Tauopathy promotes spinal cord-dependent production of toxic amyloid-beta in transgenic monkeys.

Tauopathy, characterized by the hyperphosphorylation and accumulation of the microtubule-associated protein tau, and the accumulation of Aß oligomers, constitute the major pathological hallmarks of Alzheimer's disease. However, the relationship and causal roles of these two pathological changes in neurodegeneration remain to be defined, even though they occur together or independently in several neurodegenerative diseases associated with cognitive and movement impairment. While it is widely accepted that Aß accumulation leads to tauopathy in the late stages of the disease, it is still unknown whether tauopathy influences the formation of toxic Aß oligomers. To address this, we generated transgenic cynomolgus monkey models expressing Tau (P301L) through lentiviral infection of monkey embryos. These monkeys developed age-dependent neurodegeneration and motor dysfunction. Additionally, we performed a stereotaxic injection of adult monkey and mouse brains to express Tau (P301L) via AAV9 infection. Importantly, we found that tauopathy resulting from embryonic transgenic Tau expression or stereotaxic brain injection of AAV-Tau selectively promoted the generation of Aß oligomers in the monkey spinal cord. These Aß oligomers were recognized by several antibodies to Aß1-42 and contributed to neurodegeneration. However, the generation of Aß oligomers was not observed in other brain regions of Tau transgenic monkeys or in the brains of mice injected with AAV9-Tau (P301L), suggesting that the generation of Aß oligomers is species- and brain region-dependent. Our findings demonstrate for the first time that tauopathy can trigger Aß pathology in the primate spinal cord and provide new insight into the pathogenesis and treatment of tauopathy.

SQSTM1-mediated clearance of cytoplasmic mutant TARDBP/TDP-43 in the monkey brain.

The cytoplasmic accumulation and aggregates of TARDBP/TDP-43 (TAR DNA binding protein) are a pathological hallmark in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We previously reported that the primate specific cleavage of TARDBP accounts for its cytoplasmic mislocalization in the primate brains, prompting us to further investigate how the cytoplasmic TARDBP mediates neuropathology. Here we reported that cytoplasmic mutant TARDBP reduced SQSTM1 expression selectively in the monkey brain, when compared with the mouse brain, by inducing SQSTM1 mRNA instability via its binding to the unique 3'UTR sequence (GU/UG)n of the primate SQSTM1 transcript. Overexpression of SQSTM1 could diminish the cytoplasmic C-terminal TARDBP accumulation in the monkey brain by augmenting macroautophagy/autophagy activity. Our findings provide additional clues for the pathogenesis of cytoplasmic TARDBP and a potential therapy for mutant TARDBP-mediated neuropathology.