The two-hydrophobic domain tertiary structure of reticulon proteins is critical for modulation of beta-secretase BACE1.

beta-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a membrane-bound protease that is essential for the production of beta-amyloid protein (Abeta). Given the crucial role of Abeta accumulation in Alzheimer's disease (AD), inhibition of BACE1 activity may represent a feasible therapeutic strategy in the treatment of AD. Recently, we and others identified reticulon 3 (RTN3) and reticulon 4-B/C (RTN4-B/C or Nogo-B/C) as membrane proteins that interact with BACE1 and inhibit its ability to produce Abeta.

A family of membrane proteins associated with presenilin expression and gamma-secretase function.

Presenilin 1 (PS1) forms the gamma-secretase complex with at least three components: nicastrin, APH-1, and PEN-2. This complex mediates intramembrane cleavage of amyloid precursor protein (APP) to generate beta-amyloid protein (Abeta) as well as other type 1 transmembrane proteins. Although PS1 mutations linked to familial Alzheimer's disease influence these cleavages, their biological consequences have not been fully understood.

A novel monoclonal antibody specific for the amino-truncated beta-amyloid Abeta5-40/42 produced from caspase-cleaved amyloid precursor protein.

Deposition of beta-amyloid peptide (Abeta) as senile plaques and amyloid angiopathy are the major neuropathological features of Alzheimer's disease (AD). Heterogeneity is observed in the N- and C-termini of the deposited Abeta species. Recent evidence implicates caspase activation and apoptosis in AD neurodegeneration.

Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid beta-protein.

Beta-secretase beta-site APP cleaving enzyme 1 (BACE1), is a membrane-bound aspartyl protease necessary for the generation of amyloid beta-protein (Abeta), which accumulates in the brains of individuals with Alzheimer's disease (AD). To gain insight into the mechanisms by which BACE1 activity is regulated, we used proteomic methods to search for BACE1-interacting proteins in human neuroblastoma SH-SY5Y cells, which overexpress BACE1. We identified reticulon 4-B (RTN4-B; Nogo-B) as a BACE1-associated membrane protein.

Characterization of APH-1 mutants with a disrupted transmembrane GxxxG motif.

APH-1 is one of the four essential components of presenilin (PS)-gamma-secretase complexes. There are three major isoforms of APH-1 in humans: APH-1aS, APH-1aL, and APH-1b. To gain insight into the functional role of APH-1 in gamma-secretase complexes, we analyzed the relationship between the three APH-1 forms and characterized APH-1 mutants with a disrupted transmembrane GxxxG motif.

Extracellular release of BACE1 holoproteins from human neuronal cells.

BACE1 is a membrane-bound aspartyl protease involved in production of the Alzheimer's amyloid beta-protein. The BACE1 ectodomain is partially cleaved to generate soluble BACE1, but the physiological significance of this event is unclear. During our characterization of BACE1 shedding from human neuroblastoma SH-SY5Y cells stably expressing BACE1, we unexpectedly found that detectable amounts of BACE1 holoproteins were released extracellularly along with soluble BACE1.