Altogether, these results indicate that specific binding of mAbED-C99 to the ectodomain of β-CTF (ED-C99) reduces α-secretase processing while increasing β-secretase processing of APP.
These data suggest that N3-2A/MoBA interferes predominantly with processing of APP by β-secretase and does not modulate γ-cleavage of β-CTF (Fig 2J).
These data implicate that expression of β-CTF per se is not neurotoxic, and that other mechanisms are responsible for the neurotoxic events in Alzheimer's disease brain.
While the amount of α-CTF was drastically reduced, levels of β-CTF increased.
The increased level of β-CTF is further confirmed using mAbBAM10 that is specific for β-CTF but not α-CTF.
mBRI2 interacts with mature APP and β-carboxyl-terminal fragments (β-CTF), and increases the levels of β-CTF by inhibiting its γ-cleavage (Matsuda et al, 2005; Matsuda et al, 2008; Fig 1B and C).
Both α- and β-cleavage sites of wild-type APP are located in APP672 699 region (the ectodomain of β-CTF, ED- β-CTF, or ED-C99; Supplementary Figure S1).
These results suggest that β-CTF rather than A β may be more directly responsible for causing cognitive impairment associated with AD and that GSIs may worsen cognitive impairment by enhancing the accumulation of β-CTF.
Interestingly, mAbED-C99 also dramatically enhanced cell surface β-CTF levels as well as significantly increased WB band density ratio of β-CTF to pan cadherin in both CHO/APPwt cells and primary cultured cortical cells derived from TgAPPwt mice.
