Mechanism of neurofibrillary degeneration and pharmacologic therapeutic approach

Iqbal, Khalid; Alonso, Alejandra; Gondal, J. A.; Chen, Gong; Haque, Niloufar; Khatoon, Sabiha; Sengupta, Amitabha; Wang, J.-Z.; Grundke‐Iqbal, Inge

doi:10.1007/978-3-7091-6781-6_22

Cited by 35 publications

(30 citation statements)

References 43 publications

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“…11 Because of the hyperphosphorylation, tau also loses its ability to bind to the microtubules and to stimulate their assembly. 12 CSF T-tau. As shown in Table 1, four different ELISA methods for quantification of T-tau have been published.…”

Section: Tau Proteinmentioning

confidence: 99%

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

2004

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Summary:The introduction of acetylcholine esterase (AChE) inhibitors as a symptomatic treatment of Alzheimer's disease (AD) has made patients seek medical advice at an earlier stage of the disease. This has highlighted the importance of diagnostic markers for early AD. However, there is no clinical method to determine which of the patients with mild cognitive impairment (MCI) will progress to AD with dementia, and which have a benign form of MCI without progression. In this paper, the performance of cerebrospinal fluid (CSF) protein biomarkers for AD is reviewed. The diagnostic performance of the three biomarkers, total tau, phospho-tau, and the 42 amino acid form of ␤-amyloid have been evaluated in numerous studies and their ability to identify incipient AD in MCI cases has also been studied. Some candidate AD biomarkers including ubiquitin, neurofilament proteins, growth-associated protein 43 (neuromodulin), and neuronal thread protein (AD7c) show interesting results but have been less extensively studied. It is concluded that CSF biomarkers may have clinical utility in the differentiation between AD and several important differential diagnoses, including normal aging, depression, alcohol dementia, and Parkinson's disease, and also in the identification of Creutzfeldt-Jakob disease in cases with rapidly progressive dementia. Early diagnosis of AD is not only of importance to be able to initiate symptomatic treatment with AChE inhibitors, but will be the basis for initiation of treatment with drugs aimed at slowing down or arresting the degenerative process, such as ␥-secretase inhibitors, if these prove to affect AD pathology and to have a clinical effect.

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Section: Tau Proteinmentioning

confidence: 99%

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

2004

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“…7,17,19,20 The "tau hypothesis" is based on the abnormal state of tau proteins in AD that is both highly phosphorylated and aggregated into paired helical filaments in NFTs. 17,19,21 When tau proteins are hyperphosphorylated, there is a breakdown in the system; preventing tau hyperphosphorylation and aggregation can decrease formation of NFTs. The formation of NFT contributes to AD, but it is debatable whether it is the earliest causal factor underlying AD pathogenesis as A␤ plaques typically occur before NFTs.…”

Section: Introductionmentioning

confidence: 99%

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

2008

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Summary:The only prescribed drugs for treatment of Alzheimer's disease (AD) are acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, and tacrine) and memantine, an NMDA antagonist. These drugs ameliorate mainly the symptoms of AD, such as cognitive impairments, rather than halting or preventing the causal neuropathology. There is currently no cure for AD and there is no way to stop its progression, yet there are numerous therapeutic approaches directed against various pathological hallmarks of AD that are extensively being pursued. In this context, the three major hallmark characteristics of AD (i.e., the CNS cholinergic hypofunction, formation of ␤-amyloid plaques, and tangles containing hyperphosphorylated tau proteins) are apparently linked. Such linkages may have therapeutic implications, and this review is an attempt to analyze these versus the advantages and drawbacks of some cholinergic compounds, such as acetylcholinesterase inhibitors, M1 muscarinic agonists, M2 antagonists, and nicotinic agonists. Among the reviewed treatments, M1 selective agonists emerge, in particular, as potential disease modifiers.

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“…NFTs, predominantly composed of hyperphosphorylated tau, are another pathological hallmark of AD [56] . Tau undergoes abnormal hyperphosphorylation at various sites, such as threonine 181 and 231, and serine 199, 235, 396 and 404 [35] .…”

Section: Csf T-tau and P-tau As Biomarkers Of Admentioning

confidence: 99%

“…Tau undergoes abnormal hyperphosphorylation at various sites, such as threonine 181 and 231, and serine 199, 235, 396 and 404 [35] . Due to aberrant phosphorylation, tau is unable to bind and stabilize the microtubules, contributing to neuronal loss [57] .A number of studies found increased levels of CSF t-tau in AD cases relative to controls [47,[56][57][58][59][60][61][62][63][64] . CSF t-tau has a sensitivity of 83% and a specifi city of 90% in discriminating AD from healthy controls [58] .…”

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confidence: 99%

Cerebrospinal fluid biomarkers of Alzheimer’s disease

Sui

Yang

2014

Neurosci. Bull.

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Alzheimer's disease (AD) is a fatal neurodegenerative disorder that takes about a decade to develop, making early diagnosis possible. Clinically, the diagnosis of AD is complicated, costly, and inaccurate, so it is urgent to fi nd specifi c biomarkers. Due to its multifactorial nature, a panel of biomarkers for the multiple pathologies of AD, such as cerebral amyloidogenesis, neuronal dysfunction, synapse loss, oxidative stress, and infl ammation, are most promising for accurate diagnosis. Highly sensitive and high-throughput proteomic techniques can be applied to develop a panel of novel biomarkers for AD. In this review, we discuss the metabolism and diagnostic performance of the well-established core candidate cerebrospinal fl uid (CSF) biomarkers (β-amyloid, total tau, and hyperphosphorylated tau). Meanwhile, novel promising CSF biomarkers, especially those identifi ed by proteomics, updated in the last fi ve years are also extensively discussed. Furthermore, we provide perspectives on how biomarker discovery for AD is evolving.Keywords: Alzheimer's disease; biomarker; cerebrospinal fl uid; β-amyloid; tau; proteomics ·Review· Introduction Alzheimer's disease (AD) is becoming more prevalent due to the increasing population of people aged over 65 [1] .It is estimated that it will affect 66 million by 2030 and 115 million by 2050 worldwide if no effective therapeutic strategies are found [2] . Clinically, AD is characterized by cognitive impairment, progressive disturbance of daily activities, many neuropsychiatric symptoms, and behavioral deterioration [3][4][5][6][7][8] . Pathologically, it is characterized by deposition of extracellular neuritic plaques composed of β-amyloid (Aβ) [9] and intracellular neurofibrillary tangles (NFTs) consisting of a hyperphosphorylated form of the microtubule-associated protein tau [10][11][12] . Besides, loss of neurons and synapses is also a pathological hallmark of AD [13][14][15] . The worldwide cost of dementia is huge and expected to skyrocket in the next few years. AD may become one of the most marked social, health, and economic challenges in the twenty-fi rst century [16] .Clinically, the procedure for the diagnosis of AD is diffi cult and complex. Neuropsychological tests, such as the mini-mental state examination, magnetic resonance imaging of hippocampal volume, and clinical assessment, are used to aid in diagnosis. However, a defi nitive diagnosis of AD requires confirmation at autopsy. It is estimated to take 8-10 years or longer before mild cognitive impairment (MCI) develops into AD [17,18] . Meanwhile, intervention therapies work most effectively in the early stage of AD. Thus, it is urgent and feasible to seek novel specifi c biomarkers to aid in diagnosis and the evaluation of treatments [19] . Surrounding the brain and spinal cord, cerebrospinal fluid (CSF) is an ideal source refl ecting biochemical changes in the brain of the AD patient [20] . Extensive studies have focused on seeking AD biomarkers in CSF.A comprehensive search of the Web of Science (Janua...

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Mechanism of neurofibrillary degeneration and pharmacologic therapeutic approach

Cited by 35 publications

References 43 publications

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

Cerebrospinal fluid biomarkers of Alzheimer’s disease

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