnormally phosphorylated tau and phosphorylated neurofilaments in axon, respectively. These two markers are abundant in postmortem brain samples from human patients with Alzheimer’s disease.
Drug Discovery Assays with the P301L Model
The ability of EEG to capture subtle changes induced by a drug can help select and screen leads and measure their effect on the biomarkers involved.
Assess how a compound’s effects change with varying doses, and analyze the relationship between dose and response, examining efficacy, safety, and biological effects across different concentrations to determine optimal dosing strategies.
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Characterization of a Transgenic Mouse Model of Tauopathy Using qEEG: Does Tau Pathology Produce Disrupted EEG Spectra ?
We took advantage of quantitative electroencephalography (qEEG) to characterize a transgenic mouse model of tauopathy. We implanted female P301L and wild-type (C57BL6) mice with stainless steel screws over the frontal and parietal cortices, as well as a reference electrode placed above the cerebellum. After acclimatization for 1 hour in our recording chambers, EEG was recorded continuously for 120 min.
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Powered by Cue®, SynapCell's Predictive In Vivo EEG Platform
SynapCell’s P301L mouse model and its associated EEG biomarkers are processed on Cue®, our innovative translational in vivo EEG platform, which is designed to predict the in-human efficacy of your drug candidates during the preclinical step. Cue® is the result of decades of R&D, combining SynapCell’s know-how, expertise and scientific excellence in the fields of brain surgery and EEG signal recording, processing, and analysis.
Using Cue®, we transform preclinical data into actionable insights, offering end-to-end support for informed decision-making in CNS drug discovery.
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Interesting Leads that Could Pave the Way for Promising New Therapeutic Strategies Targeting Tau Pathology
Interactions Between Aβ, Tau, and Glial Reactivity are Associated with Cognitive Decline
The complex interplay between amyloid-beta (Aβ), tau, and glial reactivity is pivotal in the development of the cognitive symptoms observed in tauopathies. In conditions like Alzheimer’s disease, Aβ accumulation and tau hyperphosphorylation contribute to neuronal dysfunction. This dysfunction triggers glial cells, such as microglia and astrocytes, to enter a reactive state, promoting neuroinflammation.
Over time, chronic glial activation exacerbates tau pathology, increasing synaptic damage and accelerating cognitive decline. This reactive glial environment creates a challenging landscape for drug discovery, as treatments targeting tau must also address the inflammatory cascade. A better understanding of glial responses in tauopathies could lead to innovative therapies that simultaneously target tau aggregation and neuroinflammation, offering a more comprehensive approach to treating these neurodegenerative diseases.
Targeting Synaptic Oligomeric Tau in Alzheimer's Disease as a Potential Culprit in the Spreading of Tau Pathology
Emerging evidence suggests that synaptic oligomeric tau plays a critical role in the spread of tau pathology in Alzheimer’s disease (AD). Unlike insoluble tau tangles, these tau oligomers are soluble. They are found at synapses, and are believed to be highly toxic. Synaptic tau oligomers can propagate across neuronal networks, driving the spread of tau pathology from one region of the brain to another.
This propagation disrupts synaptic function, contributing to neurodegeneration and cognitive impairment. To halt the progression of tau pathology in AD, a promising strategy would be to target synaptic oligomeric tau.
Let's Talk About Your Research Project!
More than a CRO, a team of collaborators – we are your dream neuroscience team specialized in preclinical EEG! We don’t just produce data, we are your partners from conceptualization to conclusion. We translate raw EEG data into meaningful, clinically-relevant endpoints, delivering clear insights to allow data-based decision-making. Choose SynapCell, a leading preclinical CNS-specialized CRO for cutting-edge EEG expertise combined with an irresistible touch of fun.
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