As the amyloid cascade hypothesis of Alzheimer's disease has it, the condition begins with growing levels of amyloid-β in the brain. The amyloid forms solid deposits with a surrounding halo of harmful biochemistry, degrading the function of nearby cells. Perhaps this is caused by failing drainage of cerebrospinal fluid, perhaps by the innate immune response to persistent infections, perhaps by other mechanisms such as the age-related failure of the immune system to clear up molecular waste as aggressively as it should. The amyloid sets the stage for mild cognitive impairment and the later deposition of altered forms of tau protein into neurofibrillary tangles. It is the tau aggregation that is associated with the real damage of Alzheimer's disease: the inflammation, the major dysfunction, the death of neurons in large numbers.
How exactly is tau wreaking such havoc, however? This is an open question, still awaiting a definitive collection of evidence and consensus. There is the hope that, given a good answer to this question, some form of molecular sabotage could prove to be the basis for a therapy to rescue patients who are far along in the progression of Alzheimer's disease. This would be an alternative to the more mainstream strategy of building ways to clear tau from the brain, analogous to the existing lines of work on anti-amyloid immunotherapies. Could this work? I'm not sure, and my feeling is that it is unlikely to be more cost effective than attempts to remove tau aggregates. Finding and blocking any one mode of damage without removing the neurofibrillary tangles will still leave all of the other modes of damage - and there will always be more than one path to harm. Biochemistry is nothing if not exceedingly complex. This is, more generally, the usual objection to adjusting the state of a diseased metabolism rather than removing the cause of disease.
The research here reports on an association between nuclear pore dysfunction and tau aggregration, and this may prove to be a significant contribution to neuronal dysfunction in tauopathies such as Alzheimer's disease. It is interesting to consider that nuclear pores in neurons contain some of the longest-lived proteins in the body. The very same molecule, the same atoms in the same configuration, might accompany you throughout life from birth to death. There is some speculation regarding these and other extremely long lived proteins as the next frontier of longevity science, the challenge that arises after all of the SENS rejuvenation programs are somewhere near completion, and we can largely repair all of the common forms of damage that cause aging. How to deal with potentially damaged molecules deep within countless vital brain cells that our biochemistry will never replace if left to its own devices? Perhaps there will be good answers to that question sooner rather than later, but it is beyond current capabilities, if not beyond present vision.
Researchers have long known that tau accumulates in the brains of individuals with Alzheimer's disease (AD), a major component of AD's hallmark neurofibrillary tangles. Precisely how tau contributes to the disease has remained a mystery. Now scientists have found that the nuclear pore complex, which controls the transport of molecules into the cell nucleus, is defective in animal and human AD cells and that the defect is associated with tau aggregation inside neurons. In a cell, the nucleus is surrounded by a membrane separating contents inside the nucleus from everything else within the cell. The nucleus communicates with the cell through the protein-rich structures known as nuclear pores. Defects in these pores have been suggested in other causes of dementia, particularly frontotemporal dementia, and in amyotrophic lateral sclerosis (ALS).
The nuclear pore complex includes more than 400 different proteins. Researchers focused on one of the major structural proteins of the pore, Nup98. In the presence of tau, the Nup98 nuclear pores are not evenly spaced throughout the structure as expected. Instead, they were physically disrupted, fewer in number, and coalesced with each other. Nup98 seemed to leak or be mislocalized in the cytoplasm of AD brain cells rather than remaining in the nuclear pore. Whenever it was mislocalized, those same cells tended to have aggregates of tau. The team found that the more extreme the AD disease was while patients were alive, at autopsy they had worse pathology related to Nup98 mislocalization with tau. In mice models, when human tau was added to cultures of living rodent neurons, Nup98 was mislocalized in the cytoplasm and functional nuclear import was disrupted.
Here, we show that phospho-tau-positive cells in human AD and tau transgenic mouse brains, as well as in cellular models of tau-related AD neuropathology, have an impaired nuclear transport. Indeed, we found that tau can interfere with nuclear pore complex (NPC) integrity in different ways. Tau directly interacts with the nucleoporin Nup98 in vitro, leads to cytoplasmic mislocalization of Nup98 in neurofibrillary tangles (NFTs) and in neurons with phospho-tau in vivo, and induces a disruption of the NPC distribution in the nuclear membrane.
Consequently, we observe failure of nuclear pore transport and diffusion-barrier properties, with changes in pore permeability to inert test molecules (dextrans) of various sizes, as well as alterations in active protein import and export, including Ran, an endogenous protein whose localization is known to be sensitive to NPC dysfunction. We further show that tau and Nup98 directly interact as assessed by co-immunoprecipitation from human AD brain tissue and surface plasmon resonance (SPR) of recombinant proteins. In addition, in vitro experiments show that Nup98 triggers tau aggregation and accelerates tau fibrilization and thereby possibly contributes to tau aggregation and tangle formation or stabilization in neuronal somata in AD and tauopathy brains.
In summary, we provide in vivo and in vitro evidence for a pathogenic model in which accumulation of tau in the somatodendritic compartment, as occurs in AD and tauopathies, increases the tau concentration in the perinuclear space and enables abnormal interaction of tau with Nups, which in turn leads to impairment in nuclear transport. These tau:Nup interactions may induce a pathological disruption of NPC function and contribute to tau-induced neurotoxicity. Targeting this pathway could provide a new therapeutic strategy for AD and similar neurodegenerative diseases.