Continuous vaccinations of 4Aβ1-15 induces specific fluctuation of inflammatory factors accompany with pathologic alterations alleviation in APP/PS1 mice

Abstract

#These authors equally contributed to this work.Keywords: Ab burdens, APP/PS1 mice, continuous vaccinations, immunotherapy, inflammatory factors, microglial activation spatial learning and memory ability, specific fluctuationsAbbreviations: 4Ab1-15, 4 alternative tandem repeats of GPGPG-linked Ab1-15 sequences; Ab, b-amyloid; APP, amyloid precursor protein; IFN-g, interferon-g; IgG, immunoglobulin G; IL-1b, interleukin-1b; IL-4, interleukin-4; PS1, presenilin-1; Th, T-helper type; TNF-a, tumor necrosis factor-aThe common pathological hallmark of Alzheimer's disease (AD) is b-amyloid plaques deposition. Immunotherapy is a revolutionary pharmacological treatment for AD, aiming at improving plaque clearance while concomitantly decreasing inflammation. Our previous study prepared antigen 4Ab1-15 and found that it could alleviate pathologic alterations in APP/PS1 transgenic mice. The objective of our study was to research the changing processes induced by immunotherapy, including the inflammatory factor levels and microglial activation that is closely associated with Ab burdens clearance. APP/PS1 mice were injected with 4Ab1-15 6 times. Each time, the inflammatory factors in sera were detected, and a specific fluctuation that first increased and then decreased was found, in which there was a turning point after the third injection. It prompted us to further detect the indicators in the brains after the third injection and the sixth injection. The results showed that the therapeutic effects for Ab burdens and behaviors were continuously improved during the whole immune processes, whereas the inflammatory factor levels and microglial activation experienced similar specific fluctuations. The novel discovery may provide convenient methods for further detection and evaluation of immunotherapy in disease courses.

Microglia and immunotherapy in Alzheimer’s disease

“…However, the level of the inflammatory cytokine IL-4 is slightly increased. 51 IFNγ and IL-4 are the two main cytokines used to distinguish between Th1 and Th2 cells. In both the peripheral and central nervous systems, passive immunization induced more Th2 than active immunization.…”

“…Pro‐inflammatory factors such as IL‐1β, IL‐6, TNF‐α and IFN‐γ are inhibited in the brain, and their inhibition is more distinct than that in the periphery after the activation of microglia. However, the level of the inflammatory cytokine IL‐4 is slightly increased 51 . IFN‐γ and IL‐4 are the two main cytokines used to distinguish between Th1 and Th2 cells.…”

The short-term improvements of enriched environment in behaviors and pathological changes of APP/PS1 mice via regulating cytokines

“…Each well is added to 200 ml sample, 37 C water bath for 2 hours, Washing by PBST and pat dry, then adding Goat anti mouse IgG HRP, 37 C water bath for 1 hour, Washing by PBST and pat dry, adding TMB substrate and avoid light for 10-15 minutes, and then adding stop solution, observed reading by enzyme-linked immunosorbent in 30 minutes, record the result at the wavelength of 490 nm, calculate the corresponding concentration according to the standard curve. 25 Detect the activity of Ach, ChAT and AchE in the hippocampus of the mice…”