ALDH2 Mouse
Description
Overview of ALDH2 Mouse Models
ALDH2 mice are knock-in (KI) models designed to replicate the human ALDH2*2 variant, present in ~40% of East Asians. These mice exhibit:
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Reduced ALDH2 enzymatic activity: Heterozygotes retain ~44% activity, while homozygotes show near-complete loss .
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Impaired acetaldehyde clearance: Prolonged blood acetaldehyde levels post-ethanol exposure .
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Accelerated disease phenotypes: Increased susceptibility to liver cancer, diabetic cardiomyopathy, and neurodegeneration .
Generation and Validation of ALDH2 Mice
Key steps in developing ALDH2*2 knock-in mice include:
| Method | Outcome | Source |
|---|---|---|
| Homologous recombination | G-to-A substitution in exon 12 of Aldh2 | |
| Cre-loxP system | Removal of neomycin-resistance cassette | |
| Phenotypic validation | Mendelian inheritance, normal lifespan |
Hepatocytes from these mice showed:
Toxicology and Oncology
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Liver carcinogenesis:
Cardiology
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Diabetic cardiomyopathy:
Neurology
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Alzheimer’s disease (AD):
Protein Stability and Dominant-Negative Effects
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ALDH2(E487K) mutation causes:
Metabolic Dysregulation
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Thermogenesis defects:
Therapeutic Testing in ALDH2 Mice
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Alda-1 efficacy:
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Limitations:
Implications for Human Health
ALDH2 mice have revealed:
Product Specs
Q&A
What are the key genetic differences between ALDH2 knockout, knock-in, and overexpressing mouse models?
ALDH2 mouse models vary significantly in their genetic modifications and phenotypic outcomes:
Answer: Knock-in mice (ALDH21/*2 and ALDH22/*2) are the most translationally relevant for studying the common East Asian ALDH22 mutation. Knockout models lack residual activity, while overexpressing mice better model homozygous states. Knock-in mice retain partial ALDH2 function, enabling testing of activators like Alda-1 or AD-9308 to restore activity .
How should researchers validate ALDH2-related phenotypes in knock-in mice?
Validation requires multi-level assessment:
Experimental Design:
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Biochemical Confirmation: Measure ALDH2 protein levels (via Western blot) and enzymatic activity (acetaldehyde clearance assays) to confirm reduced activity .
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Metabolic Profiling: Assess acetaldehyde and 4-HNE adduct levels (e.g., in paw tissue or liver) using LC-MS/MS to link ALDH2 deficiency to oxidative stress .
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Functional Testing:
Data Interpretation:
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Nociception: ALDH2*1/*2 mice show heightened phase II pain responses to formalin, correlating with 4-HNE accumulation .
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Metabolism: Aldh2 knock-in mice exhibit reduced brown adipose tissue thermogenesis, impaired fatty acid oxidation, and insulin resistance .
Answer: Phenotypic validation must integrate biochemical, functional, and histological data. For example, elevated 4-HNE adducts in paw tissue of ALDH2*1/*2 mice confirm ALDH2’s role in detoxifying reactive aldehydes .
What experimental controls are critical when using ALDH2 knock-in mice?
Control strategies depend on the research focus:
Answer: Wild-type littermates remain the gold standard for phenotypic comparisons. For drug studies (e.g., Alda-1), vehicle controls in both genotypes ensure that observed effects are ALDH2-dependent, not confounded by drug toxicity .
How do ALDH2 activators like Alda-1 and AD-9308 work in vivo, and what are their limitations?
Mechanisms:
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Alda-1: Binds to ALDH2’s catalytic site, stabilizing its active conformation and enhancing NAD+ binding affinity. Restores activity in ALDH21/*2 mice .
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AD-9308: Water-soluble ALDH2 activator; improves thermogenesis and fatty acid oxidation in Aldh2 knock-in mice .
Limitations:
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Tissue Penetration: Alda-1’s lipophilicity may limit CNS penetration, complicating central pain studies .
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Dose Dependency: Optimal dosing varies by target tissue; e.g., metabolic effects require higher doses than nociceptive modulation .
Answer: While ALDH2 activators show promise, their efficacy depends on tissue-specific ALDH2 expression and activator pharmacokinetics. Future studies should explore targeted delivery systems .
What contradictions exist in ALDH2 mouse model data, and how should researchers address them?
Reported Contradictions:
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Nociception vs. Metabolism: ALDH2*1/*2 mice exhibit increased pain sensitivity but impaired metabolic adaptation . This highlights ALDH2’s dual protective roles.
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Activator Efficacy: Alda-1 reverses hyperalgesia in ALDH2*1/*2 mice but shows variable effects on metabolic parameters depending on diet and dosage .
Resolution Strategies:
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Experimental Standardization: Define age, sex, and housing conditions (e.g., cold exposure for thermogenesis studies).
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Multi-Omics Approaches: Integrate proteomics (e.g., 4-HNE-adducted proteins) with functional assays to dissect mechanism-specific outcomes .
Answer: Contradictions often stem from differing experimental contexts. Researchers must explicitly state model-specific conditions (e.g., diet, activator dose) to contextualize findings .
How can researchers model ALDH2’s role in chronic vs. acute pathologies using these mice?
Experimental Paradigms:
Answer: Chronic models require longitudinal studies with repeated insults (e.g., weekly carrageenan injections) to mimic sustained ALDH2 deficiency. Acute models (e.g., single formalin injection) isolate immediate detoxification effects .
What are the challenges in translating ALDH2 mouse findings to human clinical trials?
Key Challenges:
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Dose Scaling: Human ALDH2*2/*2 individuals have residual activity; activator doses may differ from murine models .
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Tissue-Specific Effects: ALDH2’s role in brown adipose tissue (metabolism) vs. peripheral nerves (pain) requires organ-specific targeting .
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Ethnic-Specific Responses: ALDH22 prevalence is highest in East Asians; trials must account for population genetics .
Answer: Translational studies should prioritize biomarkers (e.g., 4-HNE adducts) to monitor ALDH2 activity in humans. Phase I trials should test activators in ALDH22 carriers first to validate target engagement .
Product Science Overview
Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme that belongs to the aldehyde dehydrogenase family. This family of enzymes is responsible for the detoxification of aldehydes, which are highly reactive and potentially toxic compounds. ALDH2, in particular, plays a significant role in the metabolism of acetaldehyde, a byproduct of alcohol metabolism, converting it into the less toxic acetic acid .
ALDH2 is a mitochondrial enzyme, meaning it is located within the mitochondria of cells. The enzyme functions as a homotetramer, consisting of four identical subunits. Each subunit contains an active site where the catalytic conversion of aldehydes takes place. The enzyme’s activity is crucial for preventing the accumulation of toxic aldehydes, which can cause cellular damage and contribute to various diseases .
There are several genetic variants of ALDH2 that can affect its enzymatic activity. One well-known variant is the ALDH2*2 allele, which is prevalent in East Asian populations. This variant results in a significantly reduced enzymatic activity, leading to the accumulation of acetaldehyde after alcohol consumption. This accumulation causes the characteristic “alcohol flush reaction,” where individuals experience facial flushing, nausea, and other symptoms .
ALDH2 has been implicated in various diseases, including alcohol-related liver disease, cardiovascular diseases, and certain types of cancer. The enzyme’s ability to detoxify reactive aldehydes makes it a potential target for therapeutic interventions. For example, enhancing ALDH2 activity could help mitigate the damage caused by oxidative stress and reduce the risk of developing aldehyde-related diseases .
Recombinant ALDH2, particularly from mouse models, is widely used in research to study the enzyme’s structure, function, and role in disease. Mouse recombinant ALDH2 is produced by expressing the mouse ALDH2 gene in a suitable host system, such as bacteria or yeast. This allows researchers to obtain large quantities of the enzyme for biochemical and structural studies .
