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.

Tau protein plays a critical role in the assembly, stabilization, and modulation of microtubules, which are important for the normal function of neurons and the brain. In diseased conditions, several pathological modifications of tau protein manifest. These changes lead to tau protein aggregation and the formation of paired helical filaments (PHF) and neurofibrillary tangles (NFT), which are common hallmarks of Alzheimer’s disease and other tauopathies. The accumulation of PHFs and NFTs results in impairment of physiological functions, apoptosis, and neuronal loss, which is reflected as cognitive impairment, and in the late stages of the disease, leads to death. The causes of this pathological transformation of tau protein haven’t been fully understood yet. In both physiological and pathological conditions, tau interacts with several proteins which maintain their proper function or can participate in their pathological modifications. Interaction partners of tau protein and associated molecular pathways can either initiate and drive the tau pathology or can act neuroprotective, by reducing pathological tau proteins or inflammation. In this review, we focus on the tau as a multifunctional protein and its known interacting partners active in regulations of different processes and the roles of these proteins in Alzheimer’s disease and tauopathies.

Delivery of therapeutic agents into the brain is a major challenge in central nervous system drug development. The blood–brain barrier (BBB) prevents access of biotherapeutics to their targets in the central nervous system and, therefore, prohibits the effective treatment of many neurological disorders. To find blood–brain barrier shuttle peptides that could target therapeutics to the brain, we applied a phage display technology on a primary endothelial rat cellular model. Two identified peptides from a 12 mer phage library, GLHTSATNLYLH and VAARTGEIYVPW, were selected and their permeability was validated using the in vitro BBB model. The permeability of peptides through the BBB was measured by ultra-performance liquid chromatography-tandem mass spectrometry coupled to a triple-quadrupole mass spectrometer (UHPLC-MS/MS). We showed higher permeability for both peptides compared to N–C reversed-sequence peptides through in vitro BBB: for peptide GLHTSATNLYLH 3.3 × 10−7 cm/s and for peptide VAARTGEIYVPW 1.5 × 10−6 cm/s. The results indicate that the peptides identified by the in vitro phage display technology could serve as transporters for the administration of biopharmaceuticals into the brain. Our results also demonstrated the importance of proper BBB model for the discovery of shuttle peptides through phage display libraries.