Animal models of Alzheimer's disease
Animal models are a critical component in disease research, as they provide a strategy to study the molecular, cellular, physiology, and pathology of diseases. There are many conserved anatomical and physiological similarities between animals and humans, which makes this work possible. Studies with animals can provide knowledge about the mechanisms behind disorders, timeline of progression, and the genetic components underlying the phenotypes, before applying these hypotheses to humans. Especially with aging diseases, such as Alzheimer’s disease (AD), an animal model will age much faster than humans, allowing more data to be collected faster. AD is a progressive neurodegenerative disease characterized by cognitive decline and memory loss and is associated with many risk factors including the accumulation of toxic proteins, decreased plasmalogen levels, impaired cholesterol transport, heart disease, poor diet, mental illness, and lack of physical activity. Here we will discuss a few common types of AD models.
There have been many different models produced that focus on a specific characteristic of AD, typically β-amyloid accumulation or hyperphosphorylated tau tangles with neurodegeneration and cognitive deficits accompanying the brain damage from toxic proteins. In 1995, Games et al published the development of the first amyloid precursor protein (APP) transgenic mouse, designed to overexpress APP and lead to an increased production of β-amyloid (1). Since then many more mouse models have been made to overexpress amyloid, but also many double transgenics where amyloid and another target are altered. These include APP/PS1 transgenics, animals that express a chimeric mouse/human APP and the human presenilin-1 (PS1) gene, which encodes one of the proteins in the gamma secretase complex and is necessary for generating β-amyloid. Another example is the APP/PS1/Tau triple mutation transgenic model, 3xTg-AD. These mice not only have the same introduced human genes as APP/PS1, but also express the human microtubule-associated protein tau (MAPT1), the gene that encodes tau. Mouse models have also been developed to only focus on neurofibrillary tangles and tau production including the two most common lines, rTg4510 and PS19. The former was created by expressing the human four-repeat isoform (4R) tau and P301L mutation in the forebrain causing tau levels at 13-fold higher than endogenous tau. PS19 also contains human 4R and the P301S mutation causing 5-fold tau overexpression and a slightly milder pathology than rTg4010, although both demonstrate neurodegeneration correlating with the level of tau expression.
Another method to cause an AD pathology is through chemical induction. One commonly studied neurotoxin model uses lipopolysaccharide (LPS), an endotoxin that causes impaired cognitive behaviour, suppressed neurogenesis, neurodegeneration, reduces plasmalogens, microglial activation, and inflammation as well as increased anxiety, decreased locomotion, and general depression. Compared to the β-amyloid and tau models, the LPS mouse model induces a pathology more similar to AD pathology seen in humans since the progression is not dependent on a toxic protein and neuroinflammation is present.
In addition to mice, other organisms have been used as models of AD. Primates are used as their anatomy and neurology are much closer to that in humans. However, their use is typically after a theory has been confirmed in a rodent model, either mice or rats, as primates are much more expensive, can take longer to age, and they are larger so if the goal is to test a pharmaceutical treatment far more drug would be required. Zebrafish are also thought to be excellent models of AD, although they do not demonstrate advanced cognitive behaviours seen in rodent models. Zebrafish produce transparent embryos, exhibit rapid development ex utero, and produce over 100 offspring per spawning making them easier to manipulate while also achieving a high sample size quickly. In addition, their genome contains many orthologous genes to those involved in AD allowing for direct comparisons when they are manipulated in the fish. An AD pathology can also be induced in zebrafish through aluminum chloride exposure which causes neurological hallmarks of AD.
There are a number of AD animal models available, and they have been crucial in determining much of what we know about the pathology, progression, brain regions affected, and biochemical alterations that occur throughout the disease. As with most disease models, there has not been one that perfectly represents all symptoms and pathologies often found in AD. Many of the models used today are the result of genetically overexpressing toxic proteins, which has not been found to be a consistent cause in AD in humans. As well, we often do not see a progression of the disease with normal development early in life and the disease beginning in late adulthood, but instead the animals are born with the defects already and some are exacerbated with age. As the search for an ideal AD model continues, one that focuses more on the brain morphology changes, alterations to neuronal function, and cellular composition may provide a more accurate comparison as that experienced in humans. The lack of translatability from animal models to humans has limited the development of clinically meaningful and successful therapies and it is for this reason that we need to continue developing new models.
Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995;373:523–7.