A nasal proteosome adjuvant activates microglia and prevents amyloid deposition

Abstract

Objective: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. Methods: 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. Results: We found reduction in the level of fibrillar amyloid (93%), insoluble ␤-amyloid (A␤; 68%), and soluble A␤ (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 A␤ (1-40) and (1-42) and improved memory function. Activated microglia (CD11b ϩ cells) colocalized with A␤ fibrils in the 24-month-old animals, and microglial activation correlated with the decrease in A␤. No microglial activation was observed in 14-month-old mice, suggesting that once A␤ 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 ϩ SRA ϩ (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.Interpretation: 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.

CNS inflammation and neurodegeneration

“…We have found that nasal administration of a proteosome-based adjuvant (Protollin) induced monocytes that cleared fibrillar amyloid, insoluble Aβ, and soluble Aβ fragments successfully in aged amyloid precursor protein-transgenic (APP-transgenic) mice (170). A clinical trial in AD subjects is planned.…”

Microglia in Alzheimer’s disease: A multifaceted relationship

“…The single intrahippocampal injection of the powerful toll-like receptor-4 (TLR4) ligand lipopolysaccharide (LPS) (2 or 4 µg/µl in 0.9% NaCl) significantly reduced cerebral Aβ load in APPswe/PS1 mice (DiCarlo et al, 2001). Additionally, the nasal vaccination with a proteosome-based adjuvant that contained purified outer membrane proteins of Neisseria meningitides and LPS decreased cerebral Aβ load in PDGF-APPswe/ind mice (Frenkel et al, 2008). The decrease in cerebral Aβ load correlated with an enhanced recruitment of microglia to Aβ fibrils and upregulation of two potent receptors involved in microglia phagocytosis, namely CD11b and SR-A (Frenkel et al, 2008).…”

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

“…RT-PCR assays were designed by Applied Biosystems (Foster City, CA) and compared with ␤-actin (ACTB) RNA levels. 29 The comparative Ct method was used for quantification of transcripts according to the manufacturer's protocol. Measurement of ⌬Ct was performed in duplicate or triplicate.…”