Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized histopathologically by the abnormal deposition of the proteins amyloid-beta (Aβ) and tau. A major issue for AD research is the lack of an animal model that accurately replicates the human disease, thus making it difficult to investigate potential risk factors for AD such as head injury. Furthermore, as age remains the strongest risk factor for most of the AD cases, transgenic models in which mutant human genes are expressed throughout the life span of the animal provide only limited insight into age-related factors in disease development. Guinea pigs (Cavia porcellus) are of interest in AD research because they have a similar Aβ sequence to humans and thus may present a useful non-transgenic animal model of AD. Brains from guinea pigs aged 3–48 months were examined to determine the presence of age-associated AD-like pathology. In addition, fluid percussion-induced brain injury was performed to characterize mechanisms underlying the association between AD risk and head injury. No statistically significant changes were detected in the overall response to aging, although we did observe some region-specific changes. Diffuse deposits of Aβ were found in the hippocampal region of the oldest animals and alterations in amyloid precursor protein processing and tau immunoreactivity were observed with age. Brain injury resulted in a strong and sustained increase in amyloid precursor protein and tau immunoreactivity without Aβ deposition, over 7 days. Guinea pigs may therefore provide a useful model for investigating the influence of environmental and non-genetic risk factors on the pathogenesis of AD.
The most widely accepted hypothesis addressing the pathologic basis of Alzheimer's disease (AD) is the “amyloid hypothesis”, which suggests that the altered metabolism of a small peptide, amyloid-beta (Aβ), is the trigger for the pathogenic cascade that ultimately results in neuronal dysfunction and death. Aβ is derived through sequential enzymatic cleavage of the amyloid precursor protein (APP), a type 1 integral membrane protein, by β-site APP cleaving enzyme (BACE) and then γ-secretase, a multi-subunit enzymatic complex. Age is the strongest risk factor that has been identified to date, yet it is still unclear as to why the clinical symptoms of AD appear in later life when the neuropathology may begin many years, even decades, earlier (Villemagne et al., 2013).
A major hindrance to AD research is the lack of an animal model that replicates all the features of the human disease, namely a chronic, age-dependant neurodegenerative disease with characteristic AD histopathology. Transgenic animal models have yielded a number of important insights into disease mechanisms and are a useful tool for therapeutic design and evaluation. However, the genetic manipulation necessary to produce them does not accurately reflect the human disease state, and accordingly limits at least some of the conclusions that can be drawn.
An alternative strategy may be to investigate potential risk factors in species with similar Aβ sequence to humans. One candidate is the guinea pig (Beck et al., 1997). In vitro studies using guinea pig neuronal cells have demonstrated that APP processing in this species is identical to that in humans (Beck et al., 2000 and Beck et al., 2003). Guinea pigs have been used in a small number of studies to investigate the effect of glutamate (Stephenson and Clemens, 1998), serotonin (Arjona et al., 2002), estrogen (Petanceska et al., 2000), testosterone (Wahjoepramono et al., 2008 and Wahjoepramono et al., 2011), β-secretase inhibitors (Hook et al., 2007 and Jeppsson et al., 2012), and cholesterol (Fassbender et al., 2001) on Aβ production. Further, the effect of protein kinase C (PKC) (Rossner et al., 2000) and gamma amino butyric acid (GABAA) receptor modulation (Marcade et al., 2008) on APP processing has also been investigated in this species.
Traumatic brain injury (TBI) has been identified as a risk factor for AD (Bachman et al., 2003 and Fleminger et al., 2003). Following TBI, cerebrospinal fluid levels of tau (Franz et al., 2003), APP and Aβ increase (Olsson et al., 2004) and postmortem analyses of brains from TBI patients show widespread distribution of Aβ containing plaques and other AD-like pathology including gliosis ( Gentleman et al., 1993, Griffin et al., 1994, Horsburgh et al., 2000 and Ikonomovic et al., 2004). In mice ( Iwata et al., 2002), rats ( Blasko et al., 2004), and sheep ( Van den Heuvel et al., 1999), APP messenger RNA and protein expression rapidly, albeit transiently, increase in response to cortical injury.
To date, no studies have investigated the relationship between aging and AD-like pathology in a non-primate species with human-like APP. Similarly, head injury models have not been performed in animals with similar Aβ sequence to humans. Therefore, a series of pilot studies was conducted to investigate the suitability of the guinea pig as a non-transgenic animal model for AD. A longitudinal aging study and a fluid percussion-induced brain injury (FPI) study were conducted to determine whether any AD-like pathology could be detected in the guinea pig brain.
