Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present a case of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) harboring the N279K mutation in the MAPT gene from the family known as pallido-ponto-nigral degeneration (PPND). This 49-year-old man was followed for 17 years. He presented at age 41 years with left leg stiffness and en-bloc turning. During the course of his illness he developed a constellation of symptoms including parkinsonism, pyramidal signs, vertical gaze palsy, dysphagia, dystonia, personality and cognitive dysfunction, weight loss and mutism. Gross neuropathological examination showed mild atrophy of the cerebral cortex, hippocampal formation, amygdala, thalamus, subthalamic nucleus and depigmentation of the substantia nigra. Microscopy revealed neuronal loss and gliosis in the same regions. Tau immunohistochemistry showed pretangles, numerous threads, grain-like structures and oligodendroglial tau-positive inclusions ("coiled bodies"). In the spinal cord the tau pathology was more abundant in gray than white matter. Pretangles and threads were present in the anterior and, to a lesser extent, in the posterior horns. FTDP-17 should be suspected in patients with a history of familial parkinsonism combined with behavioral and cognitive changes, onset before age 65 years and an aggressive clinical course.
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PMID:Frontotemporal dementia and Parkinsonism linked to chromosome 17 with the N279K tau mutation. 1731 86

According to Evidence-Based-Medicine, any proposal for the rationale treatment of mild cognitive impairment (MCI) must be based on the results of double-blind, randomized clinical trials (RCTs). However, since MCI at the present time does not constitute a homogeneous clinical syndrome, it is still inappropriate to propose a specific drug treatment. Moreover, RCTs assessing the therapeutic value of acetylcholinesterase-inhibitors (AChEIs) are negative either trying to improve symptoms (memory performance) or preventing the conversion from MCI to real Alzheimer's Disease (AD). The same negative results were obtained with drugs targeting some systems considered as the early steps of the pathophysiological cascade leading to dementia: non-steroidal anti-inflammatory compounds (rofecoxib), sex steroid hormones (testosterone, estrogens), or antioxidants (tocopherol). Either MCI is considered as the very early phase of development of AD (and then the treatments will aim at preventively antagonizing the hallmarks of the disease) or MCI is a new entity (and then the drugs will target the associated neurochemical disturbances such as tau protein or soluble Abeta oligomers); MCI could also be considered as a monosymptomatic syndrome (amnesia) leading to the development of pure pro-mnestic drugs. These three hypotheses will be presented on the basis of the neurobiology and the pharmacology, and examples of potentially active candidates will be discussed.
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PMID:Treatment of the mild cognitive impairment (MCI). 1741 6

Recent advances in our understanding of neurobiology of Alzheimer's disease (AD) demonstrate that AD starts with accumulation of amyloid beta-protein (Abeta) followed by abnormal phosphorylation of tau protein and a massive neuron death in vulnerable brain areas. We have shown that cerebrospinal fluid tau and phosphorylated tau are elevated in subjects with mild cognitive impairment, the earliest detectable clinical stage of dementia and AD, suggesting that the pathogenic cascade of AD may arrive at the stage that finally leads to an accumulation of abnormally phosphorylated tau in the MCI stage. These results may highlight the need to develop another diagnostic tool that reliably monitors and visualize brain beta-amyloid burden in living subjects who are at increased risk of developing AD. We assume that the detection of asymptomatic stage of AD followed by an early intervention may lead to maximum therapeutic benefits. In an attempt to accomplish this goal, we have generated several novel chemicals that specifically bind to Abeta peptide upon entry into mouse brain. The "amyloid imaging" seems closest to ideal biomarker if safely and successfully applied in humans because this non-invasive technique can also monitor treatment outcome following anti-Abeta therapy.
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PMID:[From neuropathology to biomarker development in Alzheimer research]. 1743 24

In order to improve diagnosis of Alzheimer's disease (AD), candidate biological markers in CSF as well as structural and functional imaging were investigated. Biomarkers are clearly needed to support detection of incipient AD in subjects with mild cognitive impairment (MCI). To date the most promising core candidate markers are total and hyperphosphorylated tau protein and amyloid beta peptides in the CSF, as well as hippocampus and whole brain volumetry using MRI. None of the candidates has been finally validated and established for clinical routine so far. International controlled multicenter cooperative studies are ongoing to further develop these core diagnostic marker candidates (phase III). The core markers are reviewed in detail. Promising novel approaches are discussed.
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PMID:[Neurobiological early diagnosis of Alzheimer's disease]. 1761 28

Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques and neurofibrillary tangles (NFTs), the major constituents of which are amyloid beta protein (A beta) and tau protein, respectively. Based on the disease pathology, numerous blood and cerebrospinal fluid (CSF) tests have been proposed for early detection of AD. However, there is no definite clinical method to determine in which patients with mild cognitive impairment will progress to AD with dementia. Therefore, to develop a novel promising biomarker for early diagnosis of AD is urgently needed. Several epidemiological studies have reported moderately increased risks for AD in diabetic patients compared with general population. In diabetes mellitus, the formation and accumulation of advanced glycation end-products (AGEs), senescent macroprotein derivatives, progress more rapidly. In addition, recent understanding of this process has confirmed that AGEs-their receptor (RAGE) interactions may play a role in the pathogenesis of neurodegenerative disorders including AD. In human AD brains, AGEs are distributed in the cytosol of neurons in the hippocampus and para-hippocampal gyrus. In this paper, we discuss the pathophysiological role for toxic AGEs (TAGE) in AD. We further review here the possibility that serum or cerebrospinal fluid levels of TAGE could become a promising biomarker for early detection of AD.
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PMID:Diagnostic utility of serum or cerebrospinal fluid levels of toxic advanced glycation end-products (TAGE) in early detection of Alzheimer's disease. 1788 85

Prevention of Alzheimer disease (AD) is a national and global imperative. Therapy is optimally initiated when individuals are asymptomatic or exhibit mild cognitive impairment (MCI). Development of therapeutically beneficial compounds requires the creation of clinical trial methodologies for primary and secondary prevention. Populations in primary prevention trials selected only on the basis of age will have low rates of emergent MCI or AD. Epidemiologically based risk factors or biomarkers can be used to enrich trials and increase the likelihood of disease occurrence during the trial. Enrichment strategies for clinical trials with MCI include use of biomarkers such as amyloid imaging, MRI with demonstration of medial temporal lobe atrophy, bilateral parietal hypometabolism on PET, and reduced amyloid beta peptide and increased tau protein in CSF. Neuropsychological measures appropriate for trials of MCI may not be identical to those measures most suited for AD trials. Attention to these and other features of trial design, clinical assessment, and use of biomarkers is critical to improving the detection of disease-modifying effects of emerging therapies in presymptomatic or minimally symptomatic populations. The neurologic health of the growing aging population demands disease-modifying therapies and the development of methods to identify and test promising candidate agents.
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PMID:Disease-modifying therapies for Alzheimer disease: challenges to early intervention. 1793 73

The deposition of highly phosphorylated microtubule-associated tau protein has been observed in ALS with cognitive impairment (ALSci). In these studies, we have examined whether the expression of two candidate protein kinases for mediating tau hyperphosphorylation (GSK3beta or CDK5) are also altered. The expression of GSK, CDK and p25/p35 was assayed in human frontal, hippocampal, cerebellar, cervical (dorsal and ventral) and lumbar (dorsal and ventral) tissue from neurologically intact control (5), ALS (5) or ALSci (5) patients using RT-PCR, Western blot or immunohistochemistry. To assess GSK-3beta activity, we examined GSK3beta, phospho-GSK3beta and phospho-beta-catenin expression. Expression levels relative to that of beta-actin were compared by ANOVA. The expression of GSK, GSK3beta and phospho-GSK3beta was increased in both ALS and ALSci compared to that of the control. This was accompanied by an increased expression of phospho-beta-catenin. No significant difference between control, ALS or ALSci was observed with respect to the expression of CDK5 or p25/p35. Both GSK3beta and phospho-GSK3beta immunoreactive neurons were mainly located in layer II and layer III in the frontal cortex and in layer II in the hippocampus. This was consistent with the previously described distribution of hyperphosphorylated tau bearing neurons in ALS and ALSci. These data suggest that GSK3beta expression is upregulated in ALS and ALSci and that GSK3beta activation is associated with the intraneuronal deposition of hyperphosphorylated tau protein. This supports the potential role for GSK3beta as a therapeutic target in ALS.
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PMID:Upregulation of GSK3beta expression in frontal and temporal cortex in ALS with cognitive impairment (ALSci). 1822 34

The aim of this review is to present current state of the art on the field of routine neurochemical dementia diagnostics (NDD) with a focus on cerebrospinal fluid (CSF) biomarkers: amyloid beta peptides, tau protein, and its phosphorylated form (pTau). After several years of experience, it is reasonably to postulate that CSF biomarkers analysis is an increasingly important tool within the early and differential diagnosis of dementia syndromes. Actual research activities are briefly discussed, too, including: (i) possibilities and limitations of the diagnosis of incipient Alzheimer's disease in preclinical stages (e.g., mild cognitive impairment), (ii) the role of multiplexing technologies in dementia biomarkers research, (iii) the role of biomarkers in differential diagnosis of dementia syndromes, (iv) approaches to improve analytical performance of available methods, and (v) research activities to identify dementia biomarkers in blood.
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PMID:Neurochemical dementia diagnostics: State of the art and research perspectives. 1827 Oct 68

Oxidative damage is associated with Alzheimer's disease and mild cognitive impairment, but its relationship to the development of neuropathological lesions involving accumulation of amyloid-beta (Abeta) peptides and hyperphosphorylated tau protein remains poorly understood. We show that inducing oxidative stress in primary chick brain neurons by exposure to sublethal doses of H(2)O(2 )increases levels of total secreted endogenous Abeta by 2.4-fold after 20 h. This occurs in the absence of changes to intracellular amyloid precursor protein or tau protein levels, while heat-shock protein 90 is elevated 2.5-fold. These results are consistent with the hypothesis that aging-associated oxidative stress contributes to increasing Abeta generation and up-regulation of molecular chaperones in Alzheimer's disease.
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PMID:Oxidative stress increases levels of endogenous amyloid-beta peptides secreted from primary chick brain neurons. 1869 Nov 84

We exploratively measured APPs alpha, a secreted fragment of the non-amyloidogenic cleavage of amyloid precursor protein via a-secretase, and tau protein phosphorylated at threonine 181 (p tau) in the cerebrospinal fluid of 10 patients with mild cognitive impairment, 20 patients with dementia of Alzheimer's type, and 10 controls. Cerebrospinal fluid APPs alpha and p tau levels were correlated with cognitive performance. P tau levels were significantly elevated in mild cognitive impairment and in patients with dementia of Alzheimer's type, APPs alpha levels were significantly reduced in patients with dementia of Alzheimer's type compared to the controls. APPs alpha levels were associated with Mini Mental State Examination total scores but not with Delayed Verbal Recall Test performance. Vice versa, pt au levels correlated only with Delayed Verbal Recall Test in patients with dementia of Alzheimer's type or mild cognitive impairment. Both, an increase in p tau levels and a decrease in cerebrospinal fluid APPs alpha, seem to refer to relevant but functionally different processes in the development of mild cognitive impairment and dementia of Alzheimer's type.
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PMID:CSF APPs alpha and phosphorylated tau protein levels in mild cognitive impairment and dementia of Alzheimer's type. 1907 34


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