P3–342: Abeta upregulates BDNF production from astrocytes: Rescue of neurons from abeta–related synaptic impairment

Astrocytes, the most abundant type of glia in the brain, are considered to play a key role in Alzheimer's disease (AD) pathologies. We have previously shown that astroglial responses against Aβ occur before obvious neuronal damage can be detected. This finding suggests that the role of astrocytes during the early stages of AD pathology must be very important, implicating them as potential therapeutic targets for the treatment of AD. In the present study, we investigated how Aβ affects gene expression patterns in astrocytes during early stages of Aβ toxicity, and specifically focused our investigation on astrocyte–derived neurotrophic factors. We used rat primary cerebral cortical cultures and astrocyte cultures for investigating gene and protein expression patterns by using real–time PCR, ELISA and western blot analyses. We also used neuronally differentiated SH–SY5Y cells for investigating whether astrocyte–derived neurotrophic factors restore neuronal synapses after impairment was induced by Aβ treatment. For primary cortical and astrocyte cultures, Aβ peptides (5 μM) were added. For neuronally differentiated SH–SY5Y cells, Aβ peptides (10 μM) were added. We assessed the synapse–protective effect of astrocyte–derived neurotrophic factors by using western blot analyses and immunocytochemistry. Using real–time PCR and ELISA analyses, we found that Aβ induced astrocytes to produce brain–derived neurotrophic factor (BDNF) after 3 h of Aβ treatment. Western blot analyses showed that expression of the BDNF receptor TrkB increased in primary cerebral cortical cultures, the same time frame that expression of BDNF increased in astrocyte cultures. Expression of another BDNF receptor, p75NTR, however, significantly decreased during this time frame. These findings suggest that, relatively soon after exposure to Aβ, astrocytes produce BDNF, which in turn binds TrkB receptors in neurons, thereby upregulating neurotrophic signaling in neurons against Aβ. Moreover, BDNF treatment in neuronally differentiated human neuroblastoma cells rescued neurons from synaptic degeneration caused by Aβ toxicity. This is the first study to demonstrate that astrocytes are capable of increasing the production of a particular neurotrophic factor, BDNF, in response to Aβ. Our findings also identify BDNF as a potential therapeutic agent for preventing Aβ–related synaptic impairment.