9 December 2011. It’s become conventional wisdom in
Alzheimerology that tau pathology tends to track with mental decline
in people with Alzheimer’s dementia, yet several years ago scientists
found, to their surprise, that certain tauopathy mice actually have
sharper cognition than wild-type mice early in life, before cognition
tanks later on. Now, a study in the December 7 Journal of
Neuroscience suggests that clues to this conundrum lie in dendritic
spines. Fred Van Leuven and colleagues at the University of Leuven in Belgium
report that young, brainy tau P301L mice have
faster-maturing, longer spines than older siblings whose cognition is slipping. The older tau mice have stubby spines and sprout more of them, relative to control mice with normal tau. In addition, biochemical and immunohistochemical experiments help bolster the notion that tau’s physiological actions differ widely from its pathological doings.
Transgenic mice expressing P301L mutant human tau develop
neurofibrillary tangles and motor problems, and most die before 10
months of age (Terwel et al., 2005). Curiously,
though, in their youth (eight to 10 weeks of age), these same mice have
increased long-term potentiation in the dentate gyrus and outperform
wild-type littermates in a test of object recognition memory (ARF related news story on Boekhoorn et al., 2006). “It was a
surprise that mutant tau could actually be beneficial,” Van Leuven said.
To probe the underlying mechanism, his team looked at what tau was doing
to dendritic spines. First author Anna Kremer and colleagues crossed tau
P301L mice—as well as the tau 4R strain expressing
wild-type human tau at similar levels—with yellow fluorescent protein
(YFP) mice to visualize axons, dendrites, and dendritic spines in vivo in
bigenic progeny. Using confocal microscopy, the researchers imaged four
brain areas affected by tauopathy and AD—the stratum, radiatum,
and stratum oriens in the hippocampus, and cortical layer III above the
striatum and above the hippocampus. They did so in young (one- to two-month-old) and adult (seven- to eight-month-old) mice. They measured the spine density,
spine length, and spine maturation index, the last being the
ratio of mushroom spines—which have mature, functional synapses—to all
other spine types.
Analyzing nearly 58,000 spines in total for 20 mice, Kremer and
colleagues found that, relative to YFP-only controls, young tau P301L
mice sprouted normal numbers of spines, but an unusually high proportion
of them were mature. In adult P301L transgenics, maturation index and
spine length returned back to control levels, yet spine density remained high. The team saw similar effects in adult tau 4R mice,
suggesting that wild-type and mutant tau may affect spine
formation and morphology in comparable ways.
The researchers analyzed tau P301L and wild-type mouse brain for
biochemical markers that could explain how tau proteins drive spine
changes. They found both human P301L tau and endogenous mouse tau in
synaptosomes, as judged by Western blot. However, immunohistochemistry
using a variety of methods failed to detect appreciable amounts of mouse
tau in dendritic spines; only human transgenic tau was there. This
suggests that “tau’s actions in physiological conditions are quite
different from its actions in pathological conditions,” Van Leuven said.
Jochen Herms of Ludwig-Maximilians University in Munich, Germany,
pointed out, as did the authors, that it is possible that spine changes could
result not only from dendritic pathology, but also from axonal signals.
Axonal pathology has been shown to cause secondary spine loss in other
tau-overexpressing transgenic mice, Herms noted in an e-mail to ARF. Tau
is predominantly an axonal protein (see Hoover et al., 2010; Zempel et al.,
moving into soma or dendrites when abnormally phosphorylated (see ARF related news story).
The mechanism behind the accelerated spine maturation
in young tau P301L mice remains unknown. Dezhi Liao of the University of
Minnesota, Minneapolis, speculated the enhancement could be due to
compensation effects. Liao and others have shown that spine density and
maturation goes up when AMPA receptor activity is blocked in cultured
neurons, for instance (Liao et al., 1999; O’Brien et al., 1998).—Esther Landhuis.
Kremer A, Maurin H, Demedts D, Devijver H, Borghgraef P, Van Leuven F.
Early Improved and Late Defective Cognition Is Reflected by Dendritic
Spines in Tau.P301L Mice. J Neurosci. 7 Dec 2011;31(49):18036-47. Abstract