Nevertheless, immunosenescence was still evident in our study with vaccinations markedly less effective in the aged cohort

Nevertheless, immunosenescence was still evident in our study with vaccinations markedly less effective in the aged cohort. % of aged animals developed detectable antibodies. The immune response in aged monkeys was PTP1B-IN-1 more delayed and significantly weaker, PTP1B-IN-1 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 Rabbit Polyclonal to SMUG1 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. == Conclusions == Our results indicate that preventive A 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 A species from the brain. Keywords:Alzheimers disease, Beta-amyloid, Oligomers, Active immunization, Preventive immunotherapy, Neuroinflammation, Microglia, Classical and alternative activation, Immunosenescence == Background == Passive and active immunization against beta-amyloid (A) has been proven efficacious in removing A aggregates from the brain [1-3]. In rodents, this clearance was associated with cognitive improvement in many but not all studies [4-9], whereas only marginal differences were noted in cognitive outcome measures between vaccinated and non-vaccinated humans [10-12]. Moreover, serious side-effects including meningoencephalitis in a subset of patients and the development of vasogenic edema have complicated human immunization studies [13,14]. One possible explanation for the lack of success in human studies might be the timing of PTP1B-IN-1 therapeutic intervention. A species begin to accumulate in the brain many years to decades before cognitive symptoms develop [15]. At the time of enrollment into vaccination studies, patients with a clinical diagnosis of probable Alzheimers disease (AD) have already developed secondary neurodegenerative changes including tau accumulation, synaptic pathology, neu-ronal loss, angiopathy, and neuroinflammation, which may be irreversible and thus unaffected by reducing the brain A burden [13,16]. Therefore, if immunization therapy were to be efficacious, it would probably need to be administered earlier. Studies in transgenic mouse models have already shown that PTP1B-IN-1 A accumulation in the brain and cognitive deficits can be markedly diminished by preventive immunization strategies initiated before the onset of significant A deposition [1,2,8]. In addition, vaccination at a time when the brain amyloid burden is still low may reduce the risk of toxic side-effects mediated by soluble amyloid species that might possibly be released from disaggregated plaques, and may decrease the risk of cerebral amyloid angiopathy-associated microhemorrhages promoted by amyloid shift from parenchyma to the vasculature [17]. Based on these considerations, there are increased efforts to start immunization during a crucial time window of preclinical AD when A pathology is still minimal [13,16,18]. The development of improved biomarker panels and ima-ging paradigms (Pittsburgh Compound B (PiB) PET scans [19]) may soon allow the more accurate identification of individuals at risk who may benefit most from early intervention. Biomarkers of interest include CSF A42, phospho-tau and PTP1B-IN-1 tau levels [20,21] and more novel markers such as YKL40, which may help distinguish between control, mild cognitive impairment (MCI) and mild AD [18,22,23]. To date, preventive immunization approaches have not been studied in a non-human primate (NHP) model, therefore we sought to evaluate the effects of immunization on the aging NHP brain before the onset of a significant A burden by addressing the following questions: 1) Does active A vaccination in an individual with low amyloid burden alter the level and composition of A species in the brain or CSF? 2) Is preventive immunization associated with microglial activation or shifts in the neuroinflammatory milieu? 3) Does immunosenescence affect the efficacy of preventive A immunization in an aging population? == Methods == == Animals == All animals were housed and maintained according to strict standards of the Association for Assessment and Accreditation of Laboratory Animal Care, and experiments were approved by the University of Pittsburgh Institutional.