New Discovery in Tau Pathology

TauTangle

New Discovery in Tau Pathology

      We frequently discuss what factors increase or reduce risk for Alzheimer’s disease (AD) and other memory-impairing disorders. However, with research constantly ongoing there is always more to learn. Recently, researchers discovered an important impact of misfolded tau protein in rat brains with AD that sheds some light on how tau increases risk, providing an important window into the mechanism of AD progression. Once researchers understand how tau impacts the brain, it will be much easier to discover ways to combat the process.

       Many theories exist as to how misfolded tau protein impacts neuronal communication and promotes degeneration, but few have been empirically proven or replicated. Without this key factor, researchers only know what biomarker causes the degeneration (tau) and what impairment it causes, but not how. Unfortunately, without understanding how misfolded tau leads to impairment, it’s difficult to counteract the mechanism causing the impairment. Luckily, a recent study discovered a unique relationship between tau, nitric oxide (NO), and cerebral vasculature that occurs even before tau forms neurofibrillary tangles (NFTs).

       Specifically, in rats with overexpression of mutant tau proteins, the tau can be translocated to the dendrite where it displaces an important protein called neuronal nitric oxide synthase (nNOS) involved in the production of NO in the brain. Under normal circumstances NO is a product of neural activity, signaling blood vessels in the area to expand increasing oxygen to support the increase in activity. This process is called neurovascular coupling. Neurovascular uncoupling occurs in disease models when tau proteins bind to the receptor on neurons that nNOS would normally bind to, thereby preventing NO production and transmission of the signal to expand blood vessels. Reduced blood flow to areas of high activity in the brain prevents many cellular processes that allow for optimal cognition. This is why vascular complications can induce cognitive impairment even without AD.

       Increased blood flow not only provides oxygen and nutrients to neurons, but also serves as a garbageman, taking away unnecessary or toxic proteins. Without clearance of these waste products, they build up much more quickly and induce dysfunction. Mutant tau proteins are one of these toxic molecules that would normally be cleared from the brain by the blood. When not cleared, the tau proteins can aggregate into NFTs inducing further dysfunction and even cell death.

       These findings indicate that tauopathy development supports the progression of its own NFT buildup, through reduction of vascular waste clearance, creating a cycle of impairment and degeneration. If we can find a way to override nNOS silencing by tau, we would expect cognition to improve with further clearance of tau tangles and Aꞵ due to increased blood flow, in turn slowing or halting disease progression.

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Sources:
With Tau in Synapses, NO Neurovascular Coupling [Internet]. Alzforum. 2020. Available from: https://www.alzforum.org/news/research-news/tau-synapses-no-neurovascular-coupling.
Park, L., et al. Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration [Internet]. Nature Neuroscience. 2020. Available from: https://www.nature.com/articles/s41593-020-0686-7.