Protein aggregates and dementia: is there a common toxicity?

Lovestone, Simon

doi:10.1136/jnnp.72.2.152

Cited by 59 publications

(32 citation statements)

References 127 publications

(89 reference statements)

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“…11,12) To examine the phosphorylation activities of GSK-3b1 and -3b2 to APP, the two variants were co-expressed with APP in HEK293T cells. Western blot analysis using a specific antiphospho-APP antibody that recognizes APP phosphorylated at Thr668 showed that both GSK-3b1 and -3b2 phosphorylated APP at Thr668, and that the phosphorylation levels were similar each other (Fig.…”

Section: Resultsmentioning

confidence: 99%

Glycogen Synthase Kinase-3.BETA.2 Has Lower Phosphorylation Activity to Tau than Glycogen Synthase Kinase-3.BETA.1

Saeki

Machida

Kinoshita

et al. 2011

Biological & Pharmaceutical Bulletin

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Glycogen synthase kinase-3b (GSK-3b) is a serine/threonine kinase that is involved in the regulation of many signaling pathways in vertebrates.1-3) GSK-3b is expressed in two splice variants. GSK-3b1 (the short form of GSK-3b) ubiquitously distributes in organs. In contrast, GSK-3b2 (the long form of GSK-3b), whose structural difference is the only 13 amino acids insert at the C-terminal side of the catalytic site, is present in central nervous system. 4,5) Although, so far, many researches on GSK-3b are concerned with GSK-3b1 because of its high level of expression in various tissues, there is little research attention to the minor form, GSK-3b2. At present, the substrate preferences and physiological significances of the two variants remains unclear.GSK-3b is known to phosphorylate the microtubule-associated protein tau at Alzhemier's disease (AD)-relevant epitopes in vivo and in vitro.6,7) The hyperphosphorylated tau is known to the major component of neurofibrillary tangles observed in AD and over-activation of GSK-3b has been implicated in the aberrant phosphorylation of tau in AD. 8,9) In addition, GSK-3b phosphorylates the intracellular domain of amyloid precursor protein (APP), which is closely implicated in AD.10-12) However, since the above reports deal with GSK-3b1, the physiological significance of the neuron specific isoform GSK-3b2 yet remains to be dissolved.In this study, we investigated whether the phosphorylation activities of GSK-3b1 and -3b2 to tau and APP are different in cells. We found that the phosphoryaltion level of tau at AD-relevant epitope (Ser396) by GSK-3b2 is considerably lower than that by GSK-3b1, while the phosphorylation levels of APP by the two variants are almost equivalent. Furthermore, in vitro analyses revealed that recombinant GSK3b2 has lower phosphorylation activity to tau than GSK-3b1, although the phosphorylation activities of the two variants to a synthetic peptide substrate, pGS-2, are almost equivalent. These results indicate that tau is an unfavorable substrate for GSK-3b2. Moreover, we found that, by the deletion analyses of C-terminal tail (CT), the phosphorylation activity of GSK3b2DCT to tau is significantly reduced as compared with that of GSK-3b1DCT. These results suggest that the lower phosphorylation activity of GSK-3b2 to tau is attributed to its unique higher-order structure of CT constructed by the 13 amino acids insertion. Furthermore, these observations may imply that changes in the balance of GSK-3b2/-3b1 in neurons underlie tau hyperphosphorylation in AD. Our data provide new insights into the physiological significances of the two variants in the regulation of tau phosphorylation in central nervous system and into the mechanism of the onset of AD via dysregulation of the GSK-3b2/-3b1 balance.

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Section: Resultsmentioning

confidence: 99%

Glycogen Synthase Kinase-3.BETA.2 Has Lower Phosphorylation Activity to Tau than Glycogen Synthase Kinase-3.BETA.1

Saeki

Machida

Kinoshita

et al. 2011

Biological & Pharmaceutical Bulletin

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“…The resulting abeta fragment is a key pathogenic intermediate in AD (Lovestone & McLoughlin, 2002;Selkoe & Schenk, 2002). Hence, APP is a large membrane-bound Cu-binding protein that is essential in maintaining synaptic function.…”

Section: Copper and Zincmentioning

confidence: 99%

Micronutrients and Alzheimer's disease

Staehelin¹

2005

Proc. Nutr. Soc.

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The current high life expectancy is overshadowed by neurodegenerative illnesses that lead to dementia and dependence. Alzheimer's disease (AD) is the most common of these conditions, and is considered to be a proteinopathy, with amyloid-b42 as a key factor, leading via a cascade of events to neurodegeneration. Major factors involved are oxidative stress, perturbed Ca homeostasis and impaired energy metabolism. Protection against oxidative stress by micronutrients (including secondary bioactive substances) has been shown in transgenic Alzheimer model systems to delay AD. Epidemiological evidence is less conclusive, but the vast majority of the evidence supports a protective effect on cognitive functions in old age and AD. Thus, a diet rich in fruits and vegetables but also containing meat and fish is the most suitable to provide adequate micronutrients. The strong link between cardiovascular risk and AD may be explained by common pathogenetic mechanisms mediated, for example, by homocysteine and thus dependant on B-vitamins (folate and vitamins B 12 and B 6 ). However, micronutrients may also be harmful. The high affinity of amyloid for metals (Fe, Al and Zn) favours the generation of reactive oxygen species and triggers an inflammatory response. Micronutrients in a balanced diet have a long-lasting, albeit low, protective impact on brain aging, hence prevention should be life long.Alzheimer's disease: Oxidative stress: Cognitive function

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“…In neurons, GSK3B is a major Tau kinase, critically involved in the maintenance of the stability of microtubules and, therefore, in the preservation of the structure and function of the neuronal cytoskeleton [28] . Studies have shown that GSK3B is overactive in AD, playing a major role in the hyperphosphorylation of Tau [24,[29][30][31] . In experimental models of AD, GSK3B has been shown to hyperphosphorylate Tau, leading to microtubule disassembly and loss of function [28] .…”

Section: Glycogen Synthase Kinase and Taumentioning

confidence: 99%

Platelet biomarkers in Alzheimer’s disease

Talib

Joaquim²,

Forlenza³

2012

WJP

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The search for diagnostic and prognostic markers in Alzheimer's disease (AD) has been an area of active research in the last decades. Biochemical markers are correlates of intracerebral changes that can be identified in biological fluids, namely: peripheral blood (total blood, red and white blood cells, platelets, plasma and serum), saliva, urine and cerebrospinal fluid. An important feature of a biomarker is that it can be measured objectively and evaluated as (1) an indicator of disease mechanisms (markers of core pathogenic processes or the expression of downstream effects of these processes), or (2) biochemical responses to pharmacological or therapeutic intervention, which can be indicative of disease modification. Platelets have been used in neuropharmacological models since the mid-fifties, as they share several homeostatic functions with neurons, such as accumulation and release of neurotransmitters, responsiveness to variations in calcium concentration, and expression of membrane-bound compounds. Recent studies have shown that platelets also express several components related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress: thus they can be used in the search for biomarkers of the disease process. For instance, platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B. Moreover, platelets express enzymes involved in membrane homeostasis (e.g., phospholipase A2), and markers of the inflammatory process and oxidative stress. In this review we summarize the available literature and discuss evidence concerning the potential use of platelet markers in AD.

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Protein aggregates and dementia: is there a common toxicity?

Cited by 59 publications

References 127 publications

Glycogen Synthase Kinase-3.BETA.2 Has Lower Phosphorylation Activity to Tau than Glycogen Synthase Kinase-3.BETA.1

Glycogen Synthase Kinase-3.BETA.2 Has Lower Phosphorylation Activity to Tau than Glycogen Synthase Kinase-3.BETA.1

Micronutrients and Alzheimer's disease

Platelet biomarkers in Alzheimer’s disease

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