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The Journal of Neuroscience, September 8, 2004, 24(36):7895-7902; doi:10.1523/JNEUROSCI.1988-04.2004

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Neurobiology of Disease
Early N-Terminal Changes and Caspase-6 Cleavage of Tau in Alzheimer's Disease

Peleg M. Horowitz,¹ Kristina R. Patterson,¹ Angela L. Guillozet-Bongaarts,¹ Matthew R. Reynolds,¹ Christopher A. Carroll,⁴ Susan T. Weintraub,⁴ David A. Bennett,⁵ Vincent L. Cryns,^1,2 Robert W. Berry,^1,3 and Lester I. Binder^1,3

¹Department of Cell and Molecular Biology, ²Cell Death Regulation Laboratory, Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, and ³Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, ⁴Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, and ⁵Department of Neurological Sciences and Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois 60612

Alzheimer's disease (AD) is a progressive amnestic dementia that involves post-translational hyperphosphorylation, enzymatic cleavage, and conformational alterations of the microtubule-associated protein tau. The truncation state of tau influences many of its pathologic characteristics, including its ability to assume AD-related conformations and to assemble into filaments. Cleavage also appears to be an important marker in AD progression. Although C-terminal truncation of tau at D421 has recently been attributed to the apoptotic enzyme caspase-3, N-terminal processing of the protein remains mostly uncharacterized. Here, we report immunohistochemical staining in a cohort of 35 cases ranging from noncognitively impaired to early AD with a panel of three N-terminal anti-tau antibodies: Tau-12, 5A6, and 9G3-pY18. Of these three, the phosphorylation-independent epitope of 5A6 was the earliest to emerge in the pathological lesions of tau, followed by the appearance of the Tau-12 epitope. The unmasking of the Tau-12 epitope in more mature 5A6-positive tangles was not correlated with tau phosphorylation at tyrosine 18 (9G3-pY18). Still, later in the course of tangle evolution, the extreme N terminus of tau was lost, correlating temporally with the appearance of a C-terminal caspase-truncated epitope lacking residues 422-441. In addition, caspase-6 cleaved the N terminus of tau in vitro, preventing immunoreactivity with both Tau-12 and 5A6. Mass spectrometry confirmed that the in vitro caspase-6 truncation site is D13, a semicanonical and hitherto undescribed caspase cleavage site in tau. Collectively, these results suggest a role for caspase-6 and N-terminal truncation of tau during neurofibrillary tangle evolution and the progression of Alzheimer's disease.

Key words: Alzheimer's disease; tau; neurofibrillary tangle; caspase; truncation; tyrosine phosphorylation

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Received May 21, 2004; revised July 21, 2004; accepted July 27, 2004.

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