Tauopathy primes co-filament assembly and dysfunction of TDP-43

While most Alzheimer’s disease (AD) which is associated with L imbic P redominant A ge-related T DP-43 E ncephalopathy (LATE) exhibits accelerated brain atrophy, the pathogenic mechanism remains elusive. We show here, in mice harboring depositions of amyloid-β and tau, the age-dependent emergence of TDP-43 proteinopathy. We demonstrate that TDP-43 dysfunction facilitates caspase 3-mediated endoproteolysis of tau, accelerates tauopathy and exacerbates neuron loss. Unexpectedly, we found that the emergence and spread of TDP-43 proteinopathy is associated with the spread of tauopathy and correlated with co-filament assembly of tau and TDP-43. Importantly, TDP-43 dysfunction precedes such co-filament assembly and TDP-43 cytoplasmic aggregates. Consistent with the idea that tauopathy could prime co-filament assembly and proteinopathy of TDP-43 to exacerbate neurodegeneration, we found tau co-filament assembly with TDP-43 in AD and AD-LATE cases. These findings suggest that TDP-43 dysfunction accelerates tauopathy, which, in turn, primes co-filament assembly and dysfunction of TDP-43 to exacerbate neuron loss in AD-LATE, a pathogenic mechanism disclosing novel targets and therapeutic strategies.