Low Levels of Brain-Derived Neurotrophic Factor Trigger Self-aggregated Amyloid ß-Induced Neuronal Cell Death in an Alzheimer's Cell Model.

ABSTRACT

Alzheimer's disease (AD) is pathologically characterized by accumulation of amyloid ß (Aß) and hyperphosphorylated tau, and thereby induction of neuronal cell death. The Aß-induced neuronal cell death has been shown to occur by several modes, such as apoptosis, necrosis, and necroptosis. Interestingly, in AD patients, the brain and serum levels of brain-derived neurotrophic factor (BDNF) have been reported to be significantly decreased. However, the relationship between Aß and BDNF in the onset of AD remains to be fully understood. Here, we used neuron-like differentiated human neuroblastoma SH-SY5Y (ndSH-SY5Y) cells to study the neurotoxicity of self-aggregated Aß1-42 peptide under different concentrations of BDNF in the culture medium. Importantly, decreasing levels of BDNF caused a considerable suppression in the extension of neurite length. Furthermore, only under low levels of BDNF, the aggregated Aß was revealed to induce neurite fragmentation and neuronal cell death in ndSH-SY5Y cells. Notably, the aggregated Aß and low levels of BDNF-induced neuronal cell death was characterized at least as caspase-6 dependent cell death and necroptosis. These results indicate that our ndSH-SY5Y cell system, cultured under decreasing levels of BDNF and aggregated Aß, has the potential to be applied in the analysis of the molecular mechanisms of the progressive neurodegenerative processes of AD and the discovery of neuroprotective drug candidates.