Alzheimer's disease (AD) affects over 50 million people worldwide and is the sixth leading cause of death in North America with no cure and limited disease-modifying therapies. Brain-derived neurotrophic factor (BDNF) is a potential therapeutic agent, as it promotes the survival and synaptic plasticity of glutamatergic and GABAergic neurons in brain regions associated with cognitive and emotive decline in AD, and mice lacking BDNF exhibits hippocampal long-term potentiation (LTP) impairment, reversible with recombinant BDNF. However, the poor blood-brain barrier (BBB) permeability and pharmacokinetic properties of BDNF limit its clinical use. To address these limitations, a BDNF nanocarrier system is designed using a novel BBB-permeable terpolymer (TP). This terpolymer-based nanoparticle system (BDNF-TPN) with optimized physiochemical properties protects BDNF in circulation and enables sufficient neuronal delivery of BDNF and neuron survival following Aβ exposure in vitro. The biodistribution and safety of BDNF-TPN are evaluated via imaging, enzyme-linked immunosorbent assay, hematologic, clinical biochemical, immunotoxicity, and histology tests. Biomarker studies demonstrate BDNF-mediated neuroprotective signaling in an APP transgenic mouse model following intravenous injection of BDNF-TPN with reduced apoptosis and neuron inflammation and increased neuronal survival and synaptic plasticity. Improved hippocampal-dependent contextual learning in APP transgenic Alzheimer's mice is observed as determined by fear-conditioning assay following two months of weekly treatments.