Brothers in arms: proBDNF/BDNF and sAPP alpha/A beta-signaling and their common interplay with ADAM10, TrkB, p75NTR, sortilin, and sorLA in the progression of Alzheimer's disease

Brain-derived neurotrophic factor (BDNF) is an important modulator for a variety of functions in the central nervous system (CNS). A wealth of evidence, such as reduced mRNA and protein level in the brain, cerebro-spinal fluid (CSF), and blood samples of Alzheimer's disease (AD) patients implicates a crucial role of BDNF in the progression of this disease. Especially, processing and subcellular localization of BDNF and its receptors TrkB and p75 are critical determinants for survival and death in neuronal cells. Similarly, the amyloid precursor protein (APP), a key player in Alzheimer's disease, and its cleavage fragments sAPP alpha and A(3 are known for their respective roles in neuroprotection and neuronal death. Common features of APP-and BDNF-signaling indicate a causal relationship in their mode of action. However, the in-terconnections of APP-and BDNF-signaling are not well understood. Therefore, we here discuss dimerization properties, localization, processing by alpha-and gamma-secretase, relevance of the common interaction partners TrkB, p75, studies sorLA, and sortilin as well as shared signaling pathways of BDNF and sAPP alpha.