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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. ORCID: and Kidd, Emma J. ORCID: 2019. Selective reduction of APP-BACE1 activity improves memory via NMDA-NR2B receptor-mediated mechanisms in aged PDAPP mice. Neurobiology of Aging 75 , pp. 136-149. 10.1016/j.neurobiolaging.2018.11.011

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Additional Information: This is an open access article under the CC-BY license.
Publisher: Elsevier
ISSN: 0197-4580
Funders: Wellcome Trust
Date of First Compliant Deposit: 14 November 2018
Date of Acceptance: 12 November 2018
Last Modified: 06 May 2023 22:10

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