AD-BXD Mouse Strain - Maze Engineers

Overview

The AD-BXD mouse strain is a recent development in genetic engineering that is used to model Alzheimer’s disease (AD). AD-BXD mice have AD-related genetics but show variability in their non-AD genetics, modeling individual differences.

Through advanced techniques and mouse crossing, researchers can create a colony of AD-BXD mice with AD genetics but show variability in their non-AD genes, amounting to 27 sub-strains. More on this later.

History

AD-BXD mice are the first strain to incorporate genetic variability into AD models.

AD research has not been translated to humans successfully, one theory is because of underlying individual differences. While previous mouse models for AD were all stable and fixed, AD-BXD mice serve as a more dynamic model.

The AD-BXD mouse strain aims to solve the stand-still in Alzheimer research. Scientists have faced a standstill with research developments, finding that their results from animal studies are not applicable to humans.

This strain has stable AD-related genetics but shows variability for non-AD genes, ultimately creating individual differences on the strain level while maintaining the AD genome.

Engineering the AD-BXD Strain

The AD-BXD strain crosses:

The 5xFAD transgenic line, a line that expresses human PSEN1 and APP transgenes and contains 5 AD-related mutations, using female 5XFAD mice, and
Male BXD genetic reference mice are created by crossing two inbred strains (DBA/2J and C57BL/6J mice) resulting in mice that have genomes which differ in about 5 million sites.

As a result of this, researchers have 27 distinct, but reproducible AD-BXD strains. From these strains, half will have the PSEN1 and APP transgenes while the other half will not.

Strain-dependent Differences

In terms of their APP and PSEN1 genes, the various AD-BXD strains will not vary and will be genetically identical.

However, in terms of other risk factors and characteristics, AD-BXD strains do show differences, for:

Amyloid plaque pathology
Aβ42
Cognitive function
Genetic risk for late-onset AD (LOAD)

Based on differences in genetics by strain, there are differences in their genetic risk for LOAD. This score can be calculated based on the presence of LOAD genes which, in turn, correlate with degrading cognitive function.

Together, these strain-dependent differences, allow researchers to explore the complex avenues behind AD and possibly discover new pathways associated with AD onset or resilience.

Physical Characteristics

Given that the AD-BXD strain is a recent development, there is limited information published on the outer physical characteristics describing the strain and sub-strains.

Behavioral Characteristics & Handling

Behaviorally, AD-BXD mice show a lot of similarities with AD patients, such as poor memory. AD-BXD mice that are impaired show significantly greater difficulty when it comes to acquiring the Fear Conditioning Task.

Difficulties in the Fear Conditioning Task indicate impairments in the cognitive domain or memory. Mice that can successfully learn the task freeze upon encountering the conditioned stimulus while impaired mice, such as AD-BXD mice, fail to freeze upon exposure to a threatening, conditioned stimulus.

Sub-strain Differences in Memory

Furthermore, in the Fear Conditioning Task, the AD-BXD sub-strain has a significant effect on the subtype of fear memory affected. For example, some sub-strains show reduced contextual fear acquisition while other AD-BXD sub-strains specifically show impaired contextual fear memory.

Early experimental results suggest:

The Apoe gene has a greater significant effect on contextual fear acquisition in females as opposed to in males
If a sub-strain carried a single copy of the Apoe D Allele, they are likelier to perform worse in the contextual fear acquisition task

Such findings demonstrate the deep insights that can be derived by running an experiment using AD-BXD mice.

Handling

AD-BXD mice, just like any other mouse strain, must be carefully handled in order not to induce stress. AD-BXD are kept on a 12-hour light/dark cycle.

For experimental purposes, group housing AD-BXD mice is okay, as long as they are all the same sex. Furthermore, mixing same-sex litermates that are transgenic or non-transgenic is also acceptable.

Health Characteristics

Since AD-BXD mice are a strain that is genetically engineered to model a serious neurodegenerative disease, AD-BXD mice come with their own set of health problems.

Plaque deposition: By 6 months of age, AD-BXD mice develop amyloid plaques. Plaque deposition, however, depends on the strain.
Gliosis: Gliosis is a reactive change in the CNS that marks glial cell damage. AD-BXD mice show gliosis by 6 months, however, this is also strain-dependent.
Cognition status: AD-BXD, as a whole, are still normal at 6 months but shows impairment by 14 months.
Sensorimotor function: Based on the strain, there are different rates of deterioration when it comes to AD-BXD mice’s sensorimotor functions as shown by poorer performance on the Balance Beam and reduced Grip Strength.

Precision Medicine and AD-BXD Mice

Lately, the AD-BXD strain has been applied for the purposes of expanding precision medicine research. Precision medicine focuses on delivering a therapy that is tailored to the individual genome and phenotype.

Although this is a novel area for application, the AD-BXD strain is being used for precision medicine research in order to identify to what extent AD manifestation and treatment are specific to the individual.

AD-BXD mice have been validated to show a high extent of overlap with humans when it comes to phenotypic, transcriptomic, as well as genetic, factors. Such findings will support the growing use of AD-BXD mice for research and precision medicine studies.

Major Experimental Uses

AD-BXD mice have been developed for the purposes of modeling AD. Therefore, their major experimental uses revolve around AD research.

Neurobiology research: Neurobiology research is a specific branch of science that focuses on topics such as neurodegeneration and Alzheimer’s disease. AD-BXD mice will help uncover answers to questions about neurodegeneration and AD.
AD research: Since, genetically, this strain can capture various genetic risk factors, it will be used to uncover insights on how significant risk factors are under specific restrictions. Furthermore, the strain can be considered for research in parallel with other AD mouse strains like APP mutants.
Precision medicine: As mentioned previously, precision medicine is going to be a goal for researchers as they try to hone in on the specific interactions between the genome, environment, and treatment.
Mouse/Human gene homologs: Research focusing on similarities between humans and mice will use AD-BXD mice in order to establish the relationship of common genes and AD pathophysiology.

References

Neuner, S. M., Heuer, S. E., Huentelman, M. J., O’connell, K. M. ., & Kaczorowski, C. C. Harnessing Genetic Complexity to Enhance Translatability of Alzheimer’s Disease Mouse Models: A Path toward Precision Medicine. Neuron, 101(3), 399–411.e5. https://doi.org/10.1016/j.neuron.2018.11.040 (2019).
Neuner, S. M., Heuer, S. E., Zhang, J. G., Philip, V. M., & Kaczorowski, C. C. (2019). Identification of pre-symptomatic gene signatures that predict resilience to cognitive decline in the genetically diverse AD-BXD model. Frontiers in genetics, 10, 35.
O’Connell, K. M., Ouellette, A. R., Neuner, S. M., Dunn, A. R., & Kaczorowski, C. C. (2019). Genetic background modifies CNS‐mediated sensorimotor decline in the AD‐BXD mouse model of genetic diversity in Alzheimer’s disease. Genes, Brain and Behavior, 18(8), e12603.