Tangle Trigger

An enzyme that cleaves tau protein in acidic cellular conditions may trigger early events in Alzheimer’s disease.

Jan 1, 2015
Jyoti Madhusoodanan

ALL TIED UP: Neurofibrillary tangles, shown here in magenta, appear to originate from the cleavage of tau by an enzyme called asparagine endopeptidase.PATHO/WIKIMEDIA COMMONS


The paper
Z. Zhang et al., “Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease,” Nature Medicine, 20:1254-62, 2014.

The background
Tangles of truncated tau proteins squished inside brain cells are a hallmark of Alzheimer’s disease (AD), though their precise origins are mysterious. Aging, the strongest risk factor for AD, is linked to a drop in neurons’ pH, hinting that acidosis might influence tau fragmentation. In 2008, Keqiang Ye of Emory University and colleagues discovered that at a pH of 6.0, a lysosomal enzyme called asparagine endopeptidase (AEP) moved into the cytoplasm and cleaved brain proteins. This led them to explore whether AEP also acted on tau.

The discovery
Assays of mouse and human brains confirmed that AEP cuts tau at two asparagine locations, N-255 and N-368; corresponding tau fragments were abundant in AD specimens of both species. The enzyme’s activity ramped up with age in mice. AEP activity in cultured rat neurons also increased in response to rising doses of amyloid-β peptide, which is a critical precursor to plaque formation in AD. Injecting an AEP-resistant version of tau into rodent brains protected mice from signs of AD.

The pathway
The results suggest that “AEP cleavage is responsible for the biochemical and pathological defects of tau [in AD],” says Ye. AEP activation by amyloid-β indicates that the enzyme may initiate the formation of tau neurofibrillary tangles in Alzheimer’s disease. Ye suggests that AEP might provide “a potential new drug target.”

The future
The result “looks compelling, and points to potential disease causality,” says Charles Glabe of the University of California, Irvine, in an e-mail. But only clinical tests will establish AEP’s true significance, he adds.