P4‐044: Therapeutic Potential of Innate Immunity Stimulation by Class B Cpg Odn in a Tauopathy Mouse Model, Rtg4510
Year: 2019
Type: article
Abstract: Immunomodulation holds promise as an effective treatment for Alzheimer's Disease (AD). Our previous study in 3xTg-AD mice with both Aβ and tau pathologies, demonstrated that immunostimulation of innate immunity with TLR9 agonist CpG ODN had beneficial effects on both pathologies without toxicity. However, several innate immunity stimulation approaches to reduce Aβ pathology through TLR signaling have shown adverse TLR-specific effects on tau pathology. To resolve whether our approach of innate immune stimulation via CpG ODN can directly reduce pathological tau or whether this effect was secondary to reduced Aβ accumulation, we used the rTg4510 tauopathy mouse model. This model develops robust forebrain tangle pathology, cognitive deficits, and significant neuronal loss. rTg4510 mice were injected at monthly intervals (from 3 to 11 months of age) with TLR9 agonist class B CpG ODN or vehicle (saline). Subsequent behavioral, histological, and biochemical analyses were applied to evaluate tau related pathology, neuroinflammation, and neurodegeneration. Plasma samples were collected at specific times in the course of treatment to characterize immune responses using Th1/Th2 mouse Luminex kits. Our initial behavioral and histological assessments show that treatment with CpG ODN resulted in improved cognition and region specific reduction of tau pathology, without increased neuroinflammation. Preliminary stereological analyses of hemibrains indicated no detrimental effects on the total neuron number, neuron density, and volume in the neocortex and hippocampal-CA1 region of mice treated with CpG ODN. Ongoing western blot analyses demonstrated significant reduction in total PHF1 phospho-tau levels (low-speed supernatant fraction) in CpG ODN-treated mice in comparison to saline-treated animals. Administration of CpG ODN was not associated with increased sarkosyl-insoluble tau pathology. Plasma collected 4 hours post-injection demonstrated elevations in both Th1/Th2 cytokines and chemokines in mice injected with CpG ODN. In addition, plasma collected 4 weeks after the final injection revealed no CpG ODN associated sustained inflammation. Further brain biochemical and stereological analyses of neurodegeneration are currently in progress. Overall, our findings represent further evidence that innate immune stimulation with CpG ODN has the potential to be a safe and effective treatment approach for Alzheimer's Disease and other tauopathies.
Source: Alzheimer s & Dementia
Institutions: New York University, Charles University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980443526