Alzheimer’s Mouse Model

Several genes involved are implicated in Alzheimer’s Disease but the mechanism for the disease remains unclear, and is even variable between patients. As such, it has been difficult to develop a good Alzheimer’s mouse model on which to test potential drugs. Existing Alzheimer’s mouse models take various forms: 1) hAPP (human APP) Alzheimer’s mouse model manipulate expression of Aβ42 and exhibit  characteristic “plaques”; 2) Mice from transgenic PSEN1 lines (PSEN1/2 genes are involved in APP processing and mutations here cause autosomal dominant Alzheimer’s Disease) show increased expression of Aβ42 but do not develop “plaques” except when crossed with hAPP mouse lines; 3) Human transgenic tau crossed a genetic model of Frontal Temporal Dementia models “tangles” but mice not exhibit “plaques”; 4) Knock-in human apoE4 (a risk factor for sporadic Alzheimer’s Disease) mice can function as a stand-alone Alzheimer’s mouse model or can be crossed with hAPP mice.

One of the most popular Alzheimer’s mouse models today is the 3xTg mouse model from Jax, which expresses human APP and tau transgenes on a mutant PS1 background. This mouse line develops “plaques” in the frontal cortex around 6 months and “tangles” at 12 months, originating in the hippocampus and spreading to cortex. Cognitive impairment originates as early as 4 months.  A potential issue with this Alzheimer’s mouse model is that the two hallmark pathologies arise independently (due to their genetic encoding) which may not mimic human disease states accurately.

Drug Testing Alzheimer’s Mouse Model

Because of the heterogeneity in the etiology of Alzheimer’s Disease cases, many drug targets have focused on clearing the end products (“plaques” and “tangles”), aiming to mitigate the effects of the disease by curbing cell death and inflammation that results from the pathology. Immunotherapy is one promising course of drug treatment for Alzheimer’s Disease. Immunotherapies are designed to harness the response of immune system to combat disease. The first study to demonstrate efficacy of immunotherapy in the removal of “plaques” was published in Nature in 2009, using an early hAPP Alzheimer’s mouse model, PDAPP.  In 2004, Oddo et al tested immunotherapies against Aβ in 3xTg mice, and found that the immunotherapy directed to the hippocampus reduced Aβ load in 3 days, and, importantly, also  reduced the number of “tangles” after 5 days. This provides evidence to support the idea that removal of “plaques” by immunotherapy is sufficient to reduce overall pathology in Alzheimer’s mouse model, and the idea that “tangles” arise as part of the toxic response to “plaques”.

Research into immunotherapies for Alzheimer’s disease continues, with efforts to improve targeting and specificity. Once such technique involves directing immunotherapeutic agents to the endoplasmic reticulum (ER), the part of the cell responsible for protein synthesis, with the aim of preventing improperly aggregated Aβ from accessing the intracellular space, where it might initiate a downstream cascade of toxicity. So far, this method has been tested only in cell lines and not in mice. Another new study targets immunotherapy to a specific isoform of Aβ and demonstrates improved results compared to existing methods with respect to reducing “plaques” and improving cognitive performance. As these technologies move forward they should be tested in various mouse models, especially those that produce, not one, but both of the hallmarks of Alzheimer’s Disease, like 3xTg mice, and tested for the ability to reduce or eradicate “tangles” as well as “plaques”.

References:

1. Hall A & Roberson E (2012). Mouse Models of Alzheimer’s Disease. Brain Research Bulletin PMCID: PMC3546481
2. “Research Models: 3xTg” Alzforum (accessed 12/15). http://www.alzforum.org/research-models/3xtg
3. Oddo S, Billings L, Kesslak JP, Cribbs D and LaFerla, F (2004). Neuron PMID: 15294141.
4. “Research Models: PDAPP(line109)” Alzforum (accessed 12/15). http://www.alzforum.org/research-models/pdappline109
5. Meli G, Lecci A, Manca A, Krako N, Albertini V, Benussi L, Ghidoni R and Cattaneo A (2014). Nature Communications PMCID: PMC4050278
6. Frost JL, Lieu B, Rahfeld JU, Kleinschmidt M, O’Nuallain B, Le KX, Lues I, Caldarone BJ, Schilling S, Demuth HU and Lemere CA (2015). Neurobiology of Aging PMCID: PMC 4641825.