Affiliations: [a] Departments of Pathology and Laboratory Medicine, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA | [b] Departments of Pathology and Neurology, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA | [c] Department of Geriatric Medicine, Tohoku University School of Medicine, Sendai, Japan
Correspondence:
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Corresponding author: Dr. J.Q. Trojanowski, Department of Pathology and Laboratory Medicine, The University of Pennsylvania School of Medicine, HUP, Maloney Bldg., Room A009, Philadelphia, PA 19104-4283, USA, E-mail: trojanowski@mail.med.upenn.edu.
Note: [*] This article is published with permission from the University of Kentucky. It is also published in the online journal Alzheimer's Disease Review; www.coa.uky.edu/ADReview/.
Abstract: Alzheimer's disease (AD) is a heterogeneous group of dementias characterized by progressive cognitive impairments as well as by the accumulation of abundant extracellular deposits of Aß and intra-neuronal neurofibrillary lesions in selectively vulnerable regions of the AD brain. The latter abnormalities (e.g. neurofibrillary tangles, dystrophic neurites, neuropil threads) are aggregates of paired helical filaments (PHFs) formed from altered tau proteins (PHFtau). Although PHFtau and normal central nervous system (CNS) tau are phosphorylated at nearly the same sites, PHFtau is phosphorylated to a greater extent, and alterations in the activity of CNS kinases and phosphatases most likely contribute to the pathogenesis of PHFtau. Since the abundance of neurofibrillary lesions correlates with the dementia in AD, the generation of PHFtau and the formation of neurofibrillary lesions may be part of a cell death pathway leading to massive neuron loss and dementia in AD. Building upon these and other insights into altered tau metabolism in AD, a series of studies suggest that the diagnosis of AD may be supported in living patients by determining the concentration of tau in cerebrospinal fluid (CSF). We review these promising studies here, and discuss them in the context of current understanding of the pathobiology of AD.
