Alzheimer's Disease Aβ Vaccine Reduces Central Nervous System Aβ Levels in a Non-Human Primate, the Caribbean Vervet

Abstract

Amyloid beta (Abeta) protein immunotherapy lowers cerebral Abeta and improves cognition in mouse models of Alzheimer's disease (AD). Here we show that Caribbean vervet monkeys (Chlorocebus aethiops, SK) develop cerebral Abeta plaques with aging and that these deposits are associated with gliosis and neuritic dystrophy. Five aged vervets were immunized with Abeta peptide over 10 months. Plasma and cerebral spinal fluid (CSF) samples were collected periodically from the immunized vervets and five aged controls; one monkey per group expired during the study. By Day 42, immunized animals generated plasma Abeta antibodies that labeled Abeta plaques in human, AD transgenic mouse and vervet brains; bound Abeta1-7; and recognized monomeric and oligomeric Abeta but not full-length amyloid precursor protein nor its C-terminal fragments. Low anti-Abeta titers were detected in CSF. Abetax-40 levels were elevated approximately 2- to 5-fold in plasma and decreased up to 64% in CSF in immunized vervets. Insoluble Abetax-42 was decreased by 66% in brain homogenates of the four immunized animals compared to archival tissues from 13 age-matched control vervets. Abeta42-immunoreactive plaques were detected in frontal cortex in 11 of the 13 control animals, but not in six brain regions examined in each of the four immunized vervets. No T cell response or inflammation was observed. Our study is the first to demonstrate age-related Abeta deposition in the vervet monkey as well as the lowering of cerebral Abeta by Abeta vaccination in a non-human primate. The findings further support Abeta immunotherapy as a potential prevention and treatment of AD.

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

“…S6D). In support of earlier findings that immunization with A␤ was mainly targeting the peptide's N terminus (39), immunized vervets failed to develop a comparable immune response to A␤33-42 (0.2-to 22-fold). Most importantly, and in likely support of their physiological relevance, immunized vervets significantly increased antibody levels to pyroglutamate-modified A␤ [e.g., A␤11(pE)-42], mutant A␤ [e.g., A␤1-42(E22Q) Dutch], and the foreign peptides ABri and ADan (Fig.…”

“…Studies in mice (22,38,41) and humans (20)(21)(22)(24)(25)(26) described natural antibodies against A␤1-40 or A␤1-42 before, without assessing their fine specificity or preference for specific assembly states in detail. Because the typical overnight coating of ELISA plates with A␤ resuspended in PBS is similar to the protocol for generating oligomeric A␤ species (42) it is likely that some of (39). Immunoreactivity at the end of the study (day 301) was divided by the baseline reactivity to individual peptides, and the result is presented as log fold change.…”

“…To further study the in vivo relevance of natural antibodies to amyloidogenic peptides, we measured immunoreactivity in plasma of a subcohort of vervet monkeys from a previously published study (39). Aged vervets can develop features of AD including cerebral amyloid plaques that stain positive with anti-human A␤ antibodies (39), indicating high homology between human and vervet A␤ similar to other nonhuman primates (40). Immunization with a mixture of human A␤1-40 and A␤1-42 almost entirely cleared cerebral A␤ plaques (39).…”

“…Aged vervets can develop features of AD including cerebral amyloid plaques that stain positive with anti-human A␤ antibodies (39), indicating high homology between human and vervet A␤ similar to other nonhuman primates (40). Immunization with a mixture of human A␤1-40 and A␤1-42 almost entirely cleared cerebral A␤ plaques (39). Although standard ELISA methods detected miniscule levels of A␤1-40 antibodies in nonimmunized vervets (39), using our peptide arrays, we were able to measure reactivities to nonaggregated and oligomeric A␤ preparations and to A␤3(pE)-42 species comparable to what we detected in human plasma (Fig.…”

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

“…175 Active immunization in a non-human primate model also reduced brain amyloid whilst increasing plasma Ab concentration, lending further support to the peripheral sink hypothesis. 176 Despite these encouraging findings, there are a number of questions that remain to be answered for immunotherapy to progress, for example, it may be that a passive immunization strategy may be more desirable and much work needs to be conducted to determine the appropriate epitopes or adjuvants to be used and treatment regime necessary to deliver not only a reduction in amyloid load, but also to reduce deterioration in cognition. Likewise, it is unclear how inter-species immune system differences may affect basic research.…”