Delta Secretase and BDNF Signalling in Alzheimer's Disease

As one of the major contributors of the central nervous system, neurons require neurotrophic factors, which are synthesized from neighbouring cells, for several cellular processes, such as neuronal survival, growth, and differentiation. Neurotrophic factors are categorized into the neurotrophin family, the neuropoietic cytokines, and the glial cell-derived neurotrophic factor. The neurotrophin family comprises four growth factors: nerve growth factor (NGF), neurotrophin-3 (NT3), neurotrophin-4 (NT4), and brain-derived neurotrophic factor (BDNF). One of the best-known neurotrophic factors is BDNF. Its importance is based on its central role in neuronal survival. Entry of the BDNF into the neurons occurs via TrkB receptors, and it is transported to the cell body along microtubules in axons. As it is known in the brains of Alzheimer's patients, the axonal transport of BDNF is destructed via the hyperphosphorylated tau. There are several causes for the hyperphosphorylation of tau. Among them, delta secretase (delta-secretase), a lysosomal cysteine protease, cleaves both amyloid precursor protein (APP) and tau. It is supposed to play an essential role in tau hyperphosphorylation, particularly in the aging brain. In this review, we focus on the activity of delta-secretase, how it leads to tau hyperphosphorylation, and how it disrupts the axonal transport of BDNF in Alzheimer's disease.