Common Mouse Models for Preclinical Alzheimer's Disease Research

After being diagnosed with Alzheimer’s in his later years, the famous British fantasy author Terry Pratchett described the disease in his writings: “On the first day of my journalistic career I saw my first corpse… All I can say is that, compared with his horrific demise, Alzheimer's is a walk in the park. Except with Alzheimer's my park keeps changing. The trees get up and walk over there, the benches go missing and the paths seem to be unwinding into particularly vindictive serpents.”.

As a neurodegenerative disease characterized by progressive cognitive impairment, Alzheimer's disease (AD) is one of the most common types of dementia in the elderly. Patients will start with repeated questioning and forgetfulness, gradually progress to wandering and getting lost, and ultimately enter a state of comprehensive decline and inability to take care of themselves. With the current rapid increase in the number of patients with AD, accelerating the prevention and treatment of AD has become an urgent matter.

Clinical Research on Alzheimer's Disease

The clinical manifestations of AD mainly include impairment of high-level cognitive functions such as memory, language, executive function, visuospatial skills, and attention, as well as non-cognitive functional impairments such as emotional and behavioral changes and psychiatric symptoms. The causes and mechanisms of AD are not fully understood yet. The consensus is that the characteristic pathological changes of AD are the abnormal deposition of β-amyloid protein (Aβ) in the brain, forming senile plaques, and the abnormal aggregation of Tau protein, forming neurofibrillary tangles. The appearance of both ultimately leads to neuronal apoptosis and synaptic dysfunction in the brain.

Common Mouse Models for Alzheimer's Disease Research

Currently approved drugs for AD do not have a significant effect on slowing down the disease progression. That’s partially due to the fact that the animal models could not fully mimic the pathological features and disease processes of AD, making it difficult to completely understand the underlying mechanisms.

Ⅰ. Aging mouse models

Aging is a critical factor for AD development. Aging mouse models are established by promoting or inducing aging (including natural aging) in animals through various methods, with aging as the cause of AD.

1. Natural aging model

In the early stages of AD research, researchers established an animal model of aging by raising mice to 18-24 months. This mouse model is easy to establish and exhibits various pathological features similar to AD patients during the aging period, such as neuronal degeneration, behavioral and memory impairment. However, the modeling time is relatively long, with a breeding cycle generally exceeding 15 months. After mice become old, they are prone to co-occurrence of other aging-related diseases, and their health status is poor, leading to their death, which makes it difficult to maintain consistency among individuals in the population. The combination of these factors can result in unreliable cohort numbers, as there is a high variance in the available models at the experimental stage.

2. D-galactose-induced aging model

D-galactose can accelerate cell aging and apoptosis, ultimately leading to natural aging characteristics in the body. After subcutaneous injection for several weeks, D-galactose can induce mice to exhibit characteristics similar to elderly mice, such as learning and memory decline, slow movement, reduced number of neurons, and decreased superoxide dismutase (SOD) activity in brain tissue. 

3. Rapid aging model

This type of model mainly refers to the SAMP8 mouse model, which is now widely used in the study of aging-related diseases. After 6 months of age, SAMP8 mice enter an accelerated aging period and exhibit age-related AD clinical features, such as learning and memory decline and Aβ deposition. This mouse model has the advantages of a short breeding cycle and obvious aging characteristics. However, its reproductive ability is poor and the price is more expensive than other mouse models.

Although aging models can reproduce the degenerative pathological process of AD, aging is only a risk factor for AD development, and cannot guarantee every aged mouse exhibits AD symptoms. Therefore, aging animal models cannot replace AD models.

II. Aβ-induced AD model

The Aβ-induced AD model is induced by injecting Aβ fragments into the hippocampal CA1 region or the lateral ventricle of mice, causing Aβ deposition and amyloid plaques in the brain. This mouse model exhibits AD pathological features such as significant Aβ deposition in the brain, proliferation of stellate glial cells around amyloid plaques, reduced activity, and cognitive dysfunction. However, the modeling process is difficult, and pathological features induced by Aβ tend to aggregate at the injection site rather than being diffusely distributed throughout the brain like in AD patients.

III. Genome editing mouse models

In the current research, AD mouse models are mainly generated by introducing human AD-related genes into the mouse genome through transgenic methods, causing the exhibition of AD pathological features. Statistics data show that most mouse models revolve around the pathology of amyloid plaques (related genes: APP, PSEN1), while there are relatively few mouse models involving the pathology of abnormal aggregation of Tau proteins (related gene: MAPT). Currently, the most frequently used mouse models in the literature are the APP/PS1, 5xFAD, Tg2576, and 3xTg-AD models (shown below). We will introduce these types of AD-related genome editing mouse models in our next section of "Neurological Diseases Research".

                                                                                                                                           
Statistics on animal models that related to AD [2]

Recommended Mouse Models for Neurological Disease Research

Beyond Alzheimer's, therapies for other neurodegenerative diseases such as Huntington's disease and amyotrophic lateral sclerosis (ALS) are also lacking. To accelerate R&D of effective treatments for these neurological diseases, Cyagen has developed a series of gene edited mouse models.  We can offer customized, off-the-shelf, and collaborative models, including gene knockouts, knock-ins, point mutations, humanized mouse models, and surgical disease models in mice and rats, to accelerate the validation of neuropharmacological experiments.

References:

[1]Tzioras， M.， McGeachan， R.I.， Durrant， C.S. et al. Synaptic degeneration in Alzheimer disease. Nat Rev Neurol 19， 19–38 (2023). https：//doi.org/10.1038/s41582-022-00749-z.

[2]Kosel F ,  Pelley J ,  Franklin T B . Behavioural and psychological symptoms of dementia in mouse models of Alzheimer's disease-related pathology[J]. Neuroscience & Biobehavioral Reviews, 2020, 112:634-647.

[3]https://www.jax.org/strain/005864

[4]Lanz TA, Carter DB, Merchant KM. Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol Dis. 2003 Aug;13(3):246-53. PubMed.

[5]Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT. APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol. 1997 Sep;56(9):965-73. PubMed.

[6]Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron. 2005 Mar 3;45(5):675-88. PubMed.

[7]Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron. 2005 Mar 3;45(5):675-88. PubMed.