We assessed whether peripheral activation of microglia by a nasal proteosome‐based adjuvant (Protollin) that has been given safely to humans can prevent amyloid deposition in young mice and affect amyloid deposition and memory function in old mice with a large amyloid load.

Amyloid precursor protein (APP) transgenic (Tg) J20 mice received nasal treatment with Protollin weekly for 8 months beginning at age 5 months. Twenty‐four‐month‐old J20 mice were treated weekly for 6 weeks.

We found reduction in the level of fibrillar amyloid (93%), insoluble β‐amyloid (Aβ; 68%), and soluble Aβ (45%) fragments in 14‐month‐old mice treated with Protollin beginning at age 5 months. Twenty‐four‐month‐old mice treated with nasal Protollin for 6 weeks had decreased soluble and insoluble Aβ (1‐40) and (1‐42) and improved memory function. Activated microglia (CD11b⁺ cells) colocalized with Aβ fibrils in the 24‐month‐old animals, and microglial activation correlated with the decrease in Aβ. No microglial activation was observed in 14‐month‐old mice, suggesting that once Aβ is cleared, there is downregulation of microglial activation. Both groups had reduction in astrocytosis. Protollin was observed in the nasal cavity and cervical lymph node but not in the brain. Activated CD11b⁺SRA⁺ (scavenger receptor A) cells were found in blood and cervical lymph node and increased interleukin‐10 in cervical lymph node. No toxicity was associated with treatment.

Our results demonstrate a novel antibody‐independent immunotherapy for both prevention and treatment of Alzheimer's disease that is mediated by peripheral activation of microglia with no apparent toxicity. Ann Neurol 2008;63:591–601