As scientists in multiple groups home in on which p-tau isoform changes in which neurodegenerative disease and when, it’s easy to forget about why the protein gets phosphorylated in the first place. Kaj Blennow of the University of Gothenburg, Sweden, thinks it might be a neuroprotective response to neuronal inactivity. A crazy idea? At the Clinical Trials on Alzheimer’s Disease conference, held November 29 through December 2 in San Francisco, Blennow told an intriguing tale from the animal kingdom to support it.
As hibernating animals, such as Arctic ground squirrels and bears, overwinter, their neurons largely lie in repose—and p-tau accumulates in tangle-like structures within their hippocampal and cortical neurons. This finding was first discovered by Thomas Arendt at the University of Leipzig, Germany (Jan 2015 news). The animals’ tau is phosphorylated on the same amino acids as in humans (Stieler et al., 2011). Come spring awakening, their p-tau brain aggregates melt away like so much snow, within hours to a day.
Likewise, Karen Duff at Columbia University Medical Center in New York and Emmanuel Planel at Université Laval in Quebec, Canada, saw reversible tau hyperphosphorylation in hypothermic wild-type mice (Apr 2007 news). Planel also linked lower body temperatures during sleep to a surge in p-tau in slumbering mice (Guisle et al., 2020).
Curious about this phenomenon, Blennow partnered with Ole Fröbert at Sweden’s Örebro University Hospital, who studies brown bears in the wild. They catch the animals in the summer to adorn them with a GPS-tracking necklace, then locate the slumbering bears in the winter and bravely draw blood samples from the beasts. “This is quite heroic research, as it must be difficult to take blood from a bear when it is sleeping,” Blennow said.
Blennow’s lab obtained blood samples from 10 bears before and during hibernation. UGot’s Wagner Brum and Laia Montoliu-Gaya analyzed the animals’ p-tau using mass spectrometry and immunoassays after adapting these assays for the bears’ slightly different tau sequence.
Lo and behold, both plasma p-tau181 and p-tau217 increased two- to threefold as the bears slept, yet fell back to normal levels in the summer. Immunoassays and mass spec assays showed the same trend. “We don’t know the mechanism here, but the researchers who study tau in hibernation think phosphorylation may be a neuroprotective response to reduced neuronal activity,” Blennow said.
Blennow proposed that if neurons never rouse again, as happens in people with age-related neurodegeneration, then the p-tau aggregates may become true tangles, and tombstones of formerly active neurons.
The physiology of wintering animals reflects an adaptation of basic mammalian biology to extreme natural environments. That said, other human disease conditions offer examples of tau phosphorylation and aggregation as a consequence of neurons being damaged and going silent, Blennow said. Chronic traumatic encephalopathy (CTE), stroke, and other secondary tauopathies come to mind.
If true, this hypothesis might have profound implications. Perhaps above all this: Would tau-targeted drugs for AD work if neuronal death, due to Aβ aggregation or another upstream event such as microglial activation, drives the disease?—Chelsea Weidman Burke
- Stieler JT, Bullmann T, Kohl F, Tøien Ø, Brückner MK, Härtig W, Barnes BM, Arendt T. The physiological link between metabolic rate depression and tau phosphorylation in mammalian hibernation. PLoS One. 2011;6(1):e14530. PubMed.
- Guisle I, Gratuze M, Petry S, Morin F, Keraudren R, Whittington RA, Hébert SS, Mongrain V, Planel E. Circadian and sleep/wake-dependent variations in tau phosphorylation are driven by temperature. Sleep. 2020 Apr 15;43(4) PubMed.