Lipocalin 2 contributes to brain iron dysregulation but does not affect cognition, plaque load, and glial activation in the J20 Alzheimer mouse model

BackgroundLipocalin 2 (Lcn2) is an acute-phase protein implicated in multiple neurodegenerative conditions. Interestingly, both neuroprotective and neurodegenerative effects have been described for Lcn2. Increased Lcn2 levels were found in human post-mortem Alzheimer (AD) brain tissue, and in vitro studies indicated that Lcn2 aggravates amyloid--induced toxicity. However, the role of Lcn2 has not been studied in an in vivo AD model. Therefore, in the current study, the effects of Lcn2 were studied in the J20 mouse model of AD.MethodsJ20 mice and Lcn2-deficient J20 (J20xLcn2 KO) mice were compared at the behavioral and neuropathological level.ResultsJ20xLcn2 KO and J20 mice presented equally strong AD-like behavioral changes, cognitive impairment, plaque load, and glial activation. Interestingly, hippocampal iron accumulation was significantly decreased in J20xLcn2 KO mice as compared to J20 mice.ConclusionsLcn2 contributes to AD-like brain iron dysregulation, and future research should further explore the importance of Lcn2 in AD

Novel crosstalk mechanisms between GluA3 and Epac2 in synaptic plasticity and memory in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease which accounts for the most cases of dementia worldwide. Impaired memory, including acquisition, consolidation, and retrieval, is one of the hallmarks in AD. At the cellular level, dysregulated synaptic plasticity partly due to reduced long-term potentiation (LTP) and enhanced long-term depression (LTD) underlies the memory deficits in AD. GluA3 containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are one of key receptors involved in rapid neurotransmission and synaptic plasticity. Recent studies revealed a novel form of GluA3 involved in neuronal plasticity that is dependent on cyclic adenosine monophosphate (cAMP), rather than N-methyl-d-aspartate (NMDA). However, this cAMP-dependent GluA3 pathway is specifically and significantly impaired by amyloid beta (Aβ), a pathological marker of AD. cAMP is a key second messenger that plays an important role in modulating memory and synaptic plasticity. We previously reported that exchange protein directly activated by cAMP 2 (Epac2), acting as a main cAMP effector, plays a specific and time-limited role in memory retrieval. From electrophysiological perspective, Epac2 facilities the maintenance of LTP, a cellular event closely associated with memory retrieval. Additionally, Epac2 was found to be involved in the GluA3-mediated plasticity. In this review, we comprehensively summarize current knowledge regarding the specific roles of GluA3 and Epac2 in synaptic plasticity and memory, and their potential association with AD

Exchange Protein Activated by Cyclic AMP 2 (Epac2) Plays a Specific and Time-Limited Role in Memory Retrieval

Knowledge on the molecular mechanisms involved in memory retrieval is limited due to the lack of tools to study this stage of the memory process. Here we report that exchange proteins activated by cAMP (Epac) play a surprisingly specific role in memory retrieval. Intrahippocampal injection of the Epac activator 8-pCPT-2'OMe-cAMP was shown to improve fear memory retrieval in contextual fear conditioning whereas acquisition and consolidation were not affected. The retrieval enhancing effect of the Epac activator was even more prominent in the passive avoidance paradigm. Down-regulation of Epac2 expression in the hippocampal CA1 area impaired fear memory retrieval when the memory test was performed 72 h after training, but not when tested after 17 days. Our data thus identify an important time-limited role for hippocampal Epac2 signaling in cognition and opens new avenues to investigate the molecular mechanisms underlying memory retrieval.