4Aβ1-15-Derived Monoclonal Antibody Reduces More Aβ Burdens and Neuroinflammation than Homologous Vaccine in APP/PS1 Mice

The common pathological hallmark of Alzheimer's disease (AD) is beta-amyloid plaque deposition. The ideal therapy would reduce the A beta burden with a low inflammatory immune response. Passive immunotherapy is an advanced treatment that dramatically reduces brain A beta pathologies in AD animal models. The objective of our study was to observe the effects of 5C8H5, a novel monoclonal antibody derived from 4A beta 1-15, on brain A beta pathology in an APP/PS1 mouse model of AD. Six-month-old transgenic mice were administered 5C8H5, 4A beta 1-15 or IgG, and same-aged wild-type untreated C57Bl/6J mice were employed as controls. Inflammatory factors and A beta 40/42 levels were detected by ELISA, while A beta plaques, microglial cell activation, microhemorrhages and neurogenesis were evaluated by immunohistochemical staining. Compared with 4A beta 1-15-treated mice, the mice in the 5C8H5 group induced more A beta clearance with less microglial cell activation in a niche of Th2-polarized immune response. The levels of proinflammatory factors, including IL-1 beta, IL-6, TNF-alpha and IFN-gamma, were significantly decreased in the CNS, while the level of anti-inflammatory IL-4 was increased. Moreover, the mice in the 5C8H5 group induced more neurogenesis without microhemorrhage exacerbation and thereby performed better in behavioral assays than did the 4A beta 1-15 group. In conclusion, the novel monoclonal antibody induces more A beta clearance and less microglial cell activation in the absence of inflammation, accompanied by an increased Th2-polarized immune response, which makes it a more promising therapeutic strategy. These data provide evidence that passive immunity could alleviate pathologic A beta alterations by modulating inflammation and should be pursued further for the treatment of AD.