Tau and tauopathies across primate species: implications for modeling neurodegenerative disorders

Abstract

Tauopathies are neurodegenerative disorders characterized by the abnormal accumulation and aggregation of hyperphosphorylated tau protein. They can be primary or secondary depending on whether tau inclusions are the predominant pathology (e.g.: frontotemporal dementia related to tau) or are found with other proteinopathies (e.g.: Alzheimer's disease), respectively. Currently, there are no effective treatments to prevent or slow down progressive tau accumulation. Animal models play a critical role in the efforts to unravel the mechanisms leading to tauopathies and identifying therapeutic targets. Nonhuman primates (NHPs) present several advantages for the study of tauopathies, as they have complex neuroanatomy and behavior that resembles human traits, and their tau gene and protein are highly conserved. Moreover, aged NHPs, like humans, can present various tau inclusions in their brains, although whether NHPs can develop human-like tau-related neurodegenerative disorders is currently debated. The main goal of this review is to analyze available reports on tau pathologies and models of tauopathies in NHPs considering the complexity of the tau protein and associated tau pathologies. Here, we first summarize current available information on human and NHP tau under physiological conditions in order to highlight species differences and gaps in knowledge. We then analyze reports on tau pathologies in aged NHPs compared to human aging and tauopathy, followed by an evaluation of current and emerging NHP models of tauopathy. Lastly, we discuss the practical and ethical challenges of doing tauopathy research in NHPs, and how to best leverage it to ultimately find solutions for patients with these disorders.

Keywords: AT8; Alzheimer’s disease; aging; frontemporal dementia; neurofibrillary tangles; nonhuman primates; tau; tauopathies.

Figure 1

Tau protein in human and nonhuman primate species. (A) Tau has four distinct regions: (1) the N-terminal projection domain (blue outline), (2) the proline-rich region (orange outline), (3) the microtubule binding domain (purple outline), and (4) the C-terminus (yellow outline). Colored boxes represent constitutively expressed exons; empty boxes are exons subject to alternative splicing that translate into (B) the six CNS isoforms of the tau protein. Expression of exons 4a, 6, and 8 is restricted to the human PNS and retina. (C) The longest CNS tau isoform in primates is the 2N4R tau. Black ticks in the protein region identifies amino acid (aa) variations in 2N4R tau in each nonhuman primate species compared to the human sequence. Common marmosets, squirrel monkeys, and gray mouse lemur tau has aa deletions, indicated by dashed black lines through the exons in which they occur. Gray mouse lemurs have an aa addition in exon 2, denoted by a solid black line through the exon. Created in https://BioRender.com.

Figure 2

Examples of AT8+ postmortem tau pathologies in human cases of Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), Pick’s disease (PiD), and corticobasal degeneration (CBD). (A) Pretangle (arrowhead) and mature NFT (arrow) in the cornu ammonis (AD). (B) Dystrophic neurites (arrowhead) in the entorhinal cortex (AD). (C) Neuritic plaque (arrow) in the insula (AD). (D) Globose NFT (arrow) in the putamen nucleus (PSP). (E) Pick bodies (arrow) in the cornu ammonis (PiD). (F) Oligodendroglial coiled bodies (arrowheads) in the putamen nucleus (PSP). (G) Thorn-shaped astrocyte (arrow) in the subpial medial temporal lobe (AD). (H) Tufted astrocyte (arrow) in the putamen (PSP). (I) Astrocytic plaque (arrow) in the caudate nucleus (CBD). Scale bar, 100 μm.

Figure 3

Approximate age in years (yrs.) of life milestones across female species from representative primate families. Chimpanzees reach sexual maturity between 8.5–14 yrs. of age and are on average 15 yrs. old when they first give birth (Walker et al., 2018); their fertility declines in their 30s and experience menopause at 45–50 yrs. old (Wood et al., 2023). In rhesus, first birth often occurs at age 4 (Pittet et al., 2017) and their fertility declines around age 17 (Lee et al., 2021); menopause was reported by 24–26 yrs. old (Walker, 1995). Common marmosets are considered primed adults between 2 and 8 yrs. of age, although they do not seem to undergo reproductive senescence (Abbott et al., 2003). Gray mouse lemurs reach sexual maturity around 0.5 yrs. (Hohenbrink et al., 2015) and, like common marmosets, do not seem to experience reproductive senescence. Their median lifespan is 5.5 yrs. (Martine and Aude, 2022) but can live up to 18 yrs. in captivity. Listed maximum lifespans in NHPs are estimated for captive animals. Mature tau pathologies, like NFTs, have been reported in extremely old animals nearing their respective species’ maximum lifespan, yet without behavioral or clinical correlates, it is difficult to assert whether tau pathology affects survivability. Created in https://BioRender.com.