Effect of tau silencing on tau pathology propagation, a treatment efficient at the earliest stages of the disease?

Cognitive decline in Alzheimer's disease (AD) correlates more strongly with tau pathology than with amyloid plaques, switching the therapeutic focus towards targeting tau pathology. Tau silencing therapies present an increasing interest as potential therapeutical approaches to treat AD due to their efficiency in reducing pathological tau burden. However, the effects of tau silencing on tau pathology formation and spreading, as well as on cognitive deficits, have not been investigated in AD or AD preclinical models expressing WT tau. In this study, we investigated the effects of Tau siRNA on tau pathology propagation in a mouse model of AD expressing 6 human WT tau isoforms, in which tau pathology formation and spreading has been initiated by intracerebral injection of pathological tau from a human AD brain. Specifically, we examined whether tau silencing affects tau pathology progression when started either simultaneously with the induction of tau pathology or subsequent to the onset of tau lesions, thereby mimicking the clinical scenario in which AD patients are typically diagnosed. Three months after tau pathology was induced, spatial learning and tau pathology were assessed. Cognitive performance was rescued, and tau pathology development was reduced when tau silencing started simultaneously with the induction of tau lesions. Nevertheless, Tau siRNA was ineffective on both cognitive performance and tau pathology propagation when administered after some development of tau pathology. Our results indicate that tau silencing therapy should be administered in early stages of the disease to achieve therapeutic efficacy on the development of tau pathology in AD.