The development of cis- and trans-specific anti-tau antibodies by these authors has added very significant tools to the armory of research into AD (and the FTLD tauopathies). They have used these well to demonstrate that, while the trans isoform of tau promotes microtubule assembly, the phosphorylated cis form accumulates in the frontal cortex and hippocampus of patients with MCI and AD. The authors discuss the beneficial effects of cis->trans isomerization catalyzed by Pin1. These demonstrated accumulations of cis-p-tau are as expected, perhaps, but have never been demonstrated before, to our knowledge. We say "expected" because others’ work has shown that Pin1 function is compromised in MCI hippocampus, with the authors concluding that the oxidative inactivation of Pin1 could be involved in the progression from MCI to AD (Butterfield et al., 2006); thus, if Pin1 is the prime mediator of trans-specific tau dephosphorylation, increases in the cis form of tau would be expected in Pin1-deficient MCI or AD brain regions. Also, our own previous work has relevance here, as we showed...  Read more

The development of cis- and trans-specific anti-tau antibodies by these authors has added very significant tools to the armory of research into AD (and the FTLD tauopathies). They have used these well to demonstrate that, while the trans isoform of tau promotes microtubule assembly, the phosphorylated cis form accumulates in the frontal cortex and hippocampus of patients with MCI and AD. The authors discuss the beneficial effects of cis->trans isomerization catalyzed by Pin1. These demonstrated accumulations of cis-p-tau are as expected, perhaps, but have never been demonstrated before, to our knowledge. We say "expected" because others’ work has shown that Pin1 function is compromised in MCI hippocampus, with the authors concluding that the oxidative inactivation of Pin1 could be involved in the progression from MCI to AD (Butterfield et al., 2006); thus, if Pin1 is the prime mediator of trans-specific tau dephosphorylation, increases in the cis form of tau would be expected in Pin1-deficient MCI or AD brain regions. Also, our own previous work has relevance here, as we showed apparent deficits of Pin1 in FTD brain and also aging-related deficits of the protein in normal brain (Thorpe et al., 2004; Hashemzadeh-Bonehi et al., 2006). This creates a good case for using targeted antibodies against the cis form of p-tau in immunotherapy to prevent AD progression. A caveat to this is that proline isomerization occurs spontaneously in solution from cis to trans and vice versa, and prolyl isomerases such as Pin1 accelerate this isomerization to equilibrium. A drug or antibody that targets and removes cis-p-tau from the environment may thus result in depletion of trans-tau as well as cis-p-tau. Thus, given the beneficial role of trans-tau in microtubule assembly, there may be adverse side effects to this kind of immunotherapy.

References:
Butterfield DA, Poon HF, St Clair D, Keller JN, Pierce WM, Klein JB, Markesbery WR. Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease. Neurobiol Dis. 2006 May;22(2):223-32. Abstract

Thorpe JR, Mosaheb S, Hashemzadeh-Bonehi L, Cairns NJ, Kay JE, Morley SJ, Rulten SL. Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias. Neurobiol Dis. 2004 Nov;17(2):237-49. Abstract

Hashemzadeh-Bonehi L, Phillips RG, Cairns NJ, Mosaheb S, Thorpe JR. Pin1 protein associates with neuronal lipofuscin: potential consequences in age-related neurodegeneration. Exp Neurol. 2006 Jun;199(2):328-38. Abstract

View all comments by Stuart Rulten
View all comments by Julian Thorpe

The cis/trans configuration of tau adds another layer of complexity to the changes tau undergoes in diseases such as AD, but first of all, this study underlines that it is the serine/threonine-specific hyperphosphorylation of tau rather than any other modification (such as truncation, glycation, or nitration) that causes, at a very early stage, a gain of toxic function of tau and a loss of physiological functions. It will be interesting to see whether the findings for a role of the cis phospho-Thr231 epitope in pathogenesis can be extended to tauopathies other than AD. Furthermore, it will be crucial to determine (as the pThr231-proline motif seems to be the only tau epitope recognized by the isomerase Pin1) whether other phospho-epitopes of tau are also predominantly in the cis configuration in AD, and which enzymes regulate their cis/trans isomerization. Overall, this is an exciting study with interesting antibody tools to be exploited in a wider context.

View all comments by Jurgen Goetz