A nasal proteosome adjuvant activates microglia and prevents amyloid deposition

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Annals of Neurology (Impact Factor: 9.98). 05/2008; 63(5):591-601. DOI: 10.1002/ana.21340
Source: PubMed


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 beta-amyloid (Abeta; 68%), and soluble Abeta (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 Abeta (1-40) and (1-42) and improved memory function. Activated microglia (CD11b+ cells) colocalized with Abeta fibrils in the 24-month-old animals, and microglial activation correlated with the decrease in Abeta. No microglial activation was observed in 14-month-old mice, suggesting that once Abeta 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.

Full-text preview

Available from:
  • Source
    • "Additionally, intrahippocampal injections of lipopolysaccharide (LPS) activated microglia to reduce diffuse Aβ deposits in Tg2576 mice (Herber et al., 2004, 2007). Moreover, intranasal immunization with the proteosomebased adjuvant and TLR2 agonist Protollin was also shown to decrease amyloid plaque formation in correlation with microglial activation (Chabot et al., 2007; Frenkel et al., 2008). Despite these beneficial effects, cellular-mediated clearance of Aβ may also elicit adverse side effects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Antibody-mediated capture of amyloid-beta (Aβ) in peripheral blood was identified as an attractive strategy to eliminate cerebral toxic amyloid in Alzheimer's disease (AD) patients and murine models. Alternatively, defective capacity of peripheral monocytes to engulf Aβ was reported in individuals with AD. In this report, we developed different approaches to investigate cellular uptake and phagocytosis of Aβ, and to examine how two immunological devices - an immunostimulatory Adjuvant System and different amyloid specific antibodies - may affect these biological events. Between one and thirteen months of age, APPswe X PS1.M146V (TASTPM) AD model mice had decreasing concentrations of Aβ in their plasma. In contrast, the proportion of blood monocytes containing Aβ tended to increase with age. Importantly, the TLR-agonist containing Adjuvant System AS01B primed monocytes to promote de novo Aβ uptake capacity, particularly in the presence of anti-Aβ antibodies. Biochemical experiments demonstrated that cells achieved Aβ uptake and internalization followed by Aβ degradation via mechanisms that required effective actin polymerization and proteolytic enzymes such as insulin-degrading enzyme. We further demonstrated that both Aβ-specific monoclonal antibodies and plasma from Aβ-immunized mice enhanced the phagocytosis of 1 μm Aβ-coated particles. Together, our data highlight a new biomarker testing to follow amyloid clearance within the blood and a mechanism of Aβ uptake by peripheral monocytes in the context of active or passive immunization, and emphasize on novel approaches to investigate this phenomenon. Copyright © 2015. Published by Elsevier B.V.
    Journal of immunological methods 05/2015; 366. DOI:10.1016/j.jim.2015.05.002 · 1.82 Impact Factor
  • Source
    • "CD11b (CR3) has been used as one of a handful of microglial activation markers. In the mouse, CD11b labels ramified resting microglia, while GFAP labels astrocytes and the intensity of the staining is generally increased with inflammatory stimuli [29,30]. There is an assumption in the field that microglial activation and astrogliosis correspond to high levels of pro-inflammatory cytokines such as IL-1β and IL-6. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The polarization to different neuroinflammatory phenotypes has been described in early Alzheimer’s disease, yet the impact of these phenotypes on amyloid-beta (Aβ) pathology remains unknown. Short-term studies show that induction of an M1 neuroinflammatory phenotype reduces Aβ, but long-term studies have not been performed that track the neuroinflammatory phenotype. Methods Wild-type and APP/PS1 transgenic mice aged 3 to 4 months received a bilateral intracranial injection of adeno-associated viral (AAV) vectors expressing IFNγ or green fluorescent protein in the frontal cortex and hippocampus. Mice were sacrificed 4 or 6 months post-injection. ELISA measurements were used for IFNγ protein levels and biochemical levels of Aβ. The neuroinflammatory phenotype was determined through quantitative PCR. Microglia, astrocytes, and Aβ levels were assessed with immunohistochemistry. Results AAV expressing IFNγ induced an M1 neuroinflammatory phenotype at 4 months and a mixed phenotype along with an increase in Aβ at 6 months. Microglial staining was increased at 6 months and astrocyte staining was decreased at 4 and 6 months in mice receiving AAV expressing IFNγ. Conclusions Expression of IFNγ through AAV successfully induced an M1 phenotype at 4 months that transitioned to a mixed phenotype by 6 months. This transition also appeared with an increase in amyloid burden suggesting that a mixed phenotype, or enhanced expression of M2a and M2c markers, could contribute to increasing amyloid burden and disease progression.
    Journal of Neuroinflammation 07/2014; 11(1):127. DOI:10.1186/1742-2094-11-127 · 5.41 Impact Factor
  • Source
    • "It was reported that SRA, expressed on microglia and macrophages, plays a role in mediating clearance of neurotoxic β-amyloid plaques in CNS tissues in Alzheimer’s disease animal models [13,14]. Along with other receptors of the SR family, such as class B2 scavenger receptors or CD36 [15], RAGE [16] and others [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by damage to the neuronal myelin sheath. One of the key effectors for inflammatory injury is the antigen-presenting cell (APC). The class A scavenger receptor (SRA), constitutively expressed by APCs, such as macrophages and dendritic cells in peripheral tissues and the CNS, was shown to play a role in the phagocytosis of myelin; however, the role of SRA in the development of experimental autoimmune encephalomyelitis (EAE) and autoimmune reaction in the periphery has not yet been studied. We investigated EAE progression in wild-type (WT) vs. SRA-/- mice using clinical score measurements and characterized CNS pathology using staining. Furthermore, we assessed SRA role in mediating anti myelin pro-inflammatory response in cell cultures. We discovered that EAE progression and CNS demyelination were significantly reduced in SRA-/- mice compared to WT mice. In addition, there was a reduction of infiltrating peripheral immune cells, such as T cells and macrophages, in the CNS lesion of SRA-/- mice, which was associated with reduced astrogliosis. Immunological assessment showed that SRA deficiency resulted in significant reduction of pro-inflammatory cytokines that play a major role in EAE progression, such as IL-2, IFN-gamma, IL-17 and IL-6. Furthermore, we discovered that SRA-/- APCs showed impairments in activation and in their ability to induce pro-inflammatory CD4+ T cell proliferation. Expression of SRA on APCs is important for CD4+ T-cells proliferation in EAE mouse model. Further studies of SRA-mediated cellular pathways in APCs may offer useful insights into the development of MS and other autoimmune diseases, providing future avenues for therapeutic intervention.
    Journal of Neuroinflammation 06/2012; 9(1):120. DOI:10.1186/1742-2094-9-120 · 5.41 Impact Factor
Show more