TNMD BRICHOS domain attenuates tau pathology and memory deficits in a mouse model of tauopathy.

The aberrant aggregation of tau leads to loss of its physiological functions and gain of toxic functions, and plays a crucial role in the pathogenesis of tauopathies including Alzheimer's disease (AD). Targeting tau aggregation is considered a promising strategy for treating tauopathies. The BRICHOS family consists of a variety of proteins containing the BRICHOS domain. Certain endogenous BRICHOS domains may inhibit the pathological aggregation of disease-associated proteins. However, the effects of the BRICHOS domains on tau aggregation remain unknown. Here we revealed that BRICHOS domains from integral membrane protein 2B (ITM2B), tenomodulin (TNMD), and out at first (OAF) bind to tau and inhibit its aggregation in vitro. Intravenous administration of TNMD BRICHOS alleviates tau aggregation, synaptic dysfunction, and memory deficits in Tau P301S transgenic mice. Thus, TNMD BRICHOS may serve as a potential therapeutic approach for the development of treatments for tauopathies.