Defective Brain Microtubule Assembly in Alzheimer's Disease

Iqbal, Khalid; Grundke‐Iqbal, Inge; Zaidi, Tanweer; Merz, Patricia A.; Wen, Gen; Shaikh, Sadia; Wisniewski, H. M.; Alafuzoff, Irina; Winblad, Bengt

doi:10.1016/s0140-6736(86)92134-3

Cited by 465 publications

(278 citation statements)

References 32 publications

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“…As mentioned earlier, PHF-tau is reported to be glycated, glycosylated, and hyperphosphorylated. PHF-tau is also known to have reduced interaction with the microtubules (Iqbal et al, 1986;Nieto et al, 1991), which could be a consequence of any one or all of these modifications. Deglycosylation and dephosphorylation of PHF-tau were shown to increase its ability to bind to microtubules (Wang et al, 1996).…”

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confidence: 99%

Characterization of In Vitro Glycation Sites of Tau

Nacharaju

Yen

1997

Journal of Neurochemistry

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Tau is a microtubule-associated protein that loses microtubule binding activity and aggregates into paired helical filaments (PHFs) in Alzheimer's disease. Nonenzymic glycation is one of the posttranslational modifications detected in PHF-tau, but not in normal tau. PHF-tau has reduced ability to bind to microtubules. To determine whether glycation of tau occurs in its microtubule binding domains, we have characterized in vitro glycation sites of the longest isoform of tau, which has four microtubule binding domains (Tau-4). The identified glycation sites are 132, 150, 163, 174, 225, 234, 259, 280, 281, 347, 353, and 369. We have also studied glycation of another isoform of tau, which has only three microtubule binding domains (Tau-3). This isoform is modified by glucose 15-20% more slowly than Tau-4. However, the glycation sites appear to be the same in both isoforms, except for Lys-280 and 281; these are located in the second microtubule binding domain, which is missing in Tau-3. Lys-150, 163, and 174 are located within or proximal to the sequence of tau that is involved in the microtubule nucleation activity, and 280, 281, 347, 353, and 369 are located in the microtubule binding domains. Glycation at these sites can affect the functional properties of tau, and advanced glycation at these sites might lead to the formation of insoluble aggregates similar to the ones seen in Alzheimer's disease.

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confidence: 99%

Characterization of In Vitro Glycation Sites of Tau

Nacharaju

Yen

1997

Journal of Neurochemistry

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“…This work also provides the new angle of resveratrol in a capability of increasing GTP levels which has not been reported in the literature so far. Although GTP is less abundant than ATP, GTP plays an important role in specific processes including microtubule assembly [48], a defective process found in AD brains [49]. Furthermore, resveratrol reversed a drop in ECP due to nutrition-restricted conditions at the late stages of the experiments, from approximately 60% of untreated cells to higher than 80% even at low concentrations of resveratrol treatment which did not cause significant reduction in cell viability.…”

Section: Discussionmentioning

confidence: 85%

Proenergetic effects of resveratrol in the murine neuronal cell line Neuro2a

Nguyen

Ooi

Piller

et al. 2013

Mol. Nutr. Food Res.

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Scope: Energy deficit is a common characteristic of neurodegenerative disorders, including Alzheimer's disease. Adenosine monophosphate activated protein kinase (AMPK) is a key enzyme maintaining energy balance by regulating the cellular uptake of glucose, β-oxidation of fatty acids, and expression of glucose transporter 4. Since resveratrol has been shown to increase the activity of AMPK, we hypothesized that it might influence energy metabolism in a model neuron-like cell line, murine Neuro2a cells.Methods and results: Resveratrol caused an elevation of adenosine triphosphate (ATP) and guanosine triphosphate (GTP) in a dose-dependent manner. The highest ATP and GTP levels achieved by treatment with resveratrol were 70.3 ± 8.2 nmol/mg protein (1.9-fold of control) and 27.2 ± 4.0 nmol/mg protein (1.7-fold of control), respectively, when cells were treated with 100 μM resveratrol for 6 h. Interestingly, increases in the total sum of all adenine nucleotides were found upon addition of resveratrol. Despite these increases in ATP, GTP, and the total adenine nucleotide pool, resveratrol treatment led to a decrease in glucose consumption and lactate release, suggesting that resveratrol does not increase energy production (e.g. via AMPK kinase activation) but rather inhibits energy-consuming processes.Conclusion: Resveratrol increases the levels of ATP and GTP, but without creating an additional glucose demand. treated with 100 µM resveratrol for 6 h. Interestingly, substantial increases in the total sum of all adenine nucleotides were found upon addition of resveratrol. Despite these increases in ATP, GTP and the total adenine nucleotide pool, resveratrol treatment led to a pronounced decrease in glucose consumption and lactate release, suggesting that resveratrol does not increase energy production (e.g. via AMPK kinase activation) but rather inhibits energy consuming processes.Conclusions: Resveratrol increases the levels of free high-energy nucleotides, including ATP and GTP, but without creating an additional glucose demand.4

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“…As dysregulation of tau processing causes neuronal degeneration correlated with AD [84] , researchers have made substantial efforts to search for targets to reverse abnormal phosphatase 2A [85] . The role of GSK-3 in the development of AD-like cognitive decline was supported by Liu et al [86] who found that inhibition of phosphoinositol-3 kinase and protein kinase C results in overactivation of GSK-3, leading to tau hyperphosphorylation and eventually impaired spatial memory.…”

Section: Other Therapeutic Approaches To Admentioning

confidence: 99%

“…Barthel et al, using positron emission tomography (PET) images of florbetaben (an 18 F-labeled Aβ-targeted PET tracer), demonstrated that nine of ten mildmoderate probable AD participants (DSM-IV and NINCDS-ADRDA criteria) were Aβ-positive, compared to only one of ten healthy controls [49] . Furthermore, in a global phase 2, open-label, non-randomized, multi-center study recruiting a total of 81 men and women with probable mild-to-moderate AD and 69 cognitively unimpaired healthy volunteers aged 55 years and older, florbetaben scans indicated a sensitivity of 80% (95% CI 71-89) and a specificity of 91% (84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98) for discriminating participants with AD from healthy controls [50] .…”

Section: Aβ As a Promising Target For Ad Treatmentmentioning

confidence: 99%

“…As dysregulation of tau processing causes neuronal degeneration correlated with AD [84] , researchers have made substantial efforts to search for targets to reverse abnormal tau processing. To date, several kinases have been identified as key players in abnormal tau phosphorylation, particularly glycogen synthase kinase 3 (GSK-3) and protein phosphatase 2A [85] .…”

Section: Other Therapeutic Approaches To Admentioning

confidence: 99%

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Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

et al. 2012

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There is no effective drug to treat Alzheimer's disease (AD), a neurodegenerative disease affecting an estimated 30 million people around the world. Strongly supported by preclinical and clinical studies, amyloid-beta (Aβ) may be a target for developing drugs against AD. Meanwhile, the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered. Neuronal regeneration, which does not occur normally in the mammalian central nervous system, can be promoted by neurotrophic factors (NTFs). Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD, thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.Keywords: Alzheimer's disease; amyloid-beta; neurotrophic factors; treatment IntroductionAlzheimer's disease (AD) is an age-related, progressive and irreversible neurodegenerative disease that causes serious cognitive dysfunction. Its pathological hallmarks are extracellular deposits of amyloid-beta (Aβ) and intracellular neurofibrillary tangles, together with drastic synaptic and neuronal reduction or loss [1] . It has been estimated that AD affects 30 million people around the world [2] , and the past two decades have witnessed an explosion in research into the underlying mechanisms as well as potential therapeutic strategies. Although it was first described by German psychiatrist Alois Alzheimer in 1906, there is still no cure for AD, partly because the cellular and molecular mechanisms underlying it are far from clear. The Food and Drug Administration in the United Stateshas approved a limited range of drugs to treat AD, including acetylcholinesterase inhibitors (AChEIs) and N-methyl-Daspartate receptor (NMDAR) antagonists [3] , although their effects are merely symptomatic and memory-improvement occurs within a limited period. Donepezil, galantamine, rivastigmine and tacrine are AChEIs that prevent the breakdown of acetylcholine released from presynaptic terminals, increasing the residence time of the neurotransmitter within the synapse and thereby prolonging the duration of its interaction with postsynaptic receptors [4] . Memantine, an NMDAR antagonist, has been approved for the treatment of moderate and severe AD; it works by preventing the excitatory neurotoxicity induced by excessive glutamate [5] .Currently, no available pharmacological agents cure or reverse the progression of this devastating neurological disorder. It is therefore urgent to improve our understanding of its pathogenesis, and then develop an effective treatment strategy. This review aimed to provide insights Neurosci Bull February 1, 2013, 29(1): 111-120 112 into the design of potentially effective pharmaceutical treatments for AD by targeting two seemingly separate but tightly connected components, Aβ and neurotrophic factors (NTFs). Aβ as a Promising Target for AD TreatmentAβ is a peptide of 36-43 amino-acids produced from amyloid precursor protein (APP) through aberrant cleavage by...

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Defective Brain Microtubule Assembly in Alzheimer's Disease

Cited by 465 publications

References 32 publications

Characterization of In Vitro Glycation Sites of Tau

Characterization of In Vitro Glycation Sites of Tau

Proenergetic effects of resveratrol in the murine neuronal cell line Neuro2a

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

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