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: 11.91). 05/2008; 63(5):591-601. DOI: 10.1002/ana.21340
Source: PubMed

ABSTRACT 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.

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    • "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. "
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    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 · 4.90 Impact Factor
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    • "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]. "
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    Journal of Neuroinflammation 06/2012; 9(1):120. DOI:10.1186/1742-2094-9-120 · 4.90 Impact Factor
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    • "Protollin was obtained from GlaxoSmithKline (Laval, Quebec, Canada). Protollin (28.6μg/ kg) was given on days 1, 3, and 5 of the first week followed by a weekly boost (Frenkel, et al., 2008). Mice received a weekly boost beginning at age 13 months until age 16 months. "
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