Tau Oligomers in Alzheimer’s Disease

Misfolding and aggregation of the microtubule-associated protein tau into neurofibrillary tangles (NFTs) is a pathological hallmark of Alzheimer’s disease and other tauopathies. However, while NFTs have long been considered the main cause of neuronal cell death associated with these disorders, it is now thought that intermediate species of tau are more likely to blame. Understanding the pathological role of pre-fibrillar tau oligomers is critical to determine their potential for therapeutic targeting.

Tau is expressed as six different isoforms, ranging from 352 – 441 amino acids in length, which result from alternative splicing of the MAPT gene¹. These are found mainly in neuronal axons, where they function to regulate microtubule assembly and stability. Each tau isoform contains a minimum of 30 distinct phosphorylation sites that, under normal conditions, are in the dephosphorylated state². Yet, during the development of tauopathies such as Alzheimer’s disease, tau becomes hyperphosphorylated and undergoes conformational changes, leading to its dimerization and self-assembly into larger oligomeric aggregates³. These ultimately associate to form NFTs, which have been widely studied for their role in neurodegenerative disease pathology.

For many years, NFTs were considered to be the main toxic species responsible for neuronal cell death observed in tauopathies. However, more recent studies have suggested this not to be the case⁴. These include the finding that caspase activation (an irreversible commitment to apoptosis) precedes NFT formation in tau transgenic mice as well as the discovery that NFT-bearing neurons are able to survive despite having compromised membrane integrity^5,6. Now, there is a growing body of evidence to indicate that tau oligomers are the most toxic species in disease and may also be responsible for the spread of pathology⁷. For example, following the sonication of tau fibrils to form tau oligomers (identifiable by Western blotting using an oligomer-specific antibody, T22) and subsequent incubation with SH‐SY5Y neuroblastoma cells, tau oligomers were found to be the toxic species and were more potent in seeding compared to mature fibrils⁸.

Although the pathological role of tau oligomers in Alzheimer’s disease remains unclear, it appears increasingly likely that these soluble tau species are the most deleterious form of the protein. Research has revealed tau oligomers to be characterized by the neurotoxicity, infectivity, and capacity for amplification that underlie disease progression, and it has been hypothesized that mitochondrial dysfunction caused by internalized tau oligomers may be fundamental⁹. Notably, elevated levels of tau oligomers may represent an important early biomarker for Alzheimer’s disease, with utility prior to the appearance of clinical symptoms¹⁰.

Because tau oligomers result from hyperphosphorylation, inhibiting the kinases involved in this process is one potential approach to therapeutic intervention. Another strategy is to block tau monomers from interacting, thereby preventing oligomer formation and seeding. In the study previously described, pre-incubating tau oligomers with excess amounts of oligomer-specific T22 antibody was shown to significantly reduce cellular toxicities in vitro, thereby demonstrating the therapeutic value of targeting oligomeric forms of tau⁸.