Physiological Tau Interactome in Brain and Its Link to Tauopathies

Alzheimer’s disease (AD) and
most of the other tauopathies
are incurable neurodegenerative diseases with unpleasant symptoms
and consequences. The common hallmark of all of these diseases is
tau pathology, but its connection with disease progress has not been
completely understood so far. Therefore, uncovering novel tau-interacting
partners and pathology affected molecular pathways can reveal the
causes of diseases as well as potential targets for the development
of AD treatment. Despite the large number of known tau-interacting
partners, a limited number of studies focused on in vivo tau interactions
in disease or healthy conditions are available. Here, we applied an
in vivo cross-linking approach, capable of capturing weak and transient
protein–protein interactions, to a unique transgenic rat model
of progressive tau pathology similar to human AD. We have identified
175 potential novel and known tau-interacting proteins by MALDI-TOF
mass spectrometry. Several of the most promising candidates for possible
drug development were selected for validation by coimmunoprecipitation
and colocalization experiments in animal and cellular models. Three
proteins, Baiap2, Gpr37l1, and Nptx1, were confirmed as novel tau-interacting
partners, and on the basis of their known functions and implications
in neurodegenerative or psychiatric disorders, we proposed their potential
role in tau pathology.