Deficits in object-in-place but not relative recency performance in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: Implications for object recognition

Abstract

Performance was examined on three variants of the spontaneous object recognition (SOR) task, in 5-month old APPswe/PS1dE9 mice and wild-type littermate controls. A deficit was observed in an object-in-place (OIP) task, in which mice are preexposed to four different objects in specific locations, and then at test two of the objects swap locations (Experiment 2). Typically more exploration is seen of the objects which have switched location, which is taken as evidence of a retrieval-generated priming mechanism. However, no significant transgenic deficit was found in a relative recency (RR) task (Experiment 1), in which mice are exposed to two different objects in two separate sample phases, and then tested with both objects. Typically more exploration of the firstpresented object is observed, which is taken as evidence of a self-generated priming mechanism. Nor was there any impairment in the simplest variant, the spontaneous object recognition (SOR) task, in which mice are preexposed to one object and then tested with the familiar and a novel object. This was true regardless of whether the sample-test interval was 5 minutes (Experiment 1) or 24 hours (Experiments 1 and 2). It is argued that SOR performance depends on retrieval-generated priming as well as self-generated priming, and our preliminary evidence suggests that the retrieval-generated priming process is especially impaired in these young transgenic animals . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 The aim of our research has been to identify early cognitive signs of AD in one specific genetic model, the double-transgenic APPswe/PS1dE9 mouse. This may be the best-characterised transgenic model of AD to date, co-expressing the mutated Swedish APP gene and also the exon-9 deleted variant of the PS1 gene [5]. Elevated levels of oligomeric Aβ in the cortex and hippocampus have been observed at 3.5 months of age in these mice; these changes are accompanied by synaptic deficits [6,7], and are also closely associated with swollen dystrophic cholinergic neurites [8].Although the amyloid plaques characteristic of AD have been reported at 4 months of age in these mice, it is only from 6 months that they are consistently observed [9]. Aβ deposition is paralleled by progressive degeneration of monaminergic [10,11] and striatal [12] neurons, and neuroinflammatory reactions [13] which mirror human AD pathology. These animals also recapitulate the age-related cognitive decline characteristic of AD [14], which is thought to depend on these neuropathological changes.The neuropathology that develops in AD in general, and in this mouse model in particular, is well specified. But precisely which aspects of this brain pathology underlie the cognitive deficits that are such a central feature of AD is still under debate [15]. In this particular mouse line, some...

Time or place? Dissociation between object-in-place and relative recency in young APPswe/PS1dE9 mice.

“…Second, both tasks were matched in the durations of both preexposure and test, and in the number of objects employed. Third, in contrast to the findings of Bonardi et al (2016), there was no sign of any APP/PS1 deficit in the relative recency task -if anything the effect was numerically larger in the APP/PS1 animals.…”

“…First, we concluded that the young transgenic mice are selectively impaired on the retrieval-generated priming process, and that their intact SOR performance depends on self-generated priming. But self-generated priming is inherently transient: given enough time all the stimulus elements will become inactive again, meaning that SOR at longer delays cannot be due to this process (Bonardi et al, 2016). It follows that these transgenic animals should only show normal SOR at relatively short sample-test delays -and this is not the case: Bonardi et al (2016) demonstrated intact SOR performance with a 24-hour delay between sample and test in these animals.…”

“…But self-generated priming is inherently transient: given enough time all the stimulus elements will become inactive again, meaning that SOR at longer delays cannot be due to this process (Bonardi et al, 2016). It follows that these transgenic animals should only show normal SOR at relatively short sample-test delays -and this is not the case: Bonardi et al (2016) demonstrated intact SOR performance with a 24-hour delay between sample and test in these animals. Although it is impossible to quantify the temporal parameters for decay between the different activity states, it stretches the bounds of plausibility to suggest that decay from A2 to inactive takes more than 24 hours.…”

“…Bonardi Pardon & Armstrong (2016) applied this logic, conducting a series of studies with 5-month old APPswe/PS1dE9 mice and their wild-type littermates. In the first of two studies they compared performance on a standard spontaneous object recognition task with that on a relative recency task in which mice were exposed to B, and 24 hours later to A, before being tested with A and B.…”

Xanthoceraside prevented synaptic loss and reversed learning-memory deficits in APP/PS1 transgenic mice

“…These studies indicate that soluble, oligomeric Aβ and tau are two major factors of synaptotoxicities [10,11]. Additionally, several studies found that dendrites and dendritic spines near amyloid plaques suffer severer damage in APP/PS1 transgenic mice, revealing the spatial correlation between Aβ, plaques, and synaptic abnormalities [12,13]. Therefore, synaptic plasticity impairment could be related to AD progression.…”