Immunological demonstration of tau protein in neurofibrillary tangles of Alzheimer's disease

Brion, Jean Pierre

doi:10.3233/jad-2006-9s321

Cited by 41 publications

(30 citation statements)

References 93 publications

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“…Since increased phosphorylation and altered microtubule stability are coincident during progression through the cell cycle [19,20] and cell cycle-related protein alterations are found in AD, it is not surprising that microtubular abnormalities and tau phosphorylation are also associated with AD [21]. While the kinases responsible for tau phosphorylation in AD are not completely characterized, high and residue-specific phosphorylation of tau occurs in mitotically active neurons where phosphorylation is driven by CDKs [22][23][24][25][26]. Of note, CDKs, such as CDK2 and CDK5, as well as Cdc-kinases and MAP2 kinases, are increased in AD in a topographical manner that overlaps with phospho-tau [27,28] and also have been shown to hyperphosphorylate tau in in vitro assays [29][30][31][32][33].…”

Section: Mitogenic Abnormalities In Alzheimer Diseasementioning

confidence: 99%

The Cell Cycle and Hormonal Fluxes in Alzheimer Disease: A Novel Therapeutic Target

Webber¹,

Casadesús²,

Zhu³

et al. 2006

CPD

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Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease (AD) including theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. Strong evidence suggests that each one contributes to disease pathogenesis, though none of these mechanisms result in all the downstream changes that occur during the course of AD. For this reason, we and others have begun the search for a causative factor that predates known features found in AD, and that might be a fundamental initiator of the pathophysiological cascade. In this regard, we propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during AD is a potential causative factor that would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of AD include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Given the early and presumably devastating consequences of cell cycle re-entry, we have made a concerted effort to elucidate the initiating factor that drives aberrant mitotic re-entry in AD. As a result of the gender bias present in AD, we suspect that postmenopausal and andropausal hormones may be involved and, with this in mind, in this review we specifically focus on the gonadotropins. Therapeutic interventions targeted at gonadotropins, if they are indeed the driving mitogenic force, could both prevent disease in those patients currently asymptomatic or halt, and even reverse, disease in those currently afflicted.

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Section: Mitogenic Abnormalities In Alzheimer Diseasementioning

confidence: 99%

The Cell Cycle and Hormonal Fluxes in Alzheimer Disease: A Novel Therapeutic Target

Webber¹,

Casadesús²,

Zhu³

et al. 2006

CPD

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“…NFTs are made of bundles of PHFs (paired helical filaments) composed of abnormally and hyperphosphorylated aggregated forms of the microtubuleassociated protein tau [4]. SPs are made of an extracellular core of the Aβ (amyloid β-peptide) peptide, deriving by proteolysis from the APP (amyloid precursor protein), surrounded by dystrophic neurites and reactive glial cells.…”

Section: Introductionmentioning

confidence: 99%

Modulation of tau pathology in tau transgenic models

Brion

Ando

Héraud

et al. 2010

Biochemical Society Transactions

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NFTs (neurofibrillary tangles) in Alzheimer's disease and in tauopathies are hallmark neuropathological lesions whose relationship with neuronal dysfunction, neuronal death and with other lesions [such as Aβ (amyloid β-peptide) pathology] are still imperfectly understood. Many transgenic mice overexpressing wild-type or mutant tau proteins have been generated to investigate the physiopathology of tauopathies. Most of the mice overexpressing wild-type tau do not develop NFTs, but can develop a severe axonopathy, whereas overexpression of mutant tau leads to NFT formation, synaptic loss and neuronal death in several models. The association between neuronal death and NFTs has, however, been challenged in some models showing a dissociation between tau aggregation and tau toxicity. Cross-breeding of mice developing NFTs with mice developing Aβ deposits increases NFT pathology, highlighting the relationship between tau and amyloid pathology. On the other hand, tau expression seems to be necessary for expression of a pathological phenotype associated with amyloid pathology. These findings suggest that there is a bilateral cross-talk between Aβ and tau pathology. These observations are discussed by the presentation of some relevant models developed recently.

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“…8,9 While the kinases responsible for tau phosphorylation in AD are not completely characterized, hyperphosphorylation of tau also occurs in healthy, mitotically active neurons where phosphorylation is driven by cyclin-dependent kinases (CDK). [10][11][12][13][14] Of note, CDKs such as CDK2 and CDK5, as well as cdc-kinases and mitogen-associated protein kinases, are increased in AD in a topographical manner that overlaps with hyperphosphorylated tau. 15,16 In vitro assays have demonstrated these kinases also cause the hyperphosphorylation of tau.…”

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confidence: 99%

The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis

Webber¹,

Perry²,

Smith³

et al. 2007

Clinical Medicine & Research

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Al zheimer Disease (AD) is the most prevalent neurodegenerative disease affecting more than 15 million people worldwide 1 and is characterized by selective neuronal degeneration resulting in progressive memory loss. 2 AD attacks several different regions of the brain including the cerebral cortex which is involved in conscious thought and language, the basal forebrain which is important in memory and learning, and the hippocampus which is essential to memory storage. Clinical manifestations of AD are varied but can include memory loss, difficulty performing familiar tasks, disorientation to time and place, misplacing things, and changes in mood or behavior. 3 Several hypotheses have been proposed in attempts to explain the pathogenesis of AD and include theories involving senile plaque and neurofibrillary tangle formation, increased oxidative stress, and cell cycle abnormalities, since evidence for each of these pathological phenomena have been well documented in AD. 4 The senile plaque, which is primarily composed of the 4.2 kDa amyloid-β polypeptide, is produced from the proteolytic cleavage of the larger amyloid-β precursor protein (AβPP) and is the extracellular hallmark of AD. To date, three genes involving AβPP or its cleavage product have been identified as containing fully penetrant, mutations resulting in early-onset AD. These mutations can be found on genes encoding AβPP itself and also on presenilin-1 and presenilin-2 genes. 5 While these mutations are known to 177 Several hypotheses have been proposed that attempt to explain the pathogenesis of Alzheimer Disease (AD) including theories involving senile plaque and neurofibrillary tangle formation, increased oxidative stress, and cell cycle abnormalities, since evidence for each of these pathological phenomena have been well documented in AD. Recent epidemiological and experimental data also support a role for the gonadotropin luteinizing hormone in AD. Paralleling the female predominance for developing AD, luteinizing hormone levels are significantly higher in females as compared to males, and furthermore, luteinizing hormone levels are higher still in individuals who succumb to AD. Luteinizing hormone, which is capable of modulating cognitive behavior, is not only present in the brain, but also has the highest receptor levels in the hippocampus, a key processor of cognition that is severely deteriorated in AD. Furthermore, we recently examined cognitive performance in a well-characterized transgenic mouse that over-expresses luteinizing hormone and found that these animals show decreased cognitive performance when compared to controls. We have also found that abolishing luteinizing hormone in amyloid-β protein precursor transgenic mice (Tg2576) using a potent gonadotropin-lowering gonadotropin-releasing hormone agonist, leuprolide acetate, resulted in improved hippocampally-related cognitive performance and decreased amyloid-β deposition. These findings, together with data indicating that luteinizing hormone modulates amyloid-β protein precursor p...

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Immunological demonstration of tau protein in neurofibrillary tangles of Alzheimer's disease

Cited by 41 publications

References 93 publications

The Cell Cycle and Hormonal Fluxes in Alzheimer Disease: A Novel Therapeutic Target

The Cell Cycle and Hormonal Fluxes in Alzheimer Disease: A Novel Therapeutic Target

Modulation of tau pathology in tau transgenic models

The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis

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