Biological Activity of a Neurotrophin Precursor and Mechanism of Neurotrophin Dysregulation in Neurodenerative Diseases

Abstract

Neurotrophins, such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), are key factors in neuronal survival and function. In Alzheimer's disease (AD), there is a change in the normal level of these neurotrophins and their precursors (proNGF and proBDNF). The mechanism/s underlying changes in the levels of these neurotrophins in AD is not fully understood. According to the amyloid cascade hypothesis, amyloid-β is the original insult in AD and tau pathology is a downstream event. Amyloid-β interferes with axonal transport and reduces BDNF levels. However, it is not clear if amyloid-β affects neurotrophin levels directly or through tau hyperphosphorylation. If tau is responsible for changes in the level of neurotrophins in AD, we expect to observe the same alteration in neurotrophin levels in other diseases with tau dysfunction such as tauopathies. We tested the levels of BDNF mRNA and proNGF protein in subjects with tauopathies. We observed significant decrease in BDNF mRNA levels in subjects with Corticobasal degeneration. Our result suggests that BDNF may be down-regulated by tau hyperphosphorylation. Moreover, we showed that there was a significant increase in the level of proNGF in Pick's disease (PiD). Interestingly, AD and PiD share common tau modifications. Our result demonstrates a role for tau dysfunction in changes in the level of proNGF. Therefore, study of the levels of NGF and BDNF in non-AD tauopathies has shed light on the mechanisms underlying neurotrophin dysregulation in AD. How do increased levels of proNGF impact the brain in AD or PiD? Is neuronal degeneration in AD or PiD due to the lack of neurotrophic support of proNGF or do increased levels of apoptotic proNGF cause neurodegeneration? Lee et al. (2001b) and Fahnestock et al. (2004a) produced two different cleavage-resistant proNGFs with opposite activities (apoptotic versus neurotrophic). Structural and procedural differences between the two cleavage resistant proNGFs and different bioassays can cause opposite activities. We showed that proNGF from Lee's lab was neurotrophic when it was expressed in the expression system used by Fahnestock et al. or when it was purified. ProNGF expressed in a different expression system was also neurotrophic. ProNGF was neurotrophic in all bioassays except the serum withdrawal assay. We conclude that proNGF is normally neurotrophic but may be apoptotic when cell survival is already compromised. We propose that in AD, cells undergo degeneration due to the lack of neurotrophic support of proNGF (impaired transport). Moreover, TrkA is downregulated in AD which compromises cell survival and may lead to apoptosis induced by increased levels of proNGF.