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• W1991466569 abstract "It has been well documented that neurotrophins, including brain-derived neurotrophic factor (BDNF), are severely affected in Alzheimer9s disease (AD) but their administration faces a myriad of technical challenges. Here we took advantage of the early astrogliosis observed in an amyloid mouse model of AD (5xFAD) and used it as an internal sensor to administer BDNF conditionally and locally. We first demonstrate the relevance of BDNF release from astrocytes by evaluating the effects of co-culturing wild type neurons and BDNF-deficient astrocytes. Next, we crossed 5xFAD mice with pGFAP:BDNF mice (only males were used) to create 5xFAD mice that over-express BDNF when and where astrogliosis is initiated (5xF:pGB mice). We evaluated the behavioral phenotype of these mice. We first found that BDNF from astrocytes is crucial for dendrite outgrowth and spine number in cultured wild type neurons. Double mutant 5xF:pGB mice displayed improvements in cognitive tasks as compared to 5xFAD littermates. In these mice, there was a rescue of BDNF/TrkB downstream signaling activity associated with an improvement of dendritic spine density and morphology. Clusters of synaptic markers, PSD-95 and synaptophysin, were also recovered in 5xF:pGB as compared to 5xFAD mice as well as the number of pre-synaptic vesicles at excitatory synapses. Additionally, experimentally-evoked LTP <i>in vivo</i> was increased in 5xF:pGB mice. The beneficial effects of conditional BDNF production and local delivery at the location of active neuropathology highlight the potential to use endogenous biomarkers with early onset such as astrogliosis as regulators of neurotrophic therapy in AD. <b>Significance statement</b> Recent evidence places astrocytes as pivotal players during synaptic plasticity and memory processes. In the present work we first provide evidence that astrocytes are essential for neuronal morphology via BDNF release. We then crossed transgenic mice (5xFAD mice) with the transgenic pGFAP-BDNF mice which express BDNF under the glial fibrillary astrocytic protein (GFAP) promoter. The resultant double mutant mice 5xF:pGB mice displayed a full rescue of hippocampal BDNF loss and related signaling compared with 5xFAD mice and a significant and specific improvement in all the evaluated cognitive tasks. These improvements did not correlate with amelioration of beta amyloid load or hippocampal adult neurogenesis rate but were accompanied by a dramatic recovery of structural and functional synaptic plasticity." @default.
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• W1991466569 date "1992-04-01" @default.
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• W1991466569 title "Spatial delirium following a right subcortical infarct with frontal deactivation." @default.
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• W1991466569 doi "https://doi.org/10.1136/jnnp.55.4.334" @default.
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