Affiliations: [a] Department of Pathology, University of Maryland, Baltimore, MD, USA | [b] Department of Neuropsychiatry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan | [c] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA | [d] College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA
Correspondence:
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Corresponding author: Rudy J. Castellani, MD, Division of Neuropathology, 22 South Greene Street, Baltimore, MD 21201, USA. Tel.: +1 410 328 5422; Fax: +1 410 328 5508; E-mail: rcastellani@som.umaryland.edu.
Note: [] Communicated by Ralph Martins
Abstract: Identification of phosphorylated tau as the major protein component of neurofibrillary tangles (NFTs) led to the concept that phosphorylated tau was inherently toxic and, as such, intimately involved in Alzheimer's disease (AD) pathogenesis. While superficially logical, this construct ignores a number of key findings in AD, including i) that NFTs are encountered in viable neurons until late stage disease; ii) that NFTs persist within the neuronal cytoplasm for decades; iii) that NFTs are encountered, sometimes in significant numbers, in cognitively intact elderly; and iv) that neurons with NFTs contain normal content and structure of microtubules. Experimental data in transgenic animal models has further demonstrated that NFTs accumulate in neurons in spite of tau suppression and behavior normalization. These data call into question the inherent toxicity of phosphorylated tau, seemingly leaving the only viable hypothesis of the ad hoc “toxic intermediate” phosphorylated tau concept. However, since we also know that phosphorylated tau sequesters redox active heavy metals and protects against oxidative stress, here we suggest that phosphorylated tau serves a protective role against cellular toxicity.
