Figure 8: Blockade of AEP cleavage prevents synaptic and cognitive dysfunction induced by APP SLA. | Nature Communications

Figure 8: Blockade of AEP cleavage prevents synaptic and cognitive dysfunction induced by APP SLA.

From: Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease

Figure 8

(a,b) AAV-mediated expression of human APP SLA and APP SLA N373AN585A detected by immunohistochemistry and western blot (WB) using an antibody specific to human APP. Scale bar, 100 μm. (c) Probe trial of Morris water maze test showing blockade of AEP cleavage prevents memory deficits induced by APP SLA (mean±s.e.m.; *P<0.05). (d) The synaptic density in the hippocampus of mice injected with AAV-APP SLA and AAV-APP SLA N373AN585A determined by electron microscopy (mean±s.e.m.; n=6; *P<0.05, **P<0.01). Scale bar, 1 μm. (e–j) Blockade of AEP cleavage preserves the electrophysiological function. The APP SLA N373AN585A mice showed higher ratio of paired pulse (e), higher averaged magnitude of LTP (f) and higher slope of I/O curve (g) than the APP SLA N373AN585A mice. (h) Possible pathways for AEP-mediated cleavage of APP, tau and SET in AD. (1) AEP might translocate from the endolysosome into the cytoplasmic space, where it cleaves tau; (2) intracellular AEP cuts SET, leading to PP2A inhibition and consequent tau hyperphosphorylation; (3) intracellular AEP can be fused with the endocytosed APP; (4) activated AEP might be secreted extracellularly, where it interacts with the ectodomain of APP; (5) AEP and APP can also form a complex, which can be internalized via endocytosis. Data were analysed using t-test (c,e,f,g) or one-way analysis of variance followed by post hoc comparison (d).

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