Journal article Open Access

Ear2 deletion causes early memory and learning deficits in APP/PS1 mice

Kummer, Markus P; Hammerschmidt, Thea; Martinez, Ana; Terwel, Dick; Eichele, Gregor; Witten, Anika; Figura, Stefanie; Stoll, Monika; Schwartz, Stephanie; Pape, Hans-Christian; Schultze, Joachim L; Weinshenker, David; Heneka, Michael T

To assess the consequences of locus ceruleus (LC) degeneration and subsequent noradrenaline (NA) deficiency in early Alzheimer’s disease (AD), mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were crossed with Ear2( / ) mice that have a severe loss of LC neurons projecting to the hippocampus and neocortex. Testing spatial memory and hippocampal long-term potentiation revealed an impairment in APP/PS1 Ear2( / ) mice, whereas APP/PS1 or Ear2( / ) mice showed only minor changes. These deficits were associated with distinct synaptic changes including reduced expression of theNMDA2A subunit and increased levels of NMDA receptor 2B in APP/PS1 Ear2( / ) mice. Acute pharmacological replacement of NA by L -threo-DOPS partially restored phosphorylation of -CaMKII and spatial memory performance in APP/PS1 Ear2( / ) mice. These changes were not accompanied by altered APP processing or amyloid  peptide (A ) deposition. Thus, early LC degeneration and subsequentNAreduction may contribute to cognitive deficits via CaMKII and NMDA receptor dysfunction independent of A  and suggests that NA supplementation could be beneficial in treating AD.

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