Tau Oligomers as Potential Targets for Alzheimer’s Diagnosis and Novel Drugs (original) (raw)
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Journal of Alzheimer's disease : JAD, 2011
Alzheimer's disease is a neurodegenerative disorder involving extracellular plaques (amyloid-β) and intracellular tangles of tau protein. Recently, tangle formation has been identified as a major event involved in the neurodegenerative process, due to the conversion of either soluble peptides or oligomers into insoluble filaments. At present, the current therapeutic strategies are aimed at natural phytocomplexes and polyphenolics compounds able to either inhibit the formation of tau filaments or disaggregate them. However, only a few polyphenolic molecules have emerged to prevent tau aggregation, and natural drugs targeting tau have not been approved yet. Fulvic acid, a humic substance, has several nutraceutical properties with potential activity to protect cognitive impairment. In this work we provide evidence to show that the aggregation process of tau protein, forming paired helical filaments (PHFs) in vitro, is inhibited by fulvic acid affecting the length of fibrils and the...
The Role of Tau Oligomers in the Onset of Alzheimer's Disease Neuropathology
ACS Chemical Neuroscience, 2014
Most neurodegenerative diseases are characterized by the presence of protein aggregates. Alzheimer's disease (AD) is the most common cause of dementia in people over age 60. One of the histopathological hallmarks of AD is the presence of tau protein aggregates. Historically, it has been thought that paired helical filaments (PHFs) were the toxic form of tau that assembled to form neurofibrillary tangles (NFTs), but recently there has been evidence that tau oligomers, which form before PHFs and NFTs, could be the structures mediating neurodegeneration even before the fibrillary tau is deposited. Here, we discuss the recent advances in tau oligomer research, their implications on AD and other tauopathies, the mechanisms of tau turnover by the principal protein clearance systems (the proteasome and autophagy), and the potential use of tau oligomers as drug targets for the development of new therapeutic approaches.
Tau-Based Therapeutic Approaches for Alzheimer's Disease - A Mini-Review
Gerontology, 2014
The accumulation of aggregated, hyperphosphorylated tau as neurofibrillary tangles and neuropil threads are cardinal features of Alzheimer's disease (AD). The other lesions found in AD include amyloid plaques and congophilic amyloid angiopathy, both associated with the extracellular accumulation of the amyloid-beta (Aβ) peptide. AD is the most common cause of dementia globally. Currently, there are no effective means to treat AD or even to slow it down. The dominant theory for the causation of AD is the amyloid cascade hypothesis, which suggests that the aggregation of Aβ as oligomers and amyloid plaques is central to the pathogenesis of AD. Numerous therapies have been developed directed to Aβ-related pathology, in particular various immunotherapeutic approaches. So far all of these have failed in clinical trials. Recently, there has been more focus on therapy directed to tau-related pathology, which correlates better with the cognitive status of patients, compared to the amylo...
Role of Tau Protein in Alzheimer Disease and its Inhibitors from Plants
Pharmaceutical and Biosciences Journal, 2019
Alzheimer is a common neurodegenerative disease that affects 45 million people worldwide. Pathogenesis usually begins with formation of plaques and neurofibrillary tangles due to abnormal folding of amyloid beta and tau proteins. Tau proteins are important member of microtubule associated proteins and involved in constitution of microtubules network in neurons which play major role in progression of Alzheimer disease. Hyper phosphorylation and aggregation of Tau protein on chromosome 17 may be the sign of several neurodegenerative pathologies like Alzheimer disease (AD), Parkinsonism, fronto-temporal dementia and Pick disease. The complete cure of AD is not possible be with already marketed drugs. From this review article it is concluded that Tau protein is an important biomarker of Alzheimer disease. Usage of extracts from various plants i.e Danggui Longhui Wang, Hymenialdisine, Morin, Salvia officinalis, Ginseng, helps in effective treatment of disease and hence a step forward to...
Role of tau in Alzheimer’s dementia and other neurodegenerative diseases
Alzheimer’s disease (AD) is defined histopathologically by beta-amyloid (Aβ) senile plaques andneurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. The question as to which of theselesions takes precedence in AD pathology has long been an issue of debate. The amyloid cascadehypothesis, currently the predominant hypothesis, considers Aβ peptide to be responsible for the majorneurodegeneration observed in AD while the cytoskeleton hypothesis states that tauhyperphosphorylation and subsequent aggregation may be central to the neurodegeneration observed inAD. This review focuses on tau mutations, phosphorylation sites, tau isoforms and theneurohistopathology of AD, and three other tauopathies to demonstrate that disease progression andneuronal loss in AD correlate also with pathological tau and not just amyloid deposition. Although tau isat the center of all these neurodegenerative diseases, there exist differences in morphology, isoforms,phosphorylation sites and mutatio...
A Novel Perspective on Tau in Alzheimers Disease
Current Alzheimer Research, 2011
Mainstream thinking is dominated by the notion that the aggregation of specific proteins within neurons, and their subsequent formation into cytoplasmic and extracellular lesions, directly elicits neuronal dysfunction and death. Current dogma, for example, maintains that phosphorylated tau protein, the major component of neurofibrillary tangles, is a central mediator of disease pathogenesis. In this article, we challenge this classic notion by proposing that tau phosphorylation represents a compensatory response mounted by neurons against oxidative stress that serves a protective function. This concept provides a better understanding of the mechanisms underlying disease pathophysiology and also provides a window for therapeutic intervention.
The Role of Tau in Alzheimer's Disease and Related Disorders
CNS Neuroscience & Therapeutics, 2010
Tau, the microtubule-associated protein, forms insoluble filaments that accumulate as neurofibrillary tangles in Alzheimer's disease (AD) and related tauopathies. Under physiological conditions, tau regulates the assembly and maintenance of the structural stability of microtubules. In the diseased brain, however, tau becomes abnormally hyperphosphorylated, which ultimately causes the microtubules to disassemble, and the free tau molecules aggregate into paired helical filaments. A large body of evidence suggests that tau hyperphosphorylation results from perturbation of cellular signaling, mainly through imbalance in the activities of different protein kinases and phosphatases. In AD, it appears that ß-amyloid peptide (Aß) plays a pivotal role in triggering this imbalance. In this review, we summarize our current understanding of the role of tau in AD and other tauopathies, and highlight key issues that need to be addressed to improve the success of developing novel therapies.