Dataset Information

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.

SUBMITTER: Evans CE

PROVIDER: S-EPMC6357873 | biostudies-other | 2019 Mar

REPOSITORIES: biostudies-other

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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 CE Thomas Rhian S RS Freeman Thomas J TJ Hvoslef-Eide Martha M Good Mark A MA Kidd Emma J EJ

Neurobiology of aging 20181123

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 in ...[more]

PMID: 30572184

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Project description:BACKGROUND:The ?-secretase, BACE1, cleaves APP to initiate generation of the ?-amyloid peptide, A?, that comprises amyloid plaques in Alzheimer's disease (AD). Reducing BACE1 activity is an attractive therapeutic approach to AD, but complete inhibition of BACE1 could have mechanism-based side-effects as BACE1-/- mice show deficits in axon guidance, myelination, memory, and other neurological processes. Since BACE1+/- mice appear normal there is interest in determining whether 50% reduction in BACE1 is potentially effective in preventing or treating AD. APP transgenic mice heterozygous for BACE1 have decreased A? but the extent of reduction varies greatly from study to study. Here we assess the effects of 50% BACE1 reduction on the widely used 5XFAD mouse model of AD. RESULTS:50% BACE1 reduction reduces A?42, plaques, and BACE1-cleaved APP fragments in female, but not in male, 5XFAD/BACE1+/- mice. 5XFAD/BACE1+/+ females have higher levels of A?42 and steady-state transgenic APP than males, likely caused by an estrogen response element in the transgene Thy-1 promoter. We hypothesize that higher transgenic APP level in female 5XFAD mice causes BACE1 to no longer be in excess over APP so that 50% BACE1 reduction has a significant A?42 lowering effect. In contrast, the lower APP level in 5XFAD males allows BACE1 to be in excess over APP even at 50% BACE1 reduction, preventing lowering of A?42 in 5XFAD/BACE1+/- males. We also developed and validated a dot blot assay with an A?42-selective antibody as an accurate and cost-effective alternative to ELISA for measuring cerebral A?42 levels. CONCLUSIONS:50% BACE1 reduction lowers A?42 in female 5XFAD mice only, potentially because BACE1 is not in excess over APP in 5XFAD females with higher transgene expression, while BACE1 is in excess over APP in 5XFAD males with lower transgene expression. Our results suggest that greater than 50% BACE1 inhibition might be necessary to significantly lower A?, given that BACE1 is likely to be in excess over APP in the human brain. Additionally, in experiments using the 5XFAD mouse model, or other Thy-1 promoter transgenic mice, equal numbers of male and female mice should be used, in order to avoid artifactual gender-related differences.

Project description:The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in preclinical species and humans. Quantitative electroencephalography (qEEG) is a translational measure that can be used to demonstrate pharmacodynamic effects across species. NMDA receptor channel blockers, such as ketamine and phencyclidine, increase the EEG gamma power band, which has been used as a pharmacodynamic biomarker in the development of NMDA receptor antagonists. However, detailed qEEG studies with ketamine or NR2B NAMs are lacking in nonhuman primates. The aim of the present study was to determine the effects on the qEEG power spectra of the NR2B NAMs traxoprodil (CP-101,606) and BMT-108908 in nonhuman primates, and to compare them to the NMDA receptor channel blockers, ketamine and lanicemine. Cynomolgus monkeys were surgically implanted with EEG radio-telemetry transmitters, and qEEG was measured after vehicle or drug administration. The relative power for a number of frequency bands was determined. Ketamine and lanicemine increased relative gamma power, whereas the NR2B NAMs traxoprodil and BMT-108908 had no effect. Robust decreases in beta power were elicited by ketamine, traxoprodil and BMT-108908; and these agents also produced decreases in alpha power and increases in delta power at the doses tested. These results suggest that measurement of power spectra in the beta and delta bands may represent a translational pharmacodynamic biomarker to demonstrate functional effects of NR2B NAMs. The results of these studies may help guide the selection of qEEG measures that can be incorporated into early clinical evaluation of NR2B NAMs in healthy humans.

Dataset Information

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

Publications

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

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