Critical Enzyme Predicts Onset of Alzheimer Disease

The critical enzyme beta-secretase1 (BACE1) is known to be elevated in brains with sporadic Alzheimer disease (AD) and two of the major pathological characteristics of AD are neuritic plaques and neurofibrillary tangles, which are used to diagnose or confirm AD at autopsy.

Neuritic plaques, which are also known as senile, dendritic, or amyloid plaques, consist of deteriorating neuronal material surrounding deposits of a sticky protein called amyloid beta peptide (Aβ). Neurofibrillary tangles consist of highly phosphorylated forms of the microtubule-associated protein tau.

Scientists at the Roskamp Institute (Sarasota, FL, USA) examined autopsied brain tissue from 18 patients with clinically well-characterized AD, 18 patients with Mild cognitive impairment (MCI), and 18 nondemented patients. BACE1 enzymatic activity assays were performed by using synthetic peptide substrates containing Swedish mutant BACE1 cleavage site (Calbiochem; San Diego, CA, USA). BACE1 protein levels were measured by enzyme-linked immunosorbent assay (ELISA). The capture antibody was anti-BACE1 monoclonal antibody (R&D Systems; Minneapolis, MN, USA) and the detection antibody was biotinylated anti-BACE1 polyclonal antibody (Thermo Scientific Pierce; Rockford, IL, USA).

They found that BACE1 enzymatic activity was significantly increased in both MCI and AD brains. In 11 of 18 MCI patients, who had undergone a mini-mental state examination (MMSE) before death, the brain cortex BACE1 levels increased during early dementia followed by a precipitous decrease as the decline in cognition progressed. Increased BACE1 activity correlated with plaque numbers and cognition status. Interestingly, they also observed that there was no significant difference in BACE1 activity between MCI and AD. They also found an increase in tumor necrosis factor alpha (TNFα) in MCI brains. TNFα is an inflammatory cytokine or cell-signaling protein required for amyloid protein induced neuronal death. Biochemical examination of the autopsy tissue showed that TNFα rather than other cytokines increases the response to BACE1 protein expression.

Yong Shen, PhD, the senior author of the study said, “We believe that BACE1 activity precedes the clinical diagnosis of AD and could be an early indicator of neuronal dysfunction or pathology in AD. Moreover, it may be a good therapeutic target for AD, as evidenced by recent promising clinical trials on BACE1 inhibitors.” The study was published in the January 2014 issue of the American Journal of Pathology.

Related Links:
Roskamp Institute
Calbiochem
R&D Systems