ABOVE: An APP-knockout neuron (right) shows extended axonal and reduced dendritic growth compared with a normal mouse neuron (left). eLife, 10:e69199, 2021


The paper
T. Liu et al., “The amyloid precursor protein is a conserved Wnt receptor,” eLife, 10:e69199, 2021.

Amyloid precursor protein, which generates amyloid-β when broken down, has long been associated with Alzheimer’s disease. But its normal function in the brain has remained relatively mysterious. Over the past decade, Bassem Hassan of the Paris Brain Institute and others have found hints that the protein (APP) is part of a complex involved in Wnt signaling—an evolutionarily conserved pathway that regulates animal development—as well as in synaptic plasticity and adult neurogenesis. 

Studying human APP and the Drosophila homolog APPL in vitro, Hassan’s team now reports that these membrane proteins bind directly to two types of Wnt peptides, Wnt3a and Wnt5a, in a way that regulates intracellular APP levels: Wnt3a increases APP’s stability and enhances its persistence, while Wnt5a promotes its breakdown. “It looks like they’re acting opposite to one another,” Hassan says, adding that APP seems to be “kind of a calibrator of Wnt signaling.” 

In additional experiments, cultured mouse neurons lacking functional APP showed unusual development, including greater axonal but reduced dendritic growth. In neurons that did contain APP—and in particular, a cysteine-rich domain that the researchers found is required for the Wnt peptides to bind the protein—the team could tweak those growth patterns by altering the relative amounts of Wnt3a and Wnt5a. While it’s unknown if this role in regulating neuronal growth is conserved in humans, the findings point to Wnt signaling as a potential factor in neurodegenerative diseases, Hassan adds. 

Christina Elliott, a molecular neuroscientist at the University of Glasgow who was not involved in the study, says it’d be interesting to see how APP-Wnt interactions work in other cell types and agrees the work could inform Alzheimer’s research. “This paper suggests the possibility that perhaps we actually should be looking at the biology of APP itself,” she says. “Perhaps amyloid-β is not as important as we think.”