Object recognition as a measure of memory in 1–2 years old transgenic minipigs carrying the APPsw mutation for Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a disabling, fatal disease, where animal models potentially can enable investigation of aetiology and treatment. The first litter of Göttingen minipigs carrying a mutation for human AD was born in 2007, showing transgene expression. In human AD patients, memory impairment is the most striking and consistent feature. The aim of the present study was to examine effects of the APPsw transgene on memory of AD minipigs compared with non-transgenic controls at two ages (1-2 years) using the spontaneous object recognition test (SORT), which is based on behavioural discrimination of familiar and novel objects. No significant difference between AD minipigs and controls was found when comparing object recognition as a measure of memory. The minipigs did explore the novel object significantly more than the familiar, indicating the expected recognition of the familiar object. Two different inter-phase intervals were used (IPI: 10-40 min). For both ages, object recognition was evident using 10 min IPI. When using 40 min IPI, object recognition was evident only at age 1 year. Comparing memory of a relatively small group of AD minipigs and controls at two rather young ages using the SORT, we were not able to show memory impairment in APPsw carrying minipigs. Being an age-dependent disease, the transgene is expected to cause AD-like symptoms in this porcine model, and the SORT should be repeated at older ages.

The pig as an animal model for human pathologies: A proteomics perspective

“…Over the past decade, several pig homologues of human genes associated with AD have been isolated and characterised [3], including the amyloid precursor protein [127] and presenilins 1 and 2 [128]. A Göttingen miniature pig model of AD based on overexpression of a mutated version of the amyloid precursor protein gene has also been developed [129,130].…”

“…Parkinson's disease (PD) is a chronic, progressive, ageassociated and often debilitating neurodegenerative disorder due to selective loss of dopaminergic neurons from the substantia nigra in the brain, associated with the presence of intra-neuronal protein inclusions of aggregated ␣-synuclein, termed Lewy bodies [131,132]. A pig model of PD has used the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine in a Göttingen minipig, which induced a Memory evaluation of the minipig model [130] Parkinson's disease MPTP-induced Parkinsonism in minipigs [135] Neurological and histological evaluation [133] Brain imaging (PET, MRI) [134] Huntington's disease Tibetan miniature pig expressing mutant Huntingtin [140] Comparison of neuropathology between species of transgenic HD animals (mouse, monkey, pig) [139] Psychological stress…”

Cholinergic profiles in the Goettingen miniature pig (Sus scrofa domesticus) brain

“…The pig brain is gyrencephalic with gray/white matter proportions closer to humans than the rodent (Howells et al, 2010). Additionally, swine are more cost-effective than non-human primates and have a shorter gestation period (Dolezalova et al, 2014) making the Goettingen miniature pig well-suited for human disease-related translational research including myocardial infarction and stroke (Schuleri et al, 2008; Dolezalova et al, 2014), Alzheimer’s (Kragh et al, 2009; Fjord-Larsen et al, 2009; Søndergaard et al, 2012; Jakobsen et al, 2013) and Parkinson’s (Mikkelsen et al, 1999; Glud et al, 2011) disease. The latter disorders are associated with cholinergic basal forebrain (CBF) neuronal degeneration (Mufson et al, 1991; Gilmor et al, 1999).…”

Pig models of neurodegenerative disorders: Utilization in cell replacement‐based preclinical safety and efficacy studies

“…Accumulation of the pathogenic protein and subsequent appearance of a clinically defined functional deficit were predicted to develop with increasing age in 1–2 years (Kragh et al, ). However, this prediction was not confirmed, as no significant difference between 1–2‐year‐old cloned, transgenic AD minipigs and age‐matched controls were found using the spontaneous object recognition test (SORT), which is based on behavioral discrimination of familiar and novel objects as a measure of memory and, further, no significant effect of age and IPI (inter‐phase intervals) was found (Sondergaard et al, ).…”