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Severe cognitive deficits are a frequent outcome of both neurodegenerative and neurodevelopmental disorders. In the attempt to define new clinical biomarkers, current research trends aim at the identification of common molecular features in these pathologies rather than searching for differences. Brain-derived neurotrophic factor (BDNF) has attracted great interest as possible biomarker because of its key role in synaptic remodeling during cognitive processes. BDNF undergoes proteolytic processing and studies in animal models have highlighted that different forms of learning and memory require either the proBDNF precursor or the mature BDNF form. Significantly, an altered expression of BDNF forms was found in postmortem brains and serum from patients with schizophrenia, Alzheimer's disease and mood disorders. Based on these studies, this review puts forward the hypothesis that abnormalities in proBDNF or mBDNF biosynthesis may correspond to different cognitive dysfunctions in these brain diseases, while the role of truncated BDNF remains unknown.

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Brain-derived neurotrophic factor (BDNF) represents promotesa key molecule for the survival and differentiation of specific populations of neurons in the central nervous system. BDNF also regulates plasticity-related processes underlying memory and learning. A common single nucleotide polymorphism (SNP) rs6265 has been identified on the coding sequence of human BDNF located at 11p13. The SNP rs6265 is a single base mutation with an adenine instead of a guanine at position 196 (G196A), resulting in the amino acid substitution Val66Met. This polymorphism only exists in humans and has been associated with a plethora of effects ranging from molecular, cellular and brain structural modifications in association with deficits in social and cognitive functions. To date, the literature on Val66Met polymorphism describes a complex and often conflicting pattern of effects. In this review, we attempt to provide a unifying model of the Val66Met effects. We discuss the clinical evidence of the association between Val66Met and memory deficits, as well as the molecular mechanisms involved including the reduced transport of BDNF mRNA to the dendrites as well as the reduced processing and secretion of BDNF protein through the regulated secretory pathway.