Tau Joins APP in the Ironworks

Mutations in tau fan the flames of Alzheimer’s, Parkinson’s, and other tauopathies. What is tau doing that gets it mixed up in so many neurodegenerative conditions? Could the answer lie not in the tangles that besmirch the brains of affected individuals, but in tau’s failure to perform a newly discovered role: promoting iron export? Ashley Bush and colleagues at the University of Melbourne in Australia report in the January 29 Nature Medicine online that without tau, amyloid precursor protein (APP) is unable to reach neurons’ surfaces, where it is needed to work the bellows that pump excess iron out of the cell. Mice missing tau develop symptoms akin to the Parkinson’s-dementia complex that afflicts many people with PD, Bush said. A gentle chelator that sops up the extra iron cures them, suggesting a potential route to treat not only Parkinson’s, but also Alzheimer’s and other conditions, Bush claims.

Tau is a microtubule-binding protein believed to support axonal traffic—but researchers are not sure what kind of cargo might be most important. “We think it is APP,” Bush said. “We feel this is the strongest evidence that the problem [in Parkinson’s] is the loss of iron homeostasis.” Cells need iron, but not too much since it can participate in the formation of dangerous free radicals. Iron is also found in amyloid plaques and tau tangles (Smith et al., 1997). Bush has been chasing the question of metal malfunction in neurodegeneration for years, systematically scouring Alzheimer’s proteins for a potential role in metal management. His group implicated presenilins in cellular uptake of zinc and copper (Greenough et al., 2011) and APP in iron export (see ARF related news story on Duce et al., 2010). In the current paper, first author Peng Lei and colleagues focused on tau but ended up extending APP’s function in iron metabolism beyond Alzheimer’s and into Parkinson’s, noted Jack Rogers of Massachusetts General Hospital in Boston, who was not involved with this study but has collaborated with Bush in the past.

Although tau knockout mice have been around for a decade, they have no neurodegeneration (Dawson et al., 2001). However, scientists had not looked beyond seven months, Bush said. Lei and colleagues decided to wait until the animals reached a year old. “Lo and behold, 12 months onward their brains fall to pieces,” Bush said.

At one year, the brains of tau knockout mice weighed less than wild-type mouse brains of the same age, and their neocortex and cerebellar cortex were atrophied. They also had fewer dopaminergic neurons in the substantia nigra and performed poorly on locomotor tests. Most relevant to Lei and Bush’s interests, the mice accumulated iron in the cortex, hippocampus, and substantia nigra, and treatment with the Parkinson’s drug L-dopa reversed the motor symptoms.

The aged tau knockout mice represent an interesting new model for PD, commented Julie Andersen of the Buck Institute for Research on Aging in Novato, California, who was not involved with the paper. The model is a chronic, age-related condition, unlike the commonly used acute parkinsonism model caused by the chemical MPTP. On the con side, she added that the neurodegeneration seems to involve less dopaminergic neuron loss than human Parkinson’s, and it occurs not only in the substantia nigra, but also in the ventral tegmental area. “It is not perfect,” she said, “but then, no mouse model for neurodegeneration is.”

Could iron and tau be connected in people? Lei examined brain tissue from people who died with Parkinson’s and detected less soluble tau, but more iron, in their substantia nigras than in the same region from age-matched controls. Other scientists have observed lowered tau concentrations in the tauopathies Alzheimer’s and frontotemporal dementia (Ksiezak-Reding et al., 1988; Zhukareva et al., 2003).

The group has been extensively testing the metal-chelating drug clioquinol as a therapeutic. Bush and Andersen used it to protect against MPTP-induced symptoms in mice (see ARF related news story on Kaur et al., 2003), and Bush and colleagues used it to bust plaques in AD model mice (see ARF related news story on Cherny et al., 2001) and treat people with AD in a pilot study (see ARF related news story on Ritchie et al., 2003). Added to mouse chow, clioquinol blocked iron accumulation, neurodegeneration, and Parkinson’s-like symptoms seen in untreated tau-deficient mice as they aged. “It worked brilliantly,” Bush said.

The inverse relationship between iron and tau reminded the researchers of their discoveries with APP and iron. They used primary cortical neurons from the tau knockout strain to look for effects on APP. Although the tau-negative neurons contained plenty of APP, it failed to mature and reach the cell surface. The knockout neurons accumulated iron and were sensitive to iron toxicity. The findings suggest that tauopathies might not only be caused by a gain of toxic function due to neurofibrillary tangles, but also a loss of tau’s natural function in iron homeostasis, Andersen said. “APP, tau, etc., play a critical physiological role,” said George Perry of the University of Texas at San Antonio, who was not involved with the study. “Those processes are really part of how cells regulate themselves normally.”

The paper “adds to the evidence that iron accumulation, which continues into old age, may be part of the ‘age’ component of age-related neurodegenerative diseases such as AD, PD, and HD, and also why men (who have higher brain iron levels than women) may get these diseases earlier than women,” wrote George Bartzokis of the University of California, Los Angeles, in an e-mail to ARF (Bartzokis et al., 2007). Bartzokis was not involved in the study.

Returning iron levels to normal, Bush thinks, should be therapeutic. Prana Biotechnology Limited in Parkville, Australia, a company Bush co-founded but is no longer associated with, has tested a second-generation clioquinol-like compound called PBT2 in Alzheimer’s, and is starting a Huntington’s trial. In addition, Rogers warned that researchers developing therapies targeted at APP or tau might want to monitor effects on iron metabolism.

Reference:
Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012 Jan 29. Doi:10.1038/nm.2613. Abstract


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