PT - JOURNAL ARTICLE AU - Peleg M. Horowitz AU - Kristina R. Patterson AU - Angela L. Guillozet-Bongaarts AU - Matthew R. Reynolds AU - Christopher A. Carroll AU - Susan T. Weintraub AU - David A. Bennett AU - Vincent L. Cryns AU - Robert W. Berry AU - Lester I. Binder TI - Early N-Terminal Changes and Caspase-6 Cleavage of Tau in Alzheimer's Disease AID - 10.1523/JNEUROSCI.1988-04.2004 DP - 2004 Sep 08 TA - The Journal of Neuroscience PG - 7895--7902 VI - 24 IP - 36 4099 - http://www.jneurosci.org/content/24/36/7895.short 4100 - http://www.jneurosci.org/content/24/36/7895.full SO - J. Neurosci.2004 Sep 08; 24 AB - 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.