β‐Adrenergic receptor agonist alleviates memory interference control deficits in APPswe/PS1dE9 mice

Abstract

AbstractBackgroundEarlier studies have demonstrated that memory dysfunction during early Alzheimer’s disease (AD) is associated with an increased susceptibility to memory interference (MI). In this study, we examined whether previously stored memory representations interfered with novel similar input patterns in 2‐month‐old APPswe/PS1dE9 (APP/PS1), mice. APP/PS1 over‐expresses the Swedish mutation of amyloid precursor protein together with presenilin1 deleted in exon 9. Amyloid beta (Aβ) plaque deposition is observed at 4‐6 months of age, not at 2 months providing us with a window to study the earliest behavioural deficits that are independent of Aβ plaque deposition.Method(1) We introduced a proactive interference step to the well‐established novel object recognition paradigm (NOR), by exposing the mice to multiple objects of different shape, size and colour. (2) Earlier studies have demonstrated that prolonged oral administration of β‐adrenoreceptor (β‐AR) agonist (−)‐Isoproterenol hydrochloride (IPE) to mice protected them from hippocampal impairment by Aβ oligomers, and enhanced hippocampal synaptic plasticity. We provided the IPE in drinking water for three weeks from P26 till P47.ResultOur results demonstrate that NOR is intact in APP/PS1 at 2 months of age. However, introducing a short‐term object based priming or interference prior to NOR leads to recognition memory deficits. This finding indicates that 2‐month‐old APP/PS1 is susceptible to proactive MI unlike their Wild Type counterpart who could clearly discriminate between a novel and a familiar object. Our findings indicate that, object‐based priming can activate its presence during target memory encoding, and thus negate learning in 2‐month‐old APP/PS1 mice before amyloidosis onset. β‐AR agonist treatment restored performance of APP/PS1 mice to normal levels protecting them from the effects of priming during the object recognition task.ConclusionThese results indicate that integration or discrimination component of object memory representations relies on and can be modulated by β‐AR activation.