Geon Neurodegeneration: From BDNF to Hyperexcitability



Brain-derived neurotrophic factor (BDNF) plays a pivotal role in cell differentiation, neuronal survival, and synaptic plasticity. Most neurodegenerative disorders are associated with both BDNF deficiency and neuronal hyperexcitability. This paper shows that the two abnormalities can be linked by the microRNA, miR-132, which is critical for regulating Tau expression. According to the MT model for excitability (Paper 2), increased Tau level, especially the 4-repeat (4R) Tau, should enhance excitability. The BDNF-TrkB pathway stimulates miR-132 expression. Hence, BDNF deficiency should lead to miR-132 deficiency, resulting in higher 4R Tau level, and consequently hyperexcitability. Pathologic TAR DNA-binding protein 43 (TDP-43) and C9ORF72 have been shown to reduce miR-132 biogenesis, which may contribute to the development of Tau-positive neurodegeneration.


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