Induction of Toll-Like Receptor 9 Signaling as a Method for Ameliorating Alzheimer's Disease-Related Pathology

Department of Neurology, New York University School of Medicine, New York, New York 10016, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2009; 29(6):1846-54. DOI: 10.1523/JNEUROSCI.5715-08.2009
Source: PubMed


The pathogenesis of Alzheimer's disease (AD) is thought to be related to the accumulation of amyloid beta (Abeta) in amyloid deposits and toxic oligomeric species. Immunomodulation is emerging as an effective means of shifting the equilibrium from Abeta accumulation to clearance; however, excessive cell mediated inflammation and cerebral microhemorrhages are two forms of toxicity which can occur with this approach. Vaccination studies have so far mainly targeted the adaptive immune system. In the present study, we have stimulated the innate immune system via the Toll-like receptor 9 (TLR9) with cytosine-guanosine-containing DNA oligodeoxynucleotides in Tg2576 AD model transgenic mice. This treatment produced a 66% and 80% reduction in the cortical (p = 0.0001) and vascular (p = 0.0039) amyloid burden, respectively, compared with nontreated AD mice. This was in association with significant reductions in Abeta42, Abeta40, and Abeta oligomer levels. We also show that treated Tg mice performed similarly to wild-type mice on a radial arm maze. Our data suggest that stimulation of innate immunity via TLR9 is highly effective at reducing the parenchymal and vascular amyloid burden, along with Abeta oligomers, without apparent toxicity.

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    • "Furthermore, stimulation of microglial cells with TLR2-, TLR4-, or TLR9-specific agonists accelerates Ab clearance both in vitro and in vivo (Michaud et al., 2013). It has been shown that the administration of the TLR9 agonist CpG oligonucleotides (ODN) containing unmethylated CpG sequences to AD model Tg2576 mice induced a reduction of cortical and vascular Ab levels, without apparent toxicity, and improved cognitive function, with a recent study in 3xTg mice showing the same approach also can reduce tau-related pathology in association with cognitive benefits (Scholtzova et al., 2009, 2014). Various CpG DNA drugs that are TLR9 agonists have been shown to be safe for both humans and rodents (Vollmer and Krieg, 2009). "
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    ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid β (Aβ) and tau proteins. Oligomeric forms of Aβ and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Aβ. However, there is very limited evidence in human studies of the clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self-protein; hence, benefits need to be balanced against risks of stimulating excessive autoimmune toxic inflammation. For greater efficacy the next generation of vaccines needs to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Aβ and tau species. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 03/2015; 85(6):1162-1176. DOI:10.1016/j.neuron.2014.12.064 · 15.05 Impact Factor
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    • "CpG ODN 1826 [5’-TCC ATG ACG TTC CTG ACG TT-3’ (CpG motifs in italics)], with a complete phosphorothioate backbone, was purchased from Integrated DNA Technologies. We used the same dose of CpG ODN 1826 as in our prior study, in which we stimulated the innate immune system in Tg2576 mice [9]. Controls were non-Tg 129/C57BL6 mice injected with saline on the same schedule. "
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    ABSTRACT: Alzheimer¿s disease (AD) is the most common cause of dementia, and currently, there is no effective treatment. The major neuropathological lesions in AD are accumulation of amyloid ß (Aß) as amyloid plaques and congophilic amyloid angiopathy, as well as aggregated tau in the form of neurofibrillary tangles (NFTs). In addition, inflammation and microglia/macrophage function play an important role in AD pathogenesis. We have hypothesized that stimulation of the innate immune system via Toll-like receptor 9 (TLR9) agonists, such as type B CpG oligodeoxynucleotides (ODNs), might be an effective way to ameliorate AD related pathology. We have previously shown in the Tg2576 AD model that CpG ODN can reduce amyloid deposition and prevent cognitive deficits. In the present study, we used the 3xTg-AD mice with both Aß and tau related pathology. The mice were divided into 2 groups treated from 7 to 20 months of age, prior to onset of pathology and from 11 to 18 months of age, when pathology is already present. We demonstrated that immunomodulatory treatment with CpG ODN reduces both Aß and tau pathologies, as well as levels of toxic oligomers, in the absence of any apparent inflammatory toxicity, in both animal groups. This pathology reduction is associated with a cognitive rescue in the 3xTg-AD mice. Our data indicates that modulation of microglial function via TLR9 stimulation is effective at ameliorating all the cardinal AD related pathologies in an AD mouse model mice suggesting such an approach would have a greater chance of achieving clinical efficacy.
    09/2014; 2(1):101. DOI:10.1186/PREACCEPT-2151623761356337
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    • "The total and soluble Aβ levels were measured using a combination of mouse monoclonal antibody 6E10 (specific to an epitope present on amino acid residues 1 to 16 of Aβ) and two different rabbit polyclonal antibodies specific for Aβ40 (R162) and Aβ42 (R165), in a double-antibody sandwich ELISA as described previously [23,24]. The optical density (OD) was measured at 450 nm. "
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    ABSTRACT: Central to the pathogenesis of Alzheimer's disease (AD) and many other neurodegenerative diseases is the conformational change of a normal self-protein into toxic oligomeric species and amyloid deposits. None of these disorders have an effective therapy, but immunization approaches hold great promise. We have previously shown that active immunization with a novel peptide when polymerized into a stable oligomeric conformation, pBri, induced a humoral immune response to toxic Abeta species in an AD model, APP/PS1 transgenic (Tg) mice, reducing plaque deposits. pBri is a glutaraldehyde polymerized form of the carboxyl fragment of an amyloidogenic protein, which is deposited in the brains of patients with a rare autosomal dominant disease due to a missense mutation in a stop codon, resulting in the translation of an intronic sequence, with no known sequence homology to any mammalian protein. In the current study we tested whether pBri-peptide-based immunomodulation is effective at reducing both vascular amyloid deposits and tau-related pathology using TgSwDI mice with extensive congophilic angiopathy and 3xTg mice with tau pathology. Our results indicate that this immunomodulation approach, which produces a humoral response to proteins in a pathological conformation, is effective at reducing both Abeta and tau-related pathologies. This immunomodulatory approach has the advantage of using a non-self-immunogen that is less likely to be associated with autoimmune toxicity. Furthermore we found that it is able to target all the cardinal features of AD concurrently.
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