Natural Non-Trasgenic Animal Models for Research in Alzheimers Disease

Abstract

The most common animal models currently used for Alzheimer disease (AD) research are transgenic mice that express a mutant form of human Aβ precursor protein (APP) and/or some of the enzymes implicated in their metabolic processing. However, these transgenic mice carry their own APP and APP-processing enzymes, which may interfere in the production of different amyloid-beta (Aβ) peptides encoded by the human transgenes. Additionally, the genetic backgrounds of the different transgenic mice are a possible confounding factor with regard to crucial aspects of AD that they may (or may not) reproduce. Thus, although the usefulness of transgenic mice is undisputed, we hypothesized that additional relevant information on the physiopathology of AD could be obtained from other natural non-transgenic models. We have analyzed the chick embryo and the dog, which may be better experimental models because their enzymatic machinery for processing APP is almost identical to that of humans. The chick embryo is extremely easy to access and manipulate. It could be an advantageous natural model in which to study the cell biology and developmental function of APP and a potential assay system for drugs that regulate APP processing. The dog suffers from an age-related syndrome of cognitive dysfunction that naturally reproduces key aspects of AD including Aβ cortical pathology, neuronal degeneration and learning and memory disabilities. However, dense core neuritic plaques and neurofibrillary tangles have not been consistently demonstrated in the dog. Thus, these species may be natural models with which to study the biology of AD, and could also serve as assay systems for Aβ-targeted drugs or new therapeutic strategies against this devastating disease.

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

“…There is growing attention to nontransgenic animals with a human Aβ peptide sequence as more physiological models for sporadic AD (Beck et al ., 2003; Sarasa & Pesini, 2009; Moreno‐Gonzalez & Soto, 2012; Sharman et al ., 2013; Bates et al ., 2014). To reveal a possible cross‐reactivity of 1D1 with APP of other animal species, brain sections of chicken, cat, guenon, guinea pig, pig, rabbit and dog were analysed by immunohistochemistry.…”

Comparison of Ionized Calcium-binding Adapter Molecule 1-Immunoreactive Microglia in the Spinal Cord Between Young Adult and Aged Dogs

“…In addition, neurofibrillary tangle pathology was observed in the spinal cord of Alzheimer patients [12,13] as well as an Alzheimer mouse model [14]. The dog is a good model for research on aging and dementia of the Alzheimer's type because these develop with common features in the human and canine brain [15][16][17]. Therefore, to compare microglia in the adult and aged spinal cord, we investigated Iba-1 immunoreactivity in the spinal cord of young adult and aged German Shepherds.…”

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

“…It would be highly desirable to have a nontransgenic model of AD to complement the existing models. Several species naturally develop features of AD with age; however, the usefulness of these species is limited, because none exhibits the full spectrum of AD-related alterations (12)(13)(14). For example, the Aβ peptide sequences of Cavia porcellus (guinea pig) and Microcebus murinus are similar to that of human (15,16), but the first fails to develop senile plaques and NFTs (15), and experiments examining synaptic function and memory have not been carried out in such models.…”