P4‐476: Aging and genetics in the lemurian primate Microcebus murinus: A useful approach for Alzheimer's disease studies

Abstract

Studying Alzheimer's disease (AD) necessitates animal models. A good model should show progressive pathology and associated cognitive deficits and should be robust enough. Most of used models are rodents but results cannot necessarily be extrapolated to humans. The use of nonhuman primates has been recommended. Mouse lemurs are small primates whose lifespan is around 13 years, are relatively easy to breed and maintain in captivity. Comparable to humans during aging, some, but not all, display the neuropathological signs of AD (AD-like animals). Immunohistochemical analysis was performed on mouse lemurs aged 1-13 years to detect Abeta deposition (n = 150), and gliosis and phosphorylated Tau (n = 50). We evaluated the safety and efficacy of immunization in young (n = 25) and old (n = 48) with an Abeta derivative. We analyzed the transcriptome of the temporal cortex using human chips. In some families, the AD-like trait seemed inheritable. We selected and crossed them to develop an AD-like lineage. Amyloid plaques were detected in 8-10% of animals, pre-tangles in few aged, and brain atrophy in some, but not all, aged. Immunotherapy in young have concluded that the Ab peptide derivative K6Abeta1-30 elicited a substantial antibody response, and importantly this effect was reversible. In old, vaccination led to a clearance of Abeta, a decrease of inflammation without T cell infiltration, and appeared to have some cognitive benefits. We identified 47 genes that discriminated young from healthy old and AD-like. Hierarchical clustering analysis indicated that each group had distinct expression profiles. Preliminary data of AD-like lineage showed a transmission over at least 3 generations of AD-like phenotype. Mouse lemurs display all pathognomonic lesions of AD: plaques, pre-tangles, cortical atrophy. They are a suitable model for assessing safety and efficiency of novel vaccines targeting Abeta pathology. Transcriptome analysis suggests the existence of compensatory mechanisms during healthy aging that disappear in AD-like. AD-like families will be part of a whole genome linkage analysis to identify chromosomic regions and candidate genes involved in the AD-like phenotype. Mouse lemurs provide a valuable natural primate model for aging and at least for some aspects of AD.