P4‐444: Development of a novel beta amyloid vaccine to treat Alzheimer's disease

domly allocated into one of 4 possible factorial conditions: 1) 6 weeks VR plus sham transplant (VR+SHAM), 2) 6 weeks VR plus skin-derived neuroprecursor transplantation (VR+NPC), 3) NPC transplantation plus 6 weeks standard housing (SH+NPC), and 4) standard housing plus sham surgery (SH+SHAM). Preand posttesting included place and object recognition memory tests (PRM and ORM). After sacrifice, hippocampal synaptic density, neurogenesis, NPCmigration and survival were measured based on single and combined histological markers. Results: Older rats were impaired on PRM but not ORM compared to 3-month old animals, which correlated with loss of synaptic density in several hippocampal subfields. VR by itself led to the restoration of synaptic density and synaptic network topology, which together predicted improvement in PRM performance (Effect size relative to SH+SHAM d 1⁄4 1.89). VR stimulated neurogenesis, but this was not linked to PRM or ORM. Intrahippocampal NPC transplantation also led to PRM improvement (d 1⁄4 1.07), however, NPC+VR led to better PRM outcomes (d1⁄4 1.74). Preliminary mapping of NPCmigration and survival shows that VR increases the likelihood of transplanted cells engrafting into the dentate gyrus. Conclusions: Epidemiological and clinical studies suggest that physical exercise may be an effective preventative strategy against dementia. By contrast, cell therapy remains an experimental approach in animals, where control of cell fate is a major obstacle to clinical translation. Here, in a naturalistic animal model of memory dysfunction, we show that VR plus cell therapy leads to better memory outcomes than cell therapy alone. The mechanism for this interaction may involve enhanced donor cell targeting into hippocampal memory circuits.