The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer’s Disease

Article type: Research Article

Authors: Dugger, Brittany N.^{a; d; *} | Whiteside, Charisse M.^{a; d} | Maarouf, Chera L.^{a; d} | Walker, Douglas G.^{a; d} | Beach, Thomas G.^{a; d} | Sue, Lucia I.^{a; d} | Garcia, Angelica^{a; d} | Dunckley, Travis^{b; d} | Meechoovet, Bessie^{b; d} | Reiman, Eric M.^{c; d} | Roher, Alex E.^{a; d}

Affiliations: [a] Banner Sun Health Research Institute, Sun City, AZ, USA | [b] Translational Genomics Research Institute, Phoenix, AZ, USA | [c] Banner Alzheimer’s Institute, Phoenix, AZ, USA | [d] Arizona Alzheimer’s Consortium

Correspondence: [*] Correspondence to: Brittany N. Dugger, PhD, University of California San Francisco, Institute for Neurodegenerative Diseases, 675 Nelson Rising Lane, NS 312, San Francisco, CA 94158, USA. Tel.: +1 415 502 6603; Fax: +1 415 476 8386; Email: [email protected].

Abstract: Tau becomes excessively phosphorylated in Alzheimer’s disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n = 18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n = 36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p = 0.009) and pT231 (p = 0.005) in AD cases but not total tau (p = 0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p = 0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage.

Keywords: Braak NFT stage, colon, HT7, liver, PHF-1, propagation, skin, spread, submandibular gland, T231

DOI: 10.3233/JAD-150859

Journal: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 345-356, 2016