Role of SORLA in Transport of TrkB and APP in Alzheimer's Disease

Progress Updates

Two well-documented risk factors in Alzheimer's disease (AD) are accelerated breakdown of the APP protein into beta-amyloid (Abeta), and insufficient support for nerve cells from the protective protein, called BDNF. Intriguingly, both pathways converge on yet another established AD risk gene that produces the neuronal sorting receptor protein, called SORLA. A more detailed understanding of how these pathways are interconnected in the healthy and in the diseased brain is the major aim of this project. Dr. Rohe’s team is evaluating the therapeutic potential of SORLA to reduce toxicity for neurons (caused by too much Abeta) and to reinstate support of neurons (caused by poor BDNF signals).

So far, Dr. Rohe’s team was able to document that SORLA not only regulates the breakdown of APP but also the transport of the BDNF receptor, called TrkB. Binding of BDNF to TrkB is central for supporting the function and survival of neurons. Because of the impaired transport of TrkB, BDNF signals received by neurons lacking SORLA are reduced. This reduction renders affected neurons vulnerable and disrupts their proper function. In support of this hypothesis, Dr. Rohe identified that SORLA deficiency disrupts the function of several brain proteins that are important for proper communication between nerve cells. Intriguingly, the disruption of these proteins coincided with impaired learning and memory in SORLA-deficient mice, further underscoring the relevance of this signaling pathway for cognitive functions. Since low levels of SORLA have been documented in AD patients, Dr. Rohe’s data provide an explanation of how low levels of the receptor protein may translate into memory deficits.