Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits

Abstract

Alzheimer's disease (AD) is characterized by the presence of parenchymal amyloid-␤ (A␤) 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. Depending on their activation state and environment, microglia can be beneficial or detrimental. In our prior work, we showed that stimulation of innate immunity with Toll-like receptor 9 agonist, class B CpG (cytosine-phosphate-guanine) 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 before and after the development of CAA, negated short-term memory deficits, as assessed by object-recognition tests, 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. 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.

Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

“…Even though ADC values were higher upon treatment, the occurrence of vasogenic edema was discarded in a parallel experiment where very high doses of the full‐length mAb m3D6 were administered. In fact, this is not a good model for causing vasogenic edema as this pathology is related to cerebral amyloid angiopathy (CAA) and the 3xTg‐AD does not develop it . Analysis of other DTI neurodegeneration related parameters like fractional anisotropy or axial and radial diffusivities may provide additional information about microstructural anomalies, which may be worth considering to include them in future studies.…”

NGF steers microglia toward a neuroprotective phenotype

“…Therefore, affecting microglial homeostatic activities offers a potentially promising therapeutic avenue for AD pathology. However, approaches currently pursued to stimulate innate immunity via the Toll‐like receptor (TLR) pathway, such as the use of class B CpG (cytosine‐phosphate‐guanine) oligodeoxynucleotides (ODNs; Scholtzova et al, ), suffer from the problem that TLR ligands need to be very carefully titrated, to avoid excessive microglial stimulation. Indeed, while stimulation of innate immunity via TLR signaling pathways has been shown to be sometimes beneficial in modulating AD pathology (Richard, Filali, Prefontaine, & Rivest, ; Su, Bai, Zhou, & Zhang, ), it can also exert adverse effects in AD models (Campbell et al, ; Heikenwalder et al, ; Lee et al, ; Su et al, ).…”

Microglia in Alzheimer’s disease

“…Based on these findings, Scholtzova and colleagues tested TLR9 stimulation with CpG-containing oligodeoxynucleotides (CpG-ODNs) in mice, demonstrating that repeated monthly injections of CpG-ODNs reduced amyloid deposition and cerebral amyloid angiopathy, and prevented cognitive deficits. In contrast to TLR4 stimulation, TLR9 stimulation decreased tau-related pathology (116). With regard to microglial activation, overall levels of CD45, CD206, and CD11b were reduced in mice treated with CpG-ODNs, although microglia within the few remaining amyloid deposits showed increased CD45 reactivity (117).…”