# Spontaneous tauopathy with parkinsonism in an aged cynomolgus macaque

## TL;DR

An aged cynomolgus macaque developed spontaneous tau-related brain changes and parkinson-like symptoms, offering a rare natural model for studying human tauopathies.

## Contribution

First detailed case of spontaneous tauopathy with parkinsonism in an aged cynomolgus macaque, linking tau pathology to neurological symptoms.

## Key findings

- Monkey T showed progressive neurological symptoms including tremors and posture issues, with no overt dopaminergic system degeneration.
- Extensive phosphorylated tau accumulation was found in the brainstem tegmentum, including neurofibrillary tangles and astrocytic inclusions.
- Monkey T had a 1.3-fold increase in 4R tau expression compared to the asymptomatic control, with balanced 3R/4R tau in the control.

## Abstract

Aged non-human primates have been reported to develop tau pathology; however, most studies lack evidence of any associated neurological symptoms. To determine whether spontaneous tauopathy in cynomolgus macaques manifests with neurological symptoms, we evaluated a symptomatic aged monkey (Monkey T) alongside an asymptomatic control (Monkey A).

Two male cynomolgus macaques, aged 33–34 years old at the time of necropsy, were examined. They were evaluated using comprehensive behavioral, pathological, and genetic analyses.

Monkey T exhibited progressive neurological symptoms for approximately two years prior to euthanasia, including tremors, nuchal dystonia, and a flexed posture, whereas Monkey A showed no abnormalities. Monkey T demonstrated persistent tremors (6.9 ± 0.7 Hz) and reduced daily motor activity, with modest improvement following L-DOPA administration. Neuropathological evaluation revealed brainstem atrophy and mild depigmentation of the substantia nigra and locus coeruleus. Extensive phosphorylated tau accumulation was observed throughout the brainstem tegmentum, including neurofibrillary tangles, threads, coiled bodies, and astrocytic inclusions. All tau lesions were positive for 4-repeat tau and negative for 3-repeat tau. MAPT sequencing identified four non-pathogenic 3′UTR variants differing between the two monkeys. Isoform analysis showed balanced 3R/4R tau expression in Monkey A but an approximately 1.3-fold increase in 4R tau in Monkey T.

The parkinsonian symptoms observed in Monkey T were more likely attributable to widespread tau pathology in the brainstem rather than overt degeneration of the nigrostriatal dopaminergic system. This case represents a rare instance of spontaneous tauopathy in an aged cynomolgus macaque, a condition that is extremely difficult to reproduce experimentally. These findings highlight the potential value of cynomolgus macaques as a relevant model for studying sporadic tauopathies, including tau seeding mechanisms.