Amyloid Beta1–42 and the Phoshorylated Tau Threonine 231 in Brains of Aged Cynomolgus Monkeys (Macaca fascicularis)

Abstract

Pathological hallmarks indicative of Alzheimer’s disease (AD), which are the plaques of amyloid beta1–42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers indicative of AD, had brain lesions similar to human patients suffering from senile dementia. Generating immunohistochemistry technique to biomarkers of amyloid beta1–42 and the phosphorylated tau 231, our study assessed the amyloidopathy, such as indicative to the senile plaques and cerebral amyloid angiopathy, and the tauopathy, to possible neurofibrillary tangles. Six aged monkeys were selected based on their spatial memory performance and profile of biomarkers of AD, divided equally to affected aged subject – with Memory-affected and low amyloid level, and aged with higher performance in memory and amyloid, as the age-matched subjects. Using immunohistochemistry, plaques of amyloid beta1–42 were observed in two out of three brains of aged subjects with memory impairment and biomarkers indicative of AD. The cerebral amyloid angiopathy was observed in both aged monkey groups, and unlike in the human, the amyloids were found to deposit in the small veins and capillaries. In one of the affected individuals, phosphorylated tau was positively stained intracellularly of the neurons, indicating a possibility of an early stage of the formation of tangles. These findings add to the body of evidence of the utility of the aged cynomolgus monkeys as a spontaneous model for Alzheimer-related disease.

Evidence of Tau Hyperphosphorylation and Dystrophic Microglia in the Common Marmoset

“…Monkeys have identical Aβ amino acid sequence to humans (Selkoe et al, 1987), which may result in similar mechanisms for Aβ production and accumulation. It has widely been reported that aged non-human primates present amyloid accumulation in the form of diffuse and compact plaques, mainly in the cortex (Cork et al, 1990; Gearing et al, 1996, 1997; Giannakopoulos et al, 1997; Kimura et al, 2003; Bons et al, 2006; Lemere et al, 2008; Oikawa et al, 2010; Perez et al, 2013; Sridharan et al, 2013; Darusman et al, 2014). Amyloid plaques in the cortex of old marmoset have been previously described as well (Maclean et al, 2000; Geula et al, 2002).…”

“…NFTs cause neuronal dysfunction and eventually lead to death (Avila et al, 2006; Stokin and Goldstein, 2006). In several aged non-human primates, hyperphosphorylated tau filaments have been observed in hippocampus and cortex of old subjects (Härtig et al, 2000; Schultz et al, 2000a,b; Oikawa et al, 2010; Perez et al, 2013; Darusman et al, 2014). To our knowledge, there are no previous reports of hyperphosphorylated tau in marmosets.…”

“…Our results coincide with the study of Perez et al (2013) in Gorilla gorilla , where Alz50-ir fibers were observed at each age analyzed (13–55 years of age). In Papio anubis (Schultz et al, 2000b), Papio hamadryas (Schultz et al, 2000a), Macaca fascicularis (Oikawa et al, 2010; Darusman et al, 2014), and Macaca mulatta (Härtig et al, 2000) hyperphosphorylated tau appears until the second decade of life. This could suggest that the beginning of tau hyperphosphorylation process varies between different species of non-human primates, the marmosets being heavily prone to be affected.…”

Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice

“…For Aβ 42 and Aβ 40 , two major Aβ isoforms, Aβ 42 is more insoluble and prone to aggregation (Miners et al 2014). The insoluble Aβ 42 progressively increases with age and further aggravates in the AD brain, which is accompanied with cognitive decline (Darusman et al 2014;Fukumoto et al 2004;Yue et al 2014). Increasing evidence has shown that Aβ oligomers trigger neurotoxicity, probably via phosphorylated tau (p-tau) (Selenica et al 2013).…”

Diet, psychosocial stress, and Alzheimer’s disease-related neuroanatomy in female nonhuman primates

“…Accumulating data indicate aging related neuropathologies like those observed in human AD also occur, suggesting that macaques may be promising models of sporadic AD [24,25]. Cynomolgus macaques ( Macaca fascicularis ), in particular, accumulate age-related cognitive deficits, brain amyloid, and tauopathies [26,27]. Age-related cognitive impairment has been associated with altered cerebrospinal fluid (CSF) biomarkers of AD-like pathology, including decreased beta-amyloid 1-42 and increased total and phosphorylated tau [28].…”