Distinct subcellular localization of tau and alpha-synuclein in lewy body disease

Lewy bodies and neurofibrillary tangles, composed of alpha-synuclein (alpha-syn) and tau, respectively, often are found together in the same brain and correlate with worsening cognition. Human postmortem studies show colocalization of alpha-syn and tau occurs in Lewy bodies, but with limited effort to quantify colocalization. In this study, postmortem middle temporal gyrus tissue from decedents (n = 9) without temporal lobe disease (control) or with Lewy body disease (LBD) was immunofluorescently labeled with antibodies to phosphorylated alpha-syn (p-alpha-syn), tau phosphorylated at Ser202/Thr205 (p-tau), or exposure of tau's phosphatase-activating domain (PAD-tau) as a marker of early tau aggregates. Immunofluorescence for major-histocompatibility complex class 2 (MHCII) and ionized calcium binding adaptor molecule 1 (Iba1) also was performed because inflammation is an additional pathological hallmark of LBDs, and they were a positive control for two markers known to colocalize. The abundance of p-alpha-syn, p-tau, and MHCII was significantly associated with diagnosis of LBD. Quantification of colocalization showed that MHCII and Iba1 colocalized, demonstrating activated immune cells are mostly microglia. However, p-alpha-syn rarely colocalized with p-tau or PAD-tau, although the overlap of p-alpha-syn with PAD-tau was significantly associated with LBD. In the rare cases pathologic alpha-syn and pathologic tau were found in the same Lewy body or Lewy neurite, tau appeared to surround alpha-syn but did not colocalize within the same structure. The relationship between tau and alpha-syn copathology is important for explaining clinical symptoms, severity, and progression, but there is no evidence for frequent, direct protein-protein interactions in the middle temporal gyrus.