Alzheimer's disease (AD) is characterized by the presence of parenchymal amyloid-beta (Aβ) plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles. Currently there are no effective treatments for AD. Immunotherapeutic approaches under development are hampered by complications related to ineffectual clearance of CAA. Genome-wide association studies have demonstrated the importance of microglia in AD pathogenesis. Microglia are the primary innate immune cells of the brain, and depending on their activation state and environment can have beneficial or detrimental effects. In our prior work we have shown that stimulation of innate immunity with Toll-like receptor 9 (TLR9) agonist, class B CpG oligodeoxynucleotides (ODNs), can reduce amyloid and tau pathologies without causing toxicity in Tg2576 and 3xTg-AD mouse models. However, these transgenic mice have relatively little CAA. In the current study we evaluated the therapeutic profile of CpG ODN in a triple transgenic mouse model, Tg-SwDI, with abundant vascular amyloid, in association with low levels of parenchymal amyloid deposits. Peripheral administration of CpG ODN, both prior to and after the development of CAA, negated short term memory deficits, as assessed by object recognition test, and was effective at improving spatial and working memory evaluated using a radial arm maze. These findings were associated with significant reductions of CAA pathology lacking adverse effects. Taken together, our extensive evidence suggests that this innovative immunomodulation may be a safe approach to ameliorate all hallmarks of AD pathology, supporting the potential clinical applicability of CpG ODN.
Recent genetic studies have underscored the emerging role of microglia in AD pathogenesis. Microglia lose their Aβ clearing capabilities with age and as AD progresses. Therefore, modulating microglia profiles provides a potential therapeutic avenue to reduce AD pathology. Current immunotherapeutic approaches have been limited by poor clearance of a core AD lesion: CAA. The present study used Tg-SwDI mice with extensive CAA and found that stimulation of the innate immune system and microglia/macrophage activation via TLR9 using CpG ODN leads to cognitive improvements and CAA reduction, without associated toxicity. Our data indicate that this novel concept of immunomodulation represents a safer method to reduce all aspects of AD pathology and provide essential information for potential clinical use of CpG ODN.
The authors declare no competing financial interests.
This manuscript was supported by NIH grants AG08051 (TW), AG20245 (TW) and NS073502 (TW), as well as Alzheimer's Association grants NIRG-10-173242 (HS) and IIRG -12-239474 (HS).The NYULMC Immune Monitoring Core is supported in part by grant UL1 TR00038 from the National Center for Advancing Translational Sciences (NCATS), NIH and grant P30CA016087 from the National Cancer Institute (NCI), NIH. We also thank the following students for their assistance: Helen Keizhen Lyo, Charlotte Herber, and Monica Lee. We also thank Dr. Adam C Mar of the NYUMC Rodent Behavior Core for his advice and contributions to the analysis of the behavioral data in this manuscript.