Distinct Transcriptome Expression of the Temporal Cortex of the Primate Microcebus murinus during Brain Aging versus Alzheimer's Disease-Like Pathology

Aging is the primary risk factor of neurodegenerative disorders such as Alzheimer's disease (AD). However, the molecular events occurring during brain aging are extremely complex and still largely unknown. For a better understanding of these age-associated modifications, animal models as close as possible to humans are needed. We thus analyzed the transcriptome of the temporal cortex of the primate Microcebus murinus using human oligonucleotide microarrays (Affymetrix). Gene expression profiles were assessed in the temporal cortex of 6 young adults, 10 healthy old animals and 2 old, “AD-like” animals that presented ß-amyloid plaques and cortical atrophy, which are pathognomonic signs of AD in humans. Gene expression data of the 14,911 genes that were detected in at least 3 samples were analyzed. By SAM (significance analysis of microarrays), we identified 47 genes that discriminated young from healthy old and “AD-like” animals. These findings were confirmed by principal component analysis (PCA). ANOVA of the expression data from the three groups identified 695 genes (including the 47 genes previously identified by SAM and PCA) with significant changes of expression in old and “AD-like” in comparison to young animals. About one third of these genes showed similar changes of expression in healthy aging and in “AD-like” animals, whereas more than two thirds showed opposite changes in these two groups in comparison to young animals. Hierarchical clustering analysis of the 695 markers indicated that each group had distinct expression profiles which characterized each group, especially the “AD-like” group. Functional categorization showed that most of the genes that were up-regulated in healthy old animals and down-regulated in “AD-like” animals belonged to metabolic pathways, particularly protein synthesis. These data suggest the existence of compensatory mechanisms during physiological brain aging that disappear in “AD-like” animals. These results open the way to new exploration of physiological and “AD-like” aging in primates

Oral Transmission of L-type Bovine Spongiform Encephalopathy in Primate Model

We report transmission of atypical L-type bovine spongiform encephalopathy to mouse lemurs after oral or intracerebral inoculation with infected bovine brain tissue. After neurologic symptoms appeared, transmissibility of the disease by both inoculation routes was confirmed by detection of disease-associated prion protein in samples of brain tissue

Antibody response and plasma A?1-40 levels in young Microcebus murinus primates immunized with A?1-42 and its derivatives

We have been developing A? derivative vaccines with the objective to improve the safety of A? targeting immunotherapy. Our A? homologs are designed to have less direct toxicity and to produce a modified immune response compared to A?. In extensive mouse studies, all our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for studies in old primates and for human trials we assessed their effect in young lemur primates (n = 25) that with age develop A? plaques and tau aggregates as seen in Alzheimer's disease.In the primates, all the peptides administered with alum adjuvant elicited a moderate to robust anti-A? IgM response. A?1-42, K6A?1-30 and K6A?1-30[E18E19] resulted in a high anti-A? IgG response, whereas A?1-30[E18E19] produced a weaker more variable IgG titer. Notably, 22 weeks after the 3rd immunization, IgM and IgG levels in derivative-vaccinated primates were similar to preimmune values whereas A?1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized A?1-40 often correlated with increase in A?1-40 in plasma, which suggests that the antibodies were binding to A? in vivo. Interestingly, significant transient weight gain was observed (K6A?1-30-, A?1-30[E18E19]- and A?1-42-treated) or a trend in the same direction (K6A?1-30[E18E19]-treated, adjuvant controls) following the injections. Based on these findings, we have chosen K6A?1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other A? derivatives. Our present findings indicate that most of our A? derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach.<br/