Faulty Endocytosis Plays a Key Role in Alzheimer's

A new study shows that the most prominent Alzheimer's disease risk gene may disrupt endocytosis in astrocytes. Moreover, the team of scientists at The Picower Institute for Learning and Memory at MIT and the Whitehead Institute for Biomedical Research found that increasing the expression of another Alzheimer's-associated gene in those cells could help alleviate the problem. Their findings were published in Cell Reports.

As part of their work, the team also found that in APOE4-carrying astrocytes, increasing expression of an Alzheimer's associated gene called PICALM reversed the endocytosis defects. "Both APOE and PICALM are Alzheimer's risk genes," said Li-Hue Tsai, corresponding author. "It is really interesting that the two genes converge on endocytosis. This indicates that faulty endocytosis plays a key role in the etiology of Alzheimer's."

By engineering human APOE3 and APOE4 into yeast cells, the team was able to replicate clear signs of APOE4's early endocytic disruption. Once they knew they could use yeast as a model, they set out to look for endocytosis proteins that could rescue the observed defect if manipulated. They found one: a yeast protein called Yap1802p. When they made the yeast cells express extra Yap1802p, early endocytosis proteins were produced at normal levels, endocytosis function operated better and APOE4 cells, which had failed to grow as healthfully as APOE3 cells did, exhibited better growth. Importantly, the gene that encodes Yap1802p has a human counterpart: PICALM. Studies have shown PICALM to have a complex but significant role in affecting Alzheimer's disease risk.

With their results in yeast, the research team returned to their human astrocyte cultures. Overexpressing PICALM in APOE4 astrocytes repaired early endocytosis function, as measured by the increased intake of test proteins. But they also saw that overexpressing PICALM in APOE3 astrocytes caused an endocytosis defect, illustrating that the effects of PICALM varies markedly in astrocytes based on APOE variant.