Amyloid-β vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid

Abstract

Vaccination with Aβ 1-42 and treatment with NCX-2216, a novel nitric oxide releasing flurbiprofen derivative, have each been shown separately to reduce amyloid deposition in transgenic mice and have been suggested as potential therapies for Alzheimer's disease. In the current study we treated doubly transgenic amyloid precursor protein and presenilin-1 (APP+PS1) mice with Aβ 1-42 vaccination, NCX-2216 or both drugs simultaneously for 9 months. We found that all treatments reduced amyloid deposition, both compact and diffuse, to the same extent while only vaccinated animals, with or without non-steroidal anti-inflammatory drug (NSAID) treatment, showed increased microglial activation associated with the remaining amyloid deposits. We also found that active Aβ vaccination resulted in significantly increased cerebral amyloid angiopathy and associated microhemorrhages, while NCX-2216 did not, in spite of similar reductions in parenchymal amyloid. Co-administration of NCX-2216 did not attenuate this effect of the vaccine. This is the first report showing that active immunization can result in increased vascular amyloid and microhemorrhage, as has been observed with passive immunization. Co-administration of an NSAID agent with Aβ vaccination does not substantially modify the effects of Aβ immunotherapy. The difference between these treatments with respect to vascular amyloid development may reflect the clearance-promoting actions of the vaccine as opposed to the production-modifying effects proposed for flurbiprofen.

Alzheimer's Disease Peptide Epitope Vaccine Reduces Insoluble But Not Soluble/Oligomeric Aβ Species in Amyloid Precursor Protein Transgenic Mice

“…Although not statistically significant, there was nonetheless approximately a 41% increase compared with the control group, and these data resemble the results generated by (Wilcock et al, 2007) with APPϩPS1 aged mice. Thus, immunization with the second generation epitope vaccine did not increase the incidence of cerebral microhemorrhages in ϳ19-month-old APP Tg 2576 mice (Fig.…”

“…It is known that AN-1792 vaccine caused an increase in cerebral vasculature deposition of A␤ (Masliah et al, 2005;Nicoll et al, 2006;Patton et al, 2006). Previously it was also shown that active A␤ 42 vaccination of double transgenic (APPϩPS1) mice resulted in significantly increased cerebral amyloid angiopathy and associated microhemorrhages (Wilcock et al, 2007). Although we did not directly investigate the effect of epitope vaccine on A␤ deposition in cerebral vasculature, we demonstrated that anti-A␤ 1-11 antibodies did not increase the incidence of cerebral microhemorrhages in the brains of immunized mice (Fig.…”

“…More recently, it was shown that cerebral amyloid angiopathy-associated microhemorrhages are increased in ϳ20-month-old APPϩpresenilin 1 (PS1) transgenic mice immunized eight times with fA␤ 42 formulated in complete Freunds adjuvant (CFA)/incomplete Freunds adjuvant (IFA) (Wilcock et al, 2007). To assess this potential adverse side effect of epitope vaccine, we selected adjacent coronal sections of mouse brains located at Ϫ1.5 bregma and visualized microhemorrhages by detecting hemosiderin (byproduct of degradation of hemoglobin, occurring at the sites of previous microhemorrhages) deposits using Prussian blue staining.…”

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

“…Inflammatory response is the reaction to resist pathologic alterations, which demonstrated that inflammation plays a vital role in influencing AD. 20 Studies have verified that the effects of inflammatory response are double-sided. Microglial are activated, releasing harmful inflammatory factors, whereas inflammatory factors induce phagocytosis of microglial, stimulating A b clearance.…”

Chemical and Physical Approaches for the Treatment of Alzheimer's Disease

“…However, revascularization would be a potential issue for long term treatment of passive immunization, for these therapies could lead to cerebral microhemorrhages related to vascular amyloid deposits [55]. Nevertheless, some monoclonal antibodies have already been tested in AD patients, like solanezumab (LY-2062430), bapineuzumab (AAB-001), and gantenerumab (RG-1450), ponezumab (PF-04360365), GSK-933776, MABT-5102A and immunoglobulins (IVIg) [13].…”