Amyloid-β (Aβ) precursor protein (APP) has something of a mixed reputation. Mutations in the protein, or in its scissor enzyme presenilin, cause early-onset familial Alzheimer disease (eFAD). On the other hand, learning and memory are also compromised by lack of APP, suggesting the protein and its processing may support neural activity. In the April 30 PNAS online, a collaboration of scientists led by Karen Ashe at the University of Minnesota, Minneapolis, reports that mice overexpressing normal APP enjoy enhanced learning and memory; however, those benefits depend both on β-site cleavage and on the APP intracellular domain (AICD). The findings may rekindle debate on the physiologic role of AICD, and also raise a cautionary flag on efforts to target BACE1 for treatment of Alzheimer disease.
The authors uncovered the role of AICD by ablating BACE1 in transgenic mice overexpressing wild-type human APP. These TgAPP mice produce about sixfold more APP than controls. They have no Aβ pathology; they do, however, outperform controls in spatial learning and memory tests (see Westermann et al., 2002). To investigate if those superior faculties relate to APP processing, first author Huifang Ma and colleagues compared the performance of TgAPP mice missing none, one, or both copies of the BACE1 gene.
The scientists first confirmed the earlier finding that BACE+/+ TgAPP mice perform better than non-transgenics in the Morris water maze. This seems to be due to altered neural activity, because hippocampal slices from the animals exhibited enhanced synaptic plasticity when tested for two specific forms of long-term potentiation (LTP). Primed LTP (P-LTP), elicited by a weak single tetanic train of pulses and followed by four strong tetanic trains, was about 30 percent higher in TgAPP tissue than in control slices. Primed post-tetanic potentiation (P-PTP) is a form of short-term synaptic plasticity, according to the paper. It was enhanced by about 20 percent. By contrast, homozygous BACE1 knockout mice performed like wild-type in the water maze test, and their hippocampal tissue showed normal P-LTP and P-PTP. Knocking out a single copy of BACE was also sufficient to abolish both the spatial learning improvement and the enhanced synaptic plasticity, according to the study.
What is the role of BACE1 in enhanced learning and memory? BACE1 cleavage of APP yields a soluble N-terminal APP fragment, sAPPβ, and exposes the C-terminal end to γ-secretase cleavage, which yields Aβ and AICD. (The competing α-secretase pathway yields sAPPα instead, and prevents formation of Aβ.) The authors found that Aβ, sAPPα, and AICD are all elevated in TgAPP compared to non-transgenic strains, yet a single BACE1 knockout, which is sufficient to cut the memory and LTP enhancements, only affected AICD, which dropped to undetectable levels in either single- or double-BACE1 knockouts.
Curiously, the researchers found no change in Aβ levels in single BACE1 knockouts, despite complete loss of AICD. The authors note that this is not entirely without precedent, since mutation or inhibition of γ-secretase can have different effects on AICD and Aβ levels. But since γ-secretase is unaltered in this case, an alternative explanation is warranted. “Potential differences in kinetics of AICD and Aβ degradation may result in a more significant drop in AICD levels than in Aβ levels when one BACE1 gene is ablated,” write the authors. They also suggest that the concentration, rather than the activity of BACE1, may modulate AICD-generating ε cleavage of γ-secretase.
These results suggest that BACE1-derived AICD may be important for the enhanced learning and memory in mice overexpressing APP, but it is unclear how this may happen. AICD may be much more than a by-product of APP processing. The intracellular domain can form complexes with other proteins, including Fe65 and Tip60, which may activate transcription (see related ARF live discussion). Moreover, a simple point mutation in AICD that abolishes a caspase site appears sufficient to protect mice against mutant human APP (see ARF related news story). The authors acknowledge that because TgAPP mice overexpress APP, the effects they observed may not reflect the physiological activity of APP. But, just in case, they offer a recommendation for drug developers. “To ensure that experimental therapies do not prevent BACE1-mediated facilitation of memory by APP, preclinical studies of experimental β-secretase inhibitors should be done not only in animal models of AD, but also in natural animals to evaluate their effects on normal cognitive function,” suggest the authors.—Tom Fagan
- Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH. The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2002 Mar 1;22(5):1858-67. PubMed.
- Ma H, Lesné S, Kotilinek L, Steidl-Nichols JV, Sherman M, Younkin L, Younkin S, Forster C, Sergeant N, Delacourte A, Vassar R, Citron M, Kofuji P, Boland LM, Ashe KH. Involvement of beta-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity. Proc Natl Acad Sci U S A. 2007 May 8;104(19):8167-72. PubMed.