Bace2 Is a β Cell-Enriched Protease that Regulates Pancreatic β Cell Function and Mass

Abstract

Decreased β cell mass and function are hallmarks of type 2 diabetes. Here we identified, through a siRNA screen, beta site amyloid precursor protein cleaving enzyme 2 (Bace2) as the sheddase of the proproliferative plasma membrane protein Tmem27 in murine and human β cells. Mice with functionally inactive Bace2 and insulin-resistant mice treated with a newly identified Bace2 inhibitor both display augmented β cell mass and improved control of glucose homeostasis due to increased insulin levels. These results implicate Bace2 in the control of β cell maintenance and provide a rational strategy to inhibit this protease for the expansion of functional pancreatic β cell mass.

BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells

“…Contrary to BACE1, BACE2 has no known role in Aβ generation or the etiology of AD (30), and to date has been implicated in the degradation of Aβ (31) and in the maintenance of pancreatic β-cell function and mass through the cleavage of transmembrane protein 27 (TMEM27) (32). Very recently, loss of BACE2 activity in zebrafish was shown to modestly influence pigmentation by an apparent alteration in melanophore migration, whereas loss of BACE1 activity had no apparent effect on pigmentation (33), consistent with the absence of hypopigmentation defect in Bace1 −/− mice.…”

The Neural Cell Adhesion Molecules L1 and CHL1 Are Cleaved by BACE1 Protease in Vivo

“…The antibodies mAb 324 and mAb 555 against L1 ectodomain were described before (44,45). BACE1 inhibitor compound J was synthesized according to the structure described before (46,47).…”

“…For inhibitor treatment, wild type 7-day-old C57Bl/6J mice were subcutaneously dosed with compound J (46,47) at 30 mg/kg or vehicle (20% Captisol) as control. After 12 h, this treatment was repeated once to prolong the drug effects in vivo.…”

“…This compound J has been previously characterized and is highly selective for BACE1 compared with structurally related aspartic proteases (46,47). To monitor the inhibition of BACE1 activity in vivo, the levels of APP and A␤ were analyzed in brain homogenates 24 h after treatment.…”

A new view of the beta cell

“…TMEM27 has previously been described as a beta cell marker and proposed to be a regulator of beta cell proliferation [14,15]. Vats et al describe the first successful generation of an antibody to a known antigen on the beta cell that has properties allowing the in vivo imaging of beta cells.…”