Article

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.

0 Followers
 · 
143 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerebrovascular amyloidosis is caused by amyloid accumulation in walls of blood vessel walls leading to hemorrhagic stroke and cognitive impairment. Transforming growth factor-β1 (TGF-β1) expression levels correlate with the degree of cerebrovascular amyloid deposition in Alzheimer's disease (AD) and TGF-β1 immunoreactivity in such cases is increased along the cerebral blood vessels. Here we show that a nasally administered proteosome-based adjuvant activates macrophages and decreases vascular amyloid in TGF-β1 mice. Animals were nasally treated with a proteosome-based adjuvant on a weekly basis for 3 months beginning at age 13 months. Using magnetic resonance imaging (MRI) we found that while control animals showed a significant cerebrovascular pathology, proteosome-based adjuvant prevents further brain damage and prevents pathological changes in the blood-brain barrier. Using an object recognition test and Y-maze, we found significant improvement in cognition in the treated group. Our findings support the potential use of a macrophage immunomodulator as a novel approach to reduce cerebrovascular amyloid, prevent microhemorrhage, and improve cognition.
    Neurobiology of aging 03/2011; 33(2):432.e1-432.e13. DOI:10.1016/j.neurobiolaging.2011.01.006 · 4.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunotherapy has emerged as a leading new approach to the reduction of amyloid deposits in the brains of Alzheimer patients. At least 4 distinct actions of anti-Abeta antibodies have been proposed as contributing to the inhibition of amyloid deposition and its clearance. Critically, each of these proposed mechanisms may be acting simultaneously, and it is feasible that different antibodies may utilize each mechanism to a different extent. One of these proposed mechanisms involves the activation of microglia and the phagocytosis of Abeta peptide. In general this is assumed to proceed through the Fcgamma-receptor binding by antibody opsonized Abeta aggregates, however modifying the microglial phenotype into one with a greater propensity for phagocytosing Abeta is also feasible, as microglia avidly phagocytose Abeta in vitro without antibody present. Evidence is presented supporting arguments that microglial activation does play a role in amyloid removal, particularly compacted amyloid deposits, under certain conditions. In addition to the specific antibody used, other considerations in comparing different reports of antibody action in APP mice include the age of the mice, the extent of pre-existing amyloid when therapy is initiated, the time point when the effects of the therapy are examined and the route of antibody administration. Future questions will consider the source of the activated microglia near the plaques after antibody administration (resident or peripheral) and the extent to which shifts in the microglial phenotype mediate some of the amyloid lowering actions of immunotherapy.
    CNS & neurological disorders drug targets 04/2009; 8(1):7-15. DOI:10.2174/187152709787601821 · 2.70 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Experimental and clinical data have demonstrated that activating the immune system in the CNS can be destructive. However, other studies have shown that enhancing an immune response can be therapeutic, and several clinical trials have been initiated with the aim of boosting immune responses in the CNS of individuals with spinal cord injury, multiple sclerosis and Alzheimer's disease. Here, we evaluate the controversies in the field and discuss the remaining scientific challenges that are associated with enhancing immune function in the CNS to treat neurological diseases.
    Nature Reviews Neuroscience 07/2008; 9(6):481-93. DOI:10.1038/nrn2398 · 31.38 Impact Factor

Preview

Download
0 Downloads
Available from