Can you perform in vivo imaging in AD models?

Yes, we offer techniques such as PET/SPECT or two-photon microscopy for non-invasive, dynamic monitoring of Aβ plaques or neuroinflammation.

How do you determine if a drug crosses the BBB?

We calculate BBB penetration by simultaneously measuring drug concentrations (PK) in blood and brain tissue CSF samples.

Which AD model is best suited for screening drugs that target Aβ plaque reduction?

The 5xFAD and APP/PS1 transgenic mouse models are highly recommended. The 5xFAD model exhibits a very rapid and aggressive plaque onset, allowing for short-term (acute or sub-chronic) efficacy studies. The APP/PS1 model provides robust and predictable plaque pathology over a longer duration.

If my therapeutic targets Tau pathology, which model should I prioritize?

The 3xTg-AD mouse model is the most appropriate as it uniquely develops both Aβ plaques and Tau neurofibrillary tangles, mimicking the full human pathology. Alternatively, the AAV-hTau vector models can be used to specifically study Tau propagation and related pathology independent of Aβ.

Can you model sporadic (non-genetic) Alzheimer's Disease, which is the most common form?

Yes. We use models that incorporate major sporadic risk factors, such as the STZ-induced model (modeling cerebral insulin resistance/Type 3 Diabetes) and APOE4 humanized mouse models (modeling the key genetic risk factor). We also utilize High-Fat/High-Cholesterol Diet models to investigate metabolic risk factors.

What are the key PD endpoints for assessing efficacy in these models?

Key endpoints for assessing efficacy include biochemical quantification of soluble and insoluble Aβ40/42 and p-Tau in brain homogenates and CSF, pathological quantification via IHC/IF of Amyloid Plaque Burden and Tau Tangle Density, cellular assessment using IHC for neuroinflammation markers (e.g., Iba1 for microglia, GFAP for astrocytes), and functional measurement through behavioral assessments (e.g., Morris Water Maze, Novel Object Recognition) to gauge cognitive improvement.

How do you measure synaptic function, which is critical for cognition?

Synaptic integrity is assessed biochemically by measuring synaptic protein levels (e.g., Synaptophysin, Neurogranin) via ELISA or Western Blot. We can also perform electrophysiology studies in a collaborative setting to measure synaptic plasticity (e.g., LTP) in brain slices.

Alzheimer's Disease (AD) Modeling & Pharmacodynamics Services

Introduction

Alzheimer's Disease (AD) is a complex, progressive neurodegenerative disorder with an historically high clinical failure rate, largely due to a lack of predictive preclinical models. The hallmark pathologies include extracellular Amyloid-β (Aβ) plaques and intracellular hyperphosphorylated Tau forming Neurofibrillary Tangles. To provide highly translational AD models and expert Pharmacodynamic (PD) modeling and analysis. This aims to accurately assess drug efficacy, determine optimal dosing, and accelerate the preclinical-to-clinical translation. Creative Biolabs combines biological experimental data with mathematical modeling to achieve a quantitative understanding of drug effects and inform decision-making.

Fig.1 In vivo and in vitro models of Alzheimer's disease. (OA Literature) Fig. 1 The major models relevant to Alzheimer's disease.¹

Available Alzheimer's Disease Models

Creative Biolabs provides a comprehensive portfolio of AD models (e.g., rodents, NHPs) specifically designed to validate diverse therapeutic strategies and accelerate the drug R&D process. Additionally, we offer NHPs Vascular Dementia (VaD) Models that mimic the clinical manifestations of AD. Our offerings bridge the gap between early-stage discovery and clinical application by covering the full pathological spectrum of AD, including familial amyloid/tau pathology, sporadic metabolic dysfunction, and acute neurotoxicity.

AD Models	Modeling & Application Values	Animal Species
Scopolamine-Induced Amnesia Model	Acute/Pharmacological Model. Induces cognitive impairment by blocking muscarinic cholinergic receptors. Used for rapid screening of cognition-enhancing drugs, such as Cholinesterase Inhibitors (e.g., Donepezil) and new Nootropics.	Mouse, Rat
Aβ-Induced AD Model	Toxin/Lesion Model. Direct injection of aggregated Amyloid-β (Aβ) protein, mimicking the Amyloid Cascade Hypothesis. Tests Aβ toxicity and clearance, and is used for screening Aβ Monoclonal Antibodies and gamma-Secretase Inhibitors.	Mouse, Rat
STZ-Induced AD Model	Chemical/Metabolic Model (Sporadic AD). Impairs cerebral glucose and insulin metabolism (Brain Type 3 Diabetes). Used to test Insulin Sensitizers (e.g., Metformin, GLP-1 receptor agonists) and PPARγ Agonists.	Mouse, Rat
5xFAD Transgenic Mouse Model	Transgenic Model (Familial AD). Characterized by very early and aggressive Aβ plaque deposition. Ideal for testing fast-acting amyloid-targeting therapies like β-Secretase Inhibitors (BACE1 Inhibitors) and Aβ Vaccines/Antibodies.	5xFAD Transgenic Mouse
APPPS1 Transgenic Mouse Model	Double Transgenic Model (Familial AD). Exhibits reliable amyloid plaque pathology at an early age. A primary model for screening amyloid-targeting therapies, including Aβ Aggregation Inhibitors, Anti-inflammatory Drugs, and Cholinesterase Inhibitors.	APP/PS1 Transgenic Mouse
APPSWE Transgenic Mouse Model	Single Transgenic Model. Later onset and less aggressive plaque pathology. Used to evaluate the long-term effects of Aβ production or clearance modulators.	APPSWE Transgenic Mouse
3xTg-AD Mouse Model	Triple Transgenic Model (Familial AD). The only model to show dual pathology of amyloid plaques and Tau Neurofibrillary Tangles. Used to test Tau Inhibitors, Aβ and Tau Dual-Target Inhibitors, and NMDA Receptor Antagonists (e.g., Memantine).	3xTg-AD Mouse
Goto-Kakizaki (GK) Rat Type II Diabetes AD Model	Metabolic/Spontaneous Model. Spontaneously develops features of Type 2 Diabetes. Investigates the link between diabetes and sporadic AD; tests Hypoglycemic Drugs, Insulin, and its derivatives.	Goto-Kakizaki Rat
AAV9-hTau-Induced AD Model	Viral Vector-Based Model (Tauopathy). Specifically overexpresses human mutant Tau protein. Used to study Tau pathology exclusively, for screening Tau Oligomerization Inhibitors, Tau Vaccines, and Tau Monoclonal Antibodies.	Mouse, Rat
High-fat Diet & CHOL-Induced AD Model	Dietary/Metabolic Model (Sporadic AD). Induces hypercholesterolemia, neuroinflammation, and oxidative stress. Used to model lifestyle risk factors; tests Statins, Hypolipidemic Agents, Antioxidants, and Anti-inflammatory Drugs.	Mouse, Rabbit
Neurotoxin (phencyclidine-PCP or cisplatin)-Induced AD Model	Toxin Model. PCP induces schizophrenia-like cognitive deficits; Cisplatin induces chemobrain. Studies neurotoxin-related cognitive impairment; tests drugs targeting NMDA Receptor Dysfunction and Neuroprotectants.	Mouse, Rat
Aluminum Chloride & D-galactosamine-Induced AD Model	Chemical Model. Studies the role of metal toxicity, oxidative stress, and inflammation in AD. Used to evaluate Metal Chelators and potent Antioxidants.	Rat

Evaluation Platform

We utilize cutting-edge experimental and analytical tools to ensure data accuracy and translational relevance. The assessment of AD models requires a multi-modal approach to quantify both the core pathologies (Aβ plaques and Tau tangles) and the resulting functional deficits in cognition and memory.

Functional Assessment: Cognitive function in preclinical models is comprehensively assessed using behavioral assays: the Morris Water Maze (MWM) evaluates spatial learning and memory, the novel object recognition (NOR) test measures recognition and short-term memory, and Fear Conditioning paradigms assess hippocampal-dependent contextual memory and fear.
Pathological Assessment: Preclinical pathological analysis quantifies Amyloid Plaque Burden and Neurofibrillary Tangle Density (Tau) in the cortex and hippocampus via Immunohistochemistry/Immunofluorescence, assesses Synaptic Integrity and Loss using IHC/Western Blot, and determines Neuronal Loss in vulnerable brain regions (e.g., hippocampal CA1) via Nissl Staining or Stereology.
Biochemical & Molecular Assessment: Preclinical studies quantify Aβ clearance and production (e.g., Aβ_40/42 and ratios) and tau phosphorylation status (e.g., p-Tau181) in brain homogenates and CSF using highly sensitive ELISA/Western Blot, and assess neuroinflammation levels by analyzing the expression of glial markers (e.g., Iba1, GFAP) and inflammatory cytokines (e.g., IL-1β, TNF-α) via IHC and qPCR.
Advanced and Translational Assessment: Preclinical studies utilize Positron Emission Tomography (PET Imaging) with Aβ or tau tracers for non-invasive, longitudinal quantification of pathology in living animals, and employ Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) to determine the Brain/CSF-to-Plasma drug concentration ratio for assessing Blood-Brain Barrier (BBB) penetration.

Applications

Candidate Selection: The most promising lead compounds identified early in the drug discovery pipeline are selected to strategically focus limited resources on molecules exhibiting optimal therapeutic potential.
Mechanism of Action (MoA) Elucidation: Provide robust confirmation of whether a drug is working via the intended mechanism.
Biomarker Validation: Validate that the selected PD biomarker accurately and effectively reflects the drug's therapeutic action in vivo, preparing it for clinical use.
Preclinical Drug Development: The models are utilized across a broad spectrum of AD drug development, including anti-amyloid agents (e.g., monoclonal antibodies, BACE inhibitors), anti-tau agents, anti-inflammatory agents, synaptic function enhancers, mitochondrial modulators, and cutting-edge gene and stem cell therapies (e.g., induced pluripotent stem cells, neural stem cells), significantly accelerating the research and development process.

Our Advantages

High Translational Relevance in Modeling: We prioritize the use of models (e.g., APOE4 humanized mice or 3xTg mice) that accurately capture the dual pathology of Aβ and Tau, while integrating critical sporadic risk factors such as the APOE4 genotype and metabolic dysfunction. This approach improves the predictive accuracy and ensures a higher translational success rate for preclinical findings.
Mechanism-Specific Protocol Customization: We offer fully customized experimental protocols and PD endpoints, tailored to the client's specific drug mechanism of action.
Accelerated Preclinical Development Timeline: Drug evaluation is streamlined by reducing the reliance on extensive, costly, and often redundant in vivo studies. This accelerated, optimized approach dramatically shortens the overall R&D timeline, enhancing efficiency.
Scientific Excellence Driven by Expert Team: All studies are designed and led by a specialized team of neuroscientists who possess extensive, deep experience in complex neurodegenerative disease research. This commitment ensures the highest standards in experimental rigor, data interpretation, and readiness for regulatory submission.
Integrated PK/PD Strategy: We implement a robust, integrated PK and PD strategy that goes beyond simple data reporting. This approach establishes a quantitative relationship between drug exposure (PK) and biological effect (PD), providing a sophisticated quantitative decision-making tool. This effectively allows for the prediction of optimal human dosing, which dramatically reduces late-stage development risk, optimizes study design, and ultimately lowers overall development costs.

Work with Us

Inquiry Stage:

Summarize the project requirements and fill in the information collection form.
Sign a CDA from both parties to further communicate information, such as targets.
Select an animal model, discuss experimental design, and determine assay parameters.
Project costing and project schedule forecasting.

Project Start:

We provide a detailed project plan, including the required sample quantities, methods, and protocols.
Both parties confirm the project details and start the project.
Confirm the timeline of the project.

Project Progress:

We provide periodic results and information on the animal's condition.
We will work together to make project adjustments as necessary.

Project Completion:

We provide a comprehensive project report promptly.
We arrange transportation for the produced samples.
We provide a discussion of the project results and help to arrange the next steps.

After-Sales Support:

Data storage and archiving.

Get in touch!

FAQs

Q: Can you perform in vivo imaging in AD models?

A: Yes, we offer techniques such as PET/SPECT or two-photon microscopy for non-invasive, dynamic monitoring of Aβ plaques or neuroinflammation.
Q: How do you determine if a drug crosses the BBB?

A: We calculate BBB penetration by simultaneously measuring drug concentrations (PK) in blood and brain tissue CSF samples.
Q: Which AD model is best suited for screening drugs that target Aβ plaque reduction?

A: The 5xFAD and APP/PS1 transgenic mouse models are highly recommended. The 5xFAD model exhibits a very rapid and aggressive plaque onset, allowing for short-term (acute or sub-chronic) efficacy studies. The APP/PS1 model provides robust and predictable plaque pathology over a longer duration.
Q: If my therapeutic targets Tau pathology, which model should I prioritize?

A: The 3xTg-AD mouse model is the most appropriate as it uniquely develops both Aβ plaques and Tau neurofibrillary tangles, mimicking the full human pathology. Alternatively, the AAV-hTau vector models can be used to specifically study Tau propagation and related pathology independent of Aβ.
Q: Can you model sporadic (non-genetic) Alzheimer's Disease, which is the most common form?

A: Yes. We use models that incorporate major sporadic risk factors, such as the STZ-induced model (modeling cerebral insulin resistance/Type 3 Diabetes) and APOE4 humanized mouse models (modeling the key genetic risk factor). We also utilize High-Fat/High-Cholesterol Diet models to investigate metabolic risk factors.
Q: What are the key PD endpoints for assessing efficacy in these models?

A: Key endpoints for assessing efficacy include biochemical quantification of soluble and insoluble Aβ_40/42 and p-Tau in brain homogenates and CSF, pathological quantification via IHC/IF of Amyloid Plaque Burden and Tau Tangle Density, cellular assessment using IHC for neuroinflammation markers (e.g., Iba1 for microglia, GFAP for astrocytes), and functional measurement through behavioral assessments (e.g., Morris Water Maze, Novel Object Recognition) to gauge cognitive improvement.
Q: How do you measure synaptic function, which is critical for cognition?

A: Synaptic integrity is assessed biochemically by measuring synaptic protein levels (e.g., Synaptophysin, Neurogranin) via ELISA or Western Blot. We can also perform electrophysiology studies in a collaborative setting to measure synaptic plasticity (e.g., LTP) in brain slices.

Published Data

Berberine (BBR) significantly improves cerebral blood flow (CBF) perfusion in 3xTg AD mouse cortex by upregulating pro-angiogenic factors (CD31, VEGF, N-cadherin, Ang-1), providing a molecular basis for its potential to restore vascular function in Alzheimer's Disease.

Fig.2 The therapeutic effect of Berberine in 3xTg AD mice. (OA Literature) Fig. 2 BBR increased cerebral cortical blood flow perfusion and increased proangiogenic factors in the brains of 3xTg AD mice.²

References

Timofeeva, Anna M et al. "Modeling Alzheimer's Disease: A Review of Gene-Modified and Induced Animal Models, Complex Cell Culture Models, and Computational Modeling." Brain Science vol. 15,5 486. Distributed under Open Access license CC BY 4.0, without modification. https://doi.org/10.3390/brainsci15050486
Ye, Chenghui et al. "Berberine Improves Cognitive Impairment by Simultaneously Impacting Cerebral Blood Flow and β-Amyloid Accumulation in an APP/tau/PS1 Mouse Model of Alzheimer's Disease." Cells vol. 10,5 1161. Distributed under Open Access license CC BY 4.0, with modification. https://doi.org/10.3390/cells10051161