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

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.

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

“…In contrast, the expression of a related alternative rRAS receptor, IRAP, which is downstream of Ang-II metabolism and also enhances cognitive function and LTP [34,72] remained unchanged. We also found evidence of increased hippocampal expression of a subset of glutamate receptors and signalling pathways, specifically NR2B receptor and ERK, which influence performance on the OiP task performance in normal mice [51,73]. Activation of ERK, which is downstream of NMDA receptor activity, plays a role in regulating memory processes [74].…”

“…Deficiencies in synaptic NMDA NR2B subunit phosphorylation and downstream ERK signalling have previously been associated with behavioural deficits in Tg2576, APP23 and 3xTg mice, due in part to the effects of excessive Aβ [75][76][77]. We have previously shown that changes in the ratio of total:phosphorylated ERK, specifically within synaptosomes, is associated with OiP performance in PDAPP mice [51]. These data indicate that localised changes in synaptosome ERK signalling observed in the DIZE-administered mice are likely to be indicative of increased signalling through the NR2B receptor.…”

“…Immediately following behavioural testing, mice were culled by cervical dislocation and their brains were removed and dissected. In Experiments 1, 2 and 4, both hemispheres were dissected into cortex, hippocampus and frontal cortex and snap frozen at − 80 °C until protein extraction as previously described [51]. In Experiment 3, the left hemisphere was dissected as above, snap frozen, and used for synaptosome extraction (see below).…”

“…Western blotting was performed using standard methods as described previously [51]. Briefly, after protein quantification, 20 μg protein/sample was resolved on either a 10 or 7.5% polyacrylamide gel and detected with the relevant antibody (NR2B, pY1472-NR2B (Millipore), GluA1, pSer845 GluA1, PSD95 (Abcam), total ERK, phospho-ERK (Cell Signalling Technologies), NR1 (BD Biosciences), Total Tau (DAKO), PHF1 (p-Tau Ser396/404; a generous gift from P. Davies) and β-actin (Sigma).…”

Role of NR2B/ERK signaling in the neuroprotective effect of dexmedetomidine against sevoflurane induced neurological dysfunction in the developing rat brain

“…NR2B overexpression can trigger cell apoptotic pathways, which may be the pathology of the neuroprotective effect of NR2B antagonists [23]. Notably NR2B activation is also closely associated with the activation of ERK signaling [24]. Moreover, NR2B-ERK signaling has been suggested to be involved in the regulation of neuronal survival and participate in the development of neurological diseases [25][26][27].…”