Dentate gyrus granule cells show stability of BDNF protein expression in mossy fiber axons with age and resistance to Alzheimer's disease neuropathology in a mouse model.

Abstract

The brain-derived neurotrophic factor (BDNF) is important in development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and never in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild type (WT) mice of both sexes were examined at 2–3 months of age, when amyloid-β (Aβ)is present in neurons but plaques are absent, and 11–20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either genotype or sex. Notably, MF BDNF protein was correlated with GC ΔFosB, a transcription factor that increases after 1–2 weeks of elevated neuronal activity. We also report the novel finding that Aβ in GCs or the GC layer was minimal even at old ages. Results indicate MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity-dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect other vulnerable neurons from increased Aβ levels and therefore has translational implications.Significance StatementDeclining hippocampal brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of Alzheimer's disease (AD). However, few studies have examined where hippocampal BDNF protein has its highest concentration, the dentate gyrus granule cell (GC) axons (mossy fibers; MFs). Using the well-established Tg2576 mouse model of AD, we found that MF BDNF did not decline with age, suggesting a notable exception to the idea that reduced hippocampal BDNF contributes to AD pathobiology. We also identified that Tg2576 GC activity correlates with MF BDNF protein, consistent with the activity-dependence of MF BDNF. In addition, Tg2576 GCs were relatively resistant to accumulation of amyloid-β, providing insight into AD resilience, which has significant therapeutic implications.