As research progresses, it is becoming clear that the situation for amyloid-β and tau in the aging brain is quite similar at the high level. As amounts increase with advancing age, perhaps due to the progressive failure of clearance mechanisms, both produce distinct solid aggregates, neurofibrillary tangles in the case of tau, but the aggregrates themselves do not appear to be the primary harmful mechanism that damages neural function and kills cells. This open access paper takes a look at what is known of tau and its involvement in age-related neurodegeneration:
Aging has long been considered as the main risk factor for several neurodegenerative disorders including a large group of diseases known as tauopathies. Even though neurofibrillary tangles (NFTs) have been examined as the main histopathological hallmark, they do not seem to play a role as the toxic entities leading to disease. Recent studies suggest that an intermediate form of tau, prior to NFT formation, the tau oligomer, is the true toxic species. However, the mechanisms by which tau oligomers trigger neurodegeneration remain unknown.
NFTs do not appear to be the main toxic entities leading to disease. In Alzheimer’s disease, tau pathology and neuronal cell loss coincide in the same brain regions, and as brain dysfunction progresses, NFTs are found in greater anatomical distributions. However, the role of NFTs in the progression of the disease is poorly understood. Compared to non-demented controls, Alzheimer’s brains exhibit up to 50% of neuronal loss in the cortex, exceeding the number of NFTs. In addition, neurons containing NFTs are functionally intact in vivo and have been found in brains of cognitively normal individuals. Further, intra-neuronal NFTs do not affect post-synaptic function and signaling cascades responsible for long-term synaptic plasticity, suggesting that synaptic deficits cannot be attributed to NFTs.
While evidence indicates that these deposits are not toxic, many studies suggest that the tau oligomer, an intermediate entity, is likely responsible for disease onset. Hyper-phosphorylated tau assembles into small aggregates known as tau oligomers in route of NFT formation. As hyper-phosphorylated tau dislodges from microtubules, its affinity for other tau monomers leads individual tau to bind each other, forming oligomeric tau, an aggregate. These tau oligomers potentiate neuronal damage, leading to neurodegeneration and traumatic brain injury. As these granular tau oligomers fuse together, they form tau fibrils, which ultimately form NFTs. These steps hint that tau oligomers may be involved in neuronal dysfunction prior to NFT formation.
When tau oligomers, rather than tau monomers or fibrils, are injected into the brain of wild-type mice, cognitive, synaptic, and mitochondrial abnormalities follow. Additionally, studies have discovered that aggregated tau inhibits fast axonal transport in the anterograde direction at all physiological tau levels, whereas tau monomers have had no effect in either direction. This suggests that monomers are not the toxic entity either. Most noteworthy, tau oligomers induce endogenous tau to misfold and propagate from affected to unaffected brain regions in mice, whereas fibrils do not. This indicates that tauopathies progress via a prion-like mechanism dependent upon tau oligomers. With this concept, tau may be able to translocate between neurons and augment toxic tau components; in fact, evidence suggests probability of tau oligomer propagation between synaptically connected neurons. If true, then pathology begins in a small area and becomes symptomatic as it spreads to other areas of the brain.
Discovering the pathological role of tau oligomers within the brain along with related mechanisms of cellular tau oligomer secretion, propagation, and uptake will allow for a better understanding of tauopathies. Further, mitochondrial dysfunction caused by internalized tau oligomers may play an important role in pathogenesis. Admittedly, little is known regarding cellular tau oligomer release. Yet with greater knowledge regarding disease pathogenesis, better therapeutic approaches can be generated. We hypothesize that preventing tau oligomers from cellular release and uptake will relieve some toxic effects induced by tau oligomers in tauopathies.