They are no match made in heaven, but in neurons, the two proteins responsible for amyloid plaques and neurofibrillary tangles—amyloid-β (Aβ) and tau—might interact temporarily. So conclude Pat McGeer and colleagues in an advanced online publication in this week’s PNAS. They report that Aβ and tau bind to each other with considerable avidity in vitro, and that the liaison promotes phosphorylation of tau.
Though plaques and tangles are the major hallmarks of AD, establishing a solid link between them has been difficult. While mutations that lead to increased production of Aβ cause AD, tau mutations that promote neurofibrillary tangles cause a different form of disease, frontotemporal dementia. This suggests that the two proteins move in distinct circles. And yet there are also reports that these circles may overlap at times. Recent evidence that the two proteins conspire pathologically has come from Frank LaFerla’s lab at the University of California, Irvine. His work has shown that antibodies that mop up Aβ also reduce neurofibrillary tangles (see ARF related news story and Oddo et al., 2006). Other evidence also points to common pathways involving microtubule trafficking (see ARF related news story) and signal transduction through the Cdk5 (see ARF related news story), GSK3 (see ARF related news story), and Akt kinases (see ARF related news story). But if confirmed, the finding by McGeer and colleagues at the University of British Columbia, Vancouver, and at the Tokyo Institute of Psychiatry, Japan, could put some icing on the Aβ/tau cake.
First author Jian-Ping Guo and colleagues used simple Western blots to show that tau and Aβ formed complexes in vitro that survive detergent (SDS) and boiling. When Aβ40 or Aβ42 was added to recombinant, full-length tau, the complexes could be detected with either tau (tau 12, recognizing both phosphorylated and unphosphorylated protein) or Aβ (4G8, which detects either Aβ40 or Aβ42) antibodies. Furthermore, adding Aβ to the mix stimulated phosphorylation of tau by GSK3β, an indication that Aβ might directly promote the formation of neurofibrillary tangles in vivo (see also ARF SfN news story).
To hone in on the tau-Aβ binding site, the authors incubated Aβ with membrane-bound tau peptides and vice versa. This revealed that binding occurs between exons 7 and 9 of tau and the mid to C-terminal end of Aβ. These tau exons harbor threonine 212 and serines 214, 356, and 396, all subject to phosphorylation. Indeed, Guo showed that phosphorylation at T212 completely eliminates Aβ binding. Coupled with Aβ’s ability to enhance phosphorylation of tau, this suggests that the relationship between the two proteins may be short-lived because Aβ would probably change tau and drive the pair apart.
The paper does not answer the question of whether the two proteins interact in this fashion in vivo. Because Aβ is cleaved from its precursor protein (AβPP) on the luminal side of vesicles or extracellularly in the case of the cell membrane, it is not obvious how the two proteins meet. Several labs have detected intraneuronal Aβ deposits (see ARF related conference story and ARF conference story), and Guo and colleagues detected Aβ/tau complexes in brain tissue samples using an ELISA test that employed a tau antibody for capture and an Aβ antibody for detection; the signal from AD brain tissue was slightly higher than normal. They also report some data for co-localization of Aβ and tau in human neurofibrillary tangles in neurons of the entorhinal cortex. Guo et al. hypothesize that “an initial step in the pathogenesis [of AD] may be the intracellular binding of soluble Aβ to soluble non-phosphorylated tau, thus promoting tau phosphorylation and Aβ nucleation.” If true, then preventing this marriage could, in one fell swoop, prevent both neurofibrillary tangles and amyloid plaques.—Tom Fagan
- Tackling Alzheimer’s from the Outside In
- Tau Accused of Blocking Transport, Causing APP to Linger and Nerve Processes to Wither
- Aiding and Abetting, Hyperactive CDK5 Gives Mouse Tangles
- Lithium Hinders Aβ Generation, Buffing Up GSK as Drug Target
- SfN: Where, How Does Intraneuronal Aβ Pack Its Punch? Part 4
- SfN: Amyloid Oligomers—Not So Elusive, After All? Part 2
- Philadelphia: The Enemy Within—Neurodegeneration From Intraneuronal Aβ
- SfN: Where, How Does Intraneuronal Aβ Pack Its Punch? Part 1
- Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, Laferla FM. Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem. 2006 Jan 20;281(3):1599-604. PubMed.
No Available Further Reading
- Guo JP, Arai T, Miklossy J, McGeer PL. Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1953-8. PubMed.