Understanding amyloid production

APP_BACE_biology-3
In a new study in Cell Reports, a group of scientists (including Rita Guerreiro and John Hardy, part of the Wellcome Trust Neurodegeneration Initiative) have tried to unpick the way in which brain cells make beta-amyloid, a key protein in Alzheimer’s disease. Here is what Rita had to say about the work:
The brains of Alzheimer’s disease patients are known to contain aggregates of beta-amyloid peptides. These peptides are generated after a larger protein (amyloid precursor protein, APP) is cleaved by a series of enzymes. One of those enzymes is BACE1. In theory, drugs that block or modulate BACE1 activity could prevent the accumulation of beta-amyloid and help treat AD.
Because of this, it is essential to completely understand how BACE1 works in the processing of APP. In this study Dr. Rajendran’s group went on to analyze, in a systematic way, the role of the cell’s major membrane-trafficking processes in amyloid production.
The results achieved by this study were possible because Dr. Rajendran’s group developed an advanced platform to assay BACE1 activity. When the authors combined this system with an unbiased RNA interference screen of Rab-GTPases (a group of proteins involved in the control of membranes within the cell), they were able to test  if any of these proteins modulated BACE1 activity. When complementing this elaborated system with a screen overexpressing Rab-GAPs (which inactivate specific Rab-GTPases) Rab11 was found to be the strongest positive regulator of BACE1. Additionally, silencing Rab11 in different cell lines reduced β-cleavage of APP and beta-amyloid production.
The authors were able to put together the membrane-trafficking events regulating beta-amyloid production by clearly demonstrating that although retromers and retromer-associated proteins control APP recycling, Rab11 controlled β-secretase endosomal recycling to the plasma membrane, affecting beta-amyloid production.
Read all about the study in Cell Reports online:
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