Elevated Levels of τ and Ubiquitin in Brain and Cerebrospinal Fluid in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is histopathologically characterized by the presence of numerous neurons with neurofibrillary tangles of paired helical filaments (PHF) in the neocortex, particularly the hippocampus. The major protein subunit of PHF, which also accumulate as neuropil threads and dystrophic neurites of the neuritic (senile) plaques, is the microtubule-associated protein τ. τ in AD brain is abnormally hyperphosphorylated. In addition to hyperphosphorylation, some of the AD τ is also ubiquitinated. The level of τ in AD brain is elevated severalfold, and this increase is in the form of the abnormally phospholylated τ. The levels of conjugated ubiquitin are also increased severalfold in AD brain. The cerbrospinal fluid (CSF) levels of both τ and ubiquitin are elevated in AD. However, some of the normal elderly and non-AD neurological control cases also show elevated levels of these two proteins in the CSF. At present, it is not clear whether the overlap in CSF τ or ubiquitin values between AD and the control groups is due to some unknown heterogeneity of AD, inclusion of presymptomatic AD cases in the control group, or lack of specificity of the CSF elevation of these markers to AD. Thus, until the results of prospective studies on many patients with AD and normal controls become available, the CSF τ and ubiquitin levels can be used only as additional tools in the psychometric and clinical diagnosis of AD.