Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX-

Abstract

Concomitant deposition of amyloid -beta protein (Aβ) and neuronal tau as neurofibrillary tangles in the human brain is a hallmark of Alzheimer disease (AD). Because these deposits increase during normal aging, it has been proposed that aging brains may also undergo AD-like changes. To investigate the neuropathological changes that occur in the aging primate brain, we examined 21 brains of cynomolgus monkeys (7–36 years old) for Aβ- and tau-positive lesions. We found, 1) extensive deposition of Aβ in brains of cynomolgus monkeys over 25 years of age, 2) selective deposition of 4-repeat tau as pretangles in neurons, and as coiled body-like structures in oligodendroglia-like cells and astrocytes, 3) preferential distribution of tau in the basal ganglia and neocortex rather than the hippocampus, and 4) age-associated increases in 30–34 kDa AT8- and RD4-positive tau fragments in sarkosyl-insoluble fractions. We further labeled tau-positive structures using diaminobezidine enhanced with nickel, and visualized nickel-labeled structures by energy-dispersive X-ray (EDX) analysis of ultrathin sections. This allowed us to distinguish between nickel-labeled tau and background electron-dense structures, and we found that tau localized to 20–25 nm straight filaments in oligodendroglia-like cells and neurons. Our results indicate that the cytopathology and distribution of tau deposits in aged cynomolgus brains resemble those of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) rather than AD. Thus, even in the presence of Aβ, age-associated deposition of tau in non-human primates likely does not occur through AD-associated mechanisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0385-5) contains supplementary material, which is available to authorized users.

A 4R tauopathy develops without amyloid deposits in aged cat brains

“…Many mammals, including wild-type mice, do not develop spontaneously NFTs during aging, but the development of a tau pathology is not specific to human species. Abnormal tau phosphorylation is also described in other aged mammals (Hartig et al, 2000;Youssef et al, 2016), such as cats (Chambers et al, 2015;Gunn-Moore et al, 2006;Head et al, 2005), dogs (Papaioannou et al, 2001;Yu et al, 2011), sheep (Braak et al, 1994a;Nelson et al, 1994;Reid et al, 2017), octogon degu (van Groen et al, 2011), brown bears (Cork et al, 1988), lemurian Microcebus (Bons et al, 1995), and cynomolgus monkeys (Oikawa et al, 2010;Uchihara et al, 2016), in the presence (Chambers et al, 2015;Cork et al, 1988;Gunn-Moore et al, 2006;Head et al, 2005;Oikawa et al, 2010;Papaioannou et al, 2001;Reid et al, 2017;Uchihara et al, 2016;van Groen et al, 2011;Yu et al, 2011), as well as in the absence (Braak et al, 1994a;Nelson et al, 1994), of Ab deposits. In cats, a previous study concluded that phosphorylated tau proteins, composed of both 3R and 4R isoforms, formed aggregates only in the presence of amyloid (Chambers et al, 2015).…”

A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies

“…Curiously, the presence of pathogenic tau in this context, which is termed “Primary Age-Related Tauopathy” is not always associated with deficits in cognition. Basal ganglia and neocortical neurons of cynomolgus monkeys also exhibit an age-associated accumulation of tau deposits, suggesting that aging-associated tau accumulation may be a general feature of primate aging [38]. A current hypothesis posits that Primary Age-Related Tauopathy, while not a brain injury in the classical sense, is a result of the mild “wear and tear” on the brain that inevitably accumulates over a lifetime [39].…”

The Exceptional Vulnerability of Humans to Alzheimer’s Disease

“…In aged squirrel monkeys, hyperphosphorylated tau is present in occasional neurons and neurites [7], and it increases with age in neurons and dystrophic microglia in marmosets [49]. Mild tauopathy in the form of hyperphosphorylated tau and silver-stained neurons has been reported in very old macaques [50]; however, this tauopathy resembles progressive supranuclear palsy/corticobasal degeneration rather than AD [51]. In addition, an unusual type of focal glial and neuronal tauopathy occurs in aged baboons ( Papio hamadryas ) [52].…”