Age-Related Lesions in the Cerebrum in Middle-Aged Female Cynomolgus Monkeys

Kodama, Rinya; Yang, Xiuying; Saski, Yuji; Iwashige, Shuichiro; Tanigawa, Yohei; Yoshikawa, Tsuyoshi; Nagaoka, Takaharu; Kamimura, Yasuhiro; Maeda, Hiroshi

doi:10.1177/0192623309358904

Cited by 13 publications

(10 citation statements)

References 17 publications

(34 reference statements)

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“…Phagocytic activity by microglial cells, however, was not evident in the foci observed in this review. Numbers of microglial cells have been shown to increase with age in cynomolgus monkey brains (Kodama et al 2010) and can persist following traumatic injury (Nagamoto-Combs et al 2007). Increased numbers of activated microglial cells have been associated with extracranial conditions including hypercholesterolemia in rabbits and heart disease in people (Streit and Sparks 1997).…”

Section: Discussionmentioning

confidence: 99%

Microscopic Background Changes in Brains of Cynomolgus Monkeys

et al. 2014

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Brain sections from control cynomolgus monkeys (Macaca fascicularis) used in toxicology studies were evaluated retrospectively in order to better understand spontaneous background changes in this species. Hematoxylin and eosin-stained slides from 76 animals (38 males and 38 females) of 9 studies were examined. Eleven animals (9 males and 2 females) were each observed to have 1 to 3 findings within the brain sections examined, for a total of 19 findings. No findings were noted in the spinal cord. The most common finding was focal to multifocal perivascular infiltration of mononuclear cells, affecting the parenchyma, the meninges, or the choroid plexus. Additionally, focal gliosis was observed in 6 animals and a single focus of hemosiderin deposition (coincident with focal gliosis and mononuclear cell infiltrate) was noted in 1 animal. Most of the glial foci were composed of cells consistent with microglial cells, with or without admixed lymphocytes. All findings were of slight or minimal severity, lacked an apparent cause, and were considered incidental and of negligible biologic significance. An awareness of the spontaneous incidence of these background findings may facilitate the discernment of toxicologically relevant effects when these findings are observed.

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Section: Discussionmentioning

confidence: 99%

Microscopic Background Changes in Brains of Cynomolgus Monkeys

et al. 2014

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“…Compared with non-demented aged humans [20,21], the aged macaques in our study had lower CSF Aβ and total tau levels and higher tau:Aβ 42 ratios. Plaques are seen in most rhesus macaques older than 21–23 years [44,45] and cynomolgus macaques older than 18–20 years [46,47]; data on plaque occurrence in pigtailed macaques are lacking. The animals in our study were right within the age range at which plaques are first seen in these species, but their degree of pathology was milder than expected from previous reports, and unlikely to be associated with cognitive symptoms.…”

Section: Discussionmentioning

confidence: 99%

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

Kofler

Lopresti

Janssen

et al. 2012

J Neuroinflammation

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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.

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“…Normal male cynomolgus monkeys had a significant increase in body weight between 4 and 6 years of age, during which they nearly doubled their body weight . Normal female cynomolgus monkeys also underwent body weight increases between the ages of 5–7 years . The ideal weight was considered to be 6–9 kg for adult males and for adult females to be 3–6 kg according to a large survey of cynomoglus monkeys in North American research facilities .…”

Section: Discussionmentioning

confidence: 99%