Skip to main content

Research Repository

Advanced Search

Selective reduction of APP-BACE1 activity improves memory via NMDA-NR2B receptor-mediated mechanisms in aged PDAPP mice

Evans, Charles E.; Thomas, Rhian S.; Freeman, Thomas J.; Hvoslef-Eide, Martha; Good, Mark A.; Kidd, Emma J.

Selective reduction of APP-BACE1 activity improves memory via NMDA-NR2B receptor-mediated mechanisms in aged PDAPP mice Thumbnail


Authors

Charles E. Evans

Thomas J. Freeman

Martha Hvoslef-Eide

Mark A. Good

Emma J. Kidd



Abstract

β-Amyloid (Aβ) accumulation is an early event of Alzheimer's disease (AD) pathogenesis. Inhibition of Aβ production by β-secretase (BACE) has been proposed as a potential therapeutic strategy for AD. However, BACE inhibitors lack specificity and have had limited clinical benefit. To better study the consequences of reducing BACE metabolism, specifically of APP, we used an antibody, 2B3, that binds to APP at the BACE cleavage site, inhibiting Aβ production. 2B3 was administered either directly into the lateral ventricles or by intraperitoneal injection to (platelet-derived growth factor promoter hAPP717V (PDAPP) mice and WT mice. 2B3 reduced soluble Aβ40 and βCTF (β-amyloid derived C-terminal fragment) and improved memory for object-in-place associations and working memory in a foraging task in PDAPP mice. 2B3 also normalized the phosphorylation of the N-methyl-D-aspartate receptor NR2B subunit and subsequent extracellular signal-regulated kinase signaling. The importance of this NR2B pathway for OiP memory was confirmed by administering the NR2B antagonist, Ro25-6981, to 18-month-old WT. In contrast, 2B3 impaired associative recognition memory in young WT mice. These data provide novel insights into the mechanism by which selective modulation of APP metabolism by BACE influences synaptic and cognitive processes in both normal mice and aged APP transgenic mice.

Citation

Evans, C. E., Thomas, R. S., Freeman, T. J., Hvoslef-Eide, M., Good, M. A., & Kidd, E. J. (2019). Selective reduction of APP-BACE1 activity improves memory via NMDA-NR2B receptor-mediated mechanisms in aged PDAPP mice. Neurobiology of Aging, 75, 136-149. https://doi.org/10.1016/j.neurobiolaging.2018.11.011

Journal Article Type Article
Acceptance Date Nov 12, 2018
Publication Date Mar 1, 2019
Deposit Date Jan 8, 2019
Publicly Available Date Jan 8, 2019
Journal Neurobiology of Aging
Print ISSN 0197-4580
Electronic ISSN 1558-1497
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 75
Pages 136-149
DOI https://doi.org/10.1016/j.neurobiolaging.2018.11.011
Keywords amyloid, amyloid precursor protein, BACE1, hippocampus, memory, NMDA, βCTF antibody
Public URL https://uwe-repository.worktribe.com/output/849728
Publisher URL http://dx.doi.org/10.1016/j.neurobiolaging.2018.11.011