Preventive immunization of aged and juvenile non-human primates to beta-amyloid

Abstract

BackgroundImmunization against beta-amyloid (Aβ) is a promising approach for the treatment of Alzheimer’s disease, but the optimal timing for the vaccination remains to be determined. Preventive immunization approaches may be more efficacious and associated with fewer side-effects; however, there is only limited information available from primate models about the effects of preclinical vaccination on brain amyloid composition and the neuroinflammatory milieu.MethodsTen non-human primates (NHP) of advanced age (18–26 years) and eight 2-year-old juvenile NHPs were immunized at 0, 2, 6, 10 and 14 weeks with aggregated Aβ42 admixed with monophosphoryl lipid A as adjuvant, and monitored for up to 6 months. Anti-Aβ antibody levels and immune activation markers were assessed in plasma and cerebrospinal fluid samples before and at several time-points after immunization. Microglial activity was determined by [11C]PK11195 PET scans acquired before and after immunization, and by post-mortem immunohistochemical and real-time PCR evaluation. Aβ oligomer composition was assessed by immunoblot analysis in the frontal cortex of aged immunized and non-immunized control animals.ResultsAll juvenile animals developed a strong and sustained serum anti-Aβ IgG antibody response, whereas only 80 % of aged animals developed detectable antibodies. The immune response in aged monkeys was more delayed and significantly weaker, and was also more variable between animals. Pre- and post-immunization [11C]PK11195 PET scans showed no evidence of vaccine-related microglial activation. Post-mortem brain tissue analysis indicated a low overall amyloid burden, but revealed a significant shift in oligomer size with an increase in the dimer:pentamer ratio in aged immunized animals compared with non-immunized controls (P < 0.01). No differences were seen in microglial density or expression of classical and alternative microglial activation markers between immunized and control animals.ConclusionsOur results indicate that preventive Aβ immunization is a safe therapeutic approach lacking adverse CNS immune system activation or other serious side-effects in both aged and juvenile NHP cohorts. A significant shift in the composition of soluble oligomers towards smaller species might facilitate removal of toxic Aβ species from the brain.

Monophosphoryl lipid A is an lipopolysaccharide-derived Toll-like receptor 4 agonist which may improve Alzheimer's disease pathology

“…MPL administration also did not result in any form of chronic inflammatory response or immune tolerance, which would allow for prolonged and repeated treatments without causing toxicity or loss of efficacy [8]. The variability in the response to MPL in this study was considerably lower compared to those seen in response to coadministration of MPL with Ab as a vaccination in previous studies, where only a subset of animals had detectable antibodies made against Ab [10,11]. This suggests that well-regulated activation of TLR4 signaling surpasses the inconsistent efficacy of an Ab vaccine therapy.…”

“…Thus, in the successfully immunized animals, reduced Ab levels appear to have led to improved cognitive function. Immunization of aged macaques with Ab 1 --42 and MPL was well tolerated with no apparent microglial activation and resulted in a shift in the size of Ab oligomers toward smaller species [11]. Although the significance of the latter finding remains to be explored, the result suggests that Ab antibodies induced by immunization can indeed affect Ab's oligomeric and, consequently, pathogenic dynamics.…”

“…Whereas previous studies used MPL as an adjuvant for Ab immunization [10,11], Michaud et al took a different approach by simply injecting MPL or LPS alone into 3-month-old APP/PS1 transgenic mice weekly for 12 consecutive weeks [8]. Although LPS had no effect on cognition (using a water T-maze) and even resulted in increased plaque load, MPL was able to decrease the number and size of plaques, decrease soluble Ab monomers and improve cognition [8], all with less variability compared to when MPL was used as an adjuvant for Ab vaccination [10,11].…”

“…The effects of MPL on tau are especially important since failed antiAb strategies did not seem to modify tau neurofibrillary tangle pathology [12], the neuropathological marker more closely associated with cognitive decline [13]. Several studies have shown that microglial activation in mouse models of AD can clear plaques but actually enhance tau pathology [14], but early studies with MPL have yet to describe this phenomenon [8,10,11]. Previous setbacks in clinical trials targeting Ab have cast considerable doubt on the amyloid cascade hypothesis of AD [2,4,15].…”

New progress in active immunotherapy targeting to amyloid beta

“…Peptide vaccine aggregated Aβ42 monophos-phoryl lipid A non-human primates Preventive Aβ immunization may be safe and effective [42] Yao et al…”