Divergent tau pathology profiles induced by distinct alpha-synuclein aggregates in non-human primates

Proteinopathies are frequently accompanied by co-pathologies, which complicate understanding the pathophysiological mechanisms of neurodegenerative diseases. In this study, we employed a well-characterised baboon cohort to investigate the occurrence of tau pathology following intrastriatal injections of two distinct α-synuclein extracts (small aggregates: SA and large aggregates: LA) derived from the brains of Parkinson's disease (PD) patients. Biochemical and histopathological analyses (6, 12, or 24 months after injections) revealed significantly higher phospho-tau expression and greater frequency of neuropil threads in both LA- (n=18) and SA-injected baboons (n=12) compared with control animals. We also observed distinct patterns of tau pathology depending on the assembly of α-synuclein aggregates. Baboons injected with SA exhibited tangle-like phosphorylated tau lesions and neuropil threads, with no significant differences across post-injection time points. Moreover, a uniform distribution of tau pathology was detected along the rostro-caudal axis of the medial temporal lobe, affecting neuronal, oligodendroglial, and astrocytic cell types. On the other hand, baboons injected with LA exhibited neuropil threads and few glial lesions but lacked phospho-tau intraneuronal aggregates. The occurrence of phospho-tau lesions was associated with phospho-synuclein pathology. These observations suggest a link between nigrostriatal synucleinopathy and limbic tau co-pathology, providing pathophysiological insights into PD dementia.