BDNF Pathway
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BDNF Pathway
Neurotrophins are required for the development and maintenance of the nervous system. The neurotrophin family consists of NGF (Nerve Growth Factor), BDNF (Brain Derived Neurotrophic Factor), NT3 (Neurotrophin-3), and NT4 (Neurotrophin-4). The functions of the neurotrophins are mediated by interacting with the TRK (Tyrosine Kinase) receptors: NGF with TRKA, BDNF and NT4 with TRKB, and NT3 with TRKC. Consequently, TRK receptor tyrosine kinases are activated, triggering multiple signaling pathways. The internalized TRK receptor remains tyrosine phosphorylated and activated, with its extracellular domain bound to the ligand neurotrophin inside the signaling endosomes, and the intracellular domain tightly associated with a number of signaling molecules such as PLC-Gamma (Phospholipase-C), PI3K (Phosphatidylinositol 3-Kinase), and proteins of the Ras-MAPK (Mitogen-Activated Protein Kinase) pathway in the cytoplasm of the responsive neurons (Ref.1).

BDNF, like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. BDNF is produced by neurons, particularly in the hippocampus and cortex and can be transported into the dendrite and may also be synthesized locally in the spine. The cellular actions of BDNF are mediated through two types of receptors: a high-affinity TRKB and a low-affinity pan-neurotrophin receptor p75 (Ref.2). Binding of BDNF initiates TRKB dimerization and transphosphorylation of tyrosine residues in its cytoplasmic domain. The phosphotyrosine residues of TRKB receptor function as binding sites for recruiting specific cytoplasmic signaling and scaffolding proteins. Binding of cytoplasmic SHC (Src Homology domain-containing adaptor protein) scaffolding proteins results in recruitment of a complex of adaptors like GRB2 (Growth Factor Receptor-Bound Protein-2) and the Ras exchange factor of SOS to the membrane, thereby stimulating transient activation of Ras (Ref.5). Ras, in turn activates PI3K, MEK1/2(MAPK/ERK Kinase) pathway, and the c-Raf/ERK1/2 (Extracellular Signal-Regulated Kinase) pathway. PI3K can also be activated through the adaptor proteins, SHC, GRB2 and GAB1 (GRB2-Associated Binding Protein-1). Phosphorylated GRB2 provides a docking site for GAB1, which in turn is bound by PI3K. However, Ras-dependent activation of PI3K is the most important pathway through which the neurotrophins promote cell survival. PI3K directly regulates certain survival pathways by activating Akt1. Among the targets of ERK are the RSKs (Ribosomal S6 Kinases). Both RSK and MEK phosphorylate CREB (cAMP Response Element Binding protein) and other transcription factors. RSK and Akt1 also phosphorylate BAD (BCL2 Associated Death Promoter) and thereby promote its inactivation. Once phosphorylated, however, the BAD protein can be complexed by 14-3-3 proteins in the cytoplasm, which prevents the association with the mitochondrially localized BCL-XL (BCL2 Related Protein Long Isoform) and BCL2 (B-Cell CLL/Lymphoma-2) and therefore inhibits apoptosis. Another signaling pathway activated by TRK involves PLC-Gamma resulting in IP3 (Inositol 1,4,5-trisphosphate) and DAG (Diacylglycerol)-mediated signals. IP3 causes an early rapid increase in Ca2+ through its release from intracellular stores (Ref.3). DAG activates PKC (Protein Kinase-C), increasing the sensitivity of the contractile apparatus to Ca2+ as well as inducing intracellular signaling mechanisms that promote long-term cellular responses (proliferation and migration). High-frequency neuronal activity and synaptic transmission also activate CalmKIV (Calcium/Calmodulin-dependent protein Kinase-IV) and facilitate the synaptic action of BDNF.

BDNF is a potent physiological survival factor that has also been implicated in a variety of pathophysiological conditions, such as Parkinson disease, Alzheimer Disease, and diabetic peripheral neuropathy. It is an important factor in psychiatric conditions such as epilepsy, depression, obsessive-compulsive disorder, and possibly bipolar disorder (Ref.4). It also improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex. Beyond promoting neuronal survival and resilience to injury, BDNF also has a powerful role in facilitating activity-dependent plasticity, which underlies the capacity for learning and memory. Brain regions where plasticity is particularly important include the hippocampus and cortex, critical centers for learning and memory. The reduction of BDNF seen in AD cripples the hippocampus in two ways: weaken synaptic encoding strength or capacity, and make the hippocampal neurons more vulnerable to insult and degeneration.