Alzheimer’s Disease through Mice Models

Written by Quynh Teresa H. Do and Edited by Gauri Ajith

Alzheimer’s disease (AD) is becoming a national crisis. AD, a form of dementia that is progressive in nature, currently affects over 5.7 million individuals in the United States; this number is predicted to triple by 2050 [1]. There is no cure for AD, but a considerable amount of research is being done by various research organizations on the prevention of the disease. One such organization is the La Ferla lab at the University of California, Irvine, which studies the development of AD in mice models.

The LaFerla lab, led by Dr. Frank A. LaFerla, is part of the UCI Institute for Memory Impairments and Neurological Disorders, which is home to one of the few Alzheimer’s Disease Research Centers in the nation. Dr. Stefania Forner, a postdoctoral fellow at the LaFerla lab, seeks to better understand Alzheimer’s disease using mouse models; she has been working on developing mice models for the study of diseases for almost half a decade. Dr. Forner contributes to research on AD development, associated diseases, potential therapeutics, the role of inflammation in neurodegenerative disorders, and the molecular causes of Alzheimer’s symptoms [2]. Individuals with AD experience the following symptoms: disorientation, mood and behavioral changes, confusion, paranoia, and difficulties with speaking, swallowing and walking. These symptoms arise from Amyloid β plaques and tau tangles, the two defining characteristics of AD. Amyloid β plaques form when misfolded protein fragments accumulate in the brain and hinder neural communication within the brain, which leads to the disruption of normal function. The other biomarker for AD, tau tangles, are associated with neurological decline. Tau is a protein that helps maintain microtubules, or the tubular structures in the structural skeleton of cells. The tangles form when the protein aggregates, diminishing the health of neurons (brain cells) and causing higher neuronal loss [3].

Mice models have been a vital tool in understanding these two biological flaws on a molecular scale. They live in easily controlled environments, making them ideal for experimentation. The first mouse model developed in the LaFerla lab for the study of AD was a transgenic mouse that was genetically modified to alter expression of Alzheimer’s amyloid β peptide in its neurons. A transgenic mouse is created when some genes from an external source are introduced into the genetic material of the mouse. The goal of this study was to use the mouse model to observe if Alzheimer’s amyloid β peptide was neurotoxic, or destructive, to the neurons. The mouse model that overexpressed amyloid β was created by inserting promoters into the mouse’s DNA; promoters are regions of DNA that assist in reading the DNA to make proteins. It is observed that over 50% of the transgenic mice die by 12 months, compared to 24 months in unmodified control mice, implying that amyloidβ peptide is neurotoxic as it causes neurons to undergo apoptosis (cell death). The researchers studied this phenomenon further by using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling, or TUNEL. TUNEL identifies apoptosis by labeling a specific end of the DNA, to detect later when the DNA breaks. Apoptotic cells were observed in the brains of 14 transgenic mice in a sample of 28. These results point towards the neurotoxicity of amyloid β, as the researchers hypothesized [4].

The latest mouse model developed in the LaFerla lab to study AD is the triple transgenic mouse model which is modified to include βAPPSwe, PS1M146V and tauP301L, which are human transgenes that mimic the development of AD. Using this mouse model, the researchers hoped to observe the functioning of muscarinic, galanin, and cannabinoid receptors during early and advanced stages of AD [5]. Muscarinic receptors are found in areas of the brain used for learning and memory; in AD, muscarinic receptor activity is decreased. Galanin and cannabinoid receptors regulate cholinergic cells within the brain; cholinergic cells are nerve cells that communicate signals using the chemical acetylcholine. An experiment was performed to study the activity of each receptor in differently aged transgenic mice (4-months and 15-months to represent the early and advanced stages of AD respectively). This was achieved by measuring the activation of G-proteins, which are associated with receptor activity and transmit signals within cells. It was found that a decrease in densities of the M2 subtype of muscarinic receptors leads to poorer memory, cognition and learning. Galanin receptor and cannabinoid receptor activity increases in reaction to M2 density reduction. These results showed that in AD, the galanin and cannabinoid receptors have neuroprotective roles against the alterations within cholinergic cells and ultimately, combat the effects of decreased M2 muscarinic receptors; these findings can be applied to the human brain [5].

As the findings of these mice model studies have contributed to a greater understanding of AD, one cannot help but wonder: are we getting closer to finding a cure for Alzheimer’s? Dr. Forner argues that we may perhaps never find a cure. “You have to be careful of false hopes. It is not as easy as we wish it would be” [6]. Her insights highlight the importance of being unbiased and realistic when studying Alzheimer’s. While there have been developments in understanding the diseases in the context of amyloid β peptide neurotoxicity and muscarinic, galanin and cannabinoid receptor activity, this does not guarantee any cure. In the future, more research must be conducted in order to help scientists better understand this complicated disease and find new mechanisms to prevent the progression of AD.

References

1. “Facts and Figures.” Alzheimer’s Association, Alzheimer’s Association, www.alz.org/alzheimers-dementia/facts-figures.
2. “Home – LaFerla Lab.” LaFerla Lab, laferlalab.bio.uci.edu/home/.
3. Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., Iwatsubog, T.,  Jack Jr., C.R., Kayei, J., Montinej, T.J., Park, D.C., Reimanl, E.M., Rowem, C.C., Siemersn, E., Sterno, Y., Yaffep, K., Carrilloq, M.C., Thiesq, B.,  Morrison-Bogoradr, M., Wagsterr, M.V., Phelps, C.H. (2011). Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia. 7: 280-292.
4. LaFerla, F. M., Tinkle, B. T., Bieberich, C. J., Haudenschild, C. C., Jay, G. (1995). The Alzheimer’s Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nature Genetics. 9: 21-30.
5. Manuel, I., Lombardero, L., Laferla, F. M., Giménez-Llort, L., Rodríguez-Puertas, R. (2016). Activity of muscarinic, galanin and cannabinoid receptors in the prodromal and advanced stages in the triple transgenic mice model of Alzheimer’s disease. Neuroscience. 329: 284-293.
6. Forner, Stefania. Personal Interview. 15 February 2019.