Hippocampal BDNF encapsulated cell bio‐delivery improves spontaneous behavioral alternations in the Y‐maze test in AppNL‐G‐F mice.

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is an age‐related disease characterized by synaptic dysfunction, brain inflammation, and neurodegeneration against which there is no effective cure available. Brain‐Derived Neurotrophic Factor (BDNF) is a key molecule involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain permeability. In this study, we used an innovative encapsulated cell biodelivery (ECB) device containing cells capable of locally delivering BDNF to characterize its neuroprotective effects in the novel AD APP‐knock‐in mouse model AppNL‐G‐F.MethodECB devices with human ARPE‐19 cells modified to release BDNF were surgically bilaterally implanted in the hippocampus of 3‐month‐old AppNL‐G‐F mice. BDNF effects on AD pathology were evaluated after 1, 2, and 3 months of treatment by immunohistochemical and biochemical analysis. In the 3‐month‐treated groups, exploratory and memory performances were also evaluated using Elevated Plus Maze (EPM) and Y‐maze tests.ResultThe ECB implants were well tolerated with no signs of unwanted side effects or weight loss. A high BDNF staining was detected in most of the brains in the area surrounding the devices at 1‐3 months, but retrieved devices showed variability of BDNF release. Interestingly, three months of BDNF treatment significantly improved AppNL‐G‐F mice´s anxiety behavior in EPM and improved the spontaneous behavioral alternations in the Y‐maze test.ConclusionThe results of this study are encouraging and support the BDNF device as a promising approach for treating cognitive AD decline. Optimization of the mouse‐sized devices to reduce the variability of BDNF release is needed for future experiments and translated to larger devices for clinical translation.