Aβ Oligomers Cause Localized Ca 2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines

“Despite numerous studies on the pathway of APP misprocessing and its consequences for neurons the modes of A toxicity have remained enigmatic (Haass and Selkoe, 2007; Small and Duff, 2008).”

“Nevertheless, there were differences in structure because dot blots with antibody A11, which recognizes a more toxic generic amyloid conformation (Kayed et al., 2003), were more intense for F12 medium than for Nb (Fig.”

“There is a moderate decrease of ATP which is more apparent with F12 than with Nb medium, suggesting that F12, which was used in the original procedure (Lambert et al., 1998), could have some toxic effects on its own.”

“These include loss of synapses and neurons, deficiency in neurotransmitters and metabolism, aggregation of amyloid- (A )-peptides into extracellular “amyloid plaques” and Tau protein into intracellular “neurofibrillary tangles” (Selkoe, 2004; Binder et al., 2005; Ballatore et al., 2007).”

“…conversely Tau is considered necessary for the progression of neurodegeneration, as seen in cell and animal models (Rapoport et al., 2002; King et al., 2006; Roberson et al., 2007), and indeed the Tau pathology correlates well with clinical symptoms (Braak and Braak, 1991; Clavaguera et al., 2009).”

“We also tested extracellular ATP (100 M, 3 h), which functions as a stress signal and induces Ca 2 influx via P2 receptors and has been implicated in neurodegenerative disease (Burnstock, 2007).”

“4e,f), and involving NMDA receptors and others (De Felice et al., 2007; Shankar et al., 2007).”

“As shown previously (Stamer et al., 2002; Hollenbeck and Saxton, 2005; Thies and Mandelkow, 2007), such mitochondrial traffic jams cause a local drop of energy (ATP) and consequently spine destruction through the perturbation of the actin network and loss of synaptic components (Whiteman et al.,…”

“In addition a change in MT dynamics alters their posttranslational modifications and thus perturbs polarized trafficking of cargo (Li and Gundersen, 2008; Conde and Cáceres, 2009; Konishi and Setou, 2009).”

“We also note that in our preparations we did not consistently observe a band at 56 kDa, a species that has been reported to be toxic for transgenic mice (Lesné et al., 2006) but can be visualized in certain conditions (Walsh et al., 2005; Ashe, 2006; Bernstein et al., 2009).”

“Previous studies have focused primarily on global effects of A on changes in Tau (e.g., phosphorylation, cleavage) and resulting cell death (Yankner et al., 1989; Mattson, 1990; Busciglio et al., 1995; Park and Ferreira, 2005; King et al., 2006), with less attention to the localized changes due to…”

“As shown previously (Stamer et al., 2002; Hollenbeck and Saxton, 2005; Thies and Mandelkow, 2007), such mitochondrial traffic jams cause a local drop of energy (ATP) and consequently spine destruction through the perturbation of the actin network and loss of synaptic components (Whiteman et al.,…”

“4e,f), and involving NMDA receptors and others (De Felice et al., 2007; Shankar et al., 2007).”

“Thirdly, Ca 2 uncouples mitochondrial motors from microtubule tracks (Wang and Schwarz, 2009).”

“…upstream of changes in Tau, but conversely Tau is considered necessary for the progression of neurodegeneration, as seen in cell and animal models (Rapoport et al., 2002; King et al., 2006; Roberson et al., 2007), and indeed the Tau pathology correlates well with clinical symptoms (Braak and…”

“On the SDS gels, the different media (F12 or Nb) yielded similar bands, with the caveat that these gels can obscure the coexistence of multiple oligomeric species (Glabe, 2008).”

“We note that, apart from its minor amount, the fiber component would be of lesser importance since its toxicity is lower than that of oligomers (Klein et al., 2004; Ono et al., 2009).”

“, proteasome, mitochondria) and perturbation of calcium homeostasis (Mattson, 2007).”

“Examples of local effects are the early loss of synapses and the appearance of Tau in somata and dendrites (Götz and Ittner, 2008).”

“The neurofibrillary changes follow a typical pathway of spreading which corresponds to clinical symptoms, hence Tau pathology is considered as one of the culprits in the disease (Braak and Braak, 1991; Spires-Jones et al., 2009).”

“…focused primarily on global effects of A on changes in Tau (e.g., phosphorylation, cleavage) and resulting cell death (Yankner et al., 1989; Mattson, 1990; Busciglio et al., 1995; Park and Ferreira, 2005; King et al., 2006), with less attention to the localized changes due to Tau redistribution.”

“Despite numerous studies on the pathway of APP misprocessing and its consequences for neurons the modes of A toxicity have remained enigmatic (Haass and Selkoe, 2007; Small and Duff, 2008).”

“We note that, apart from its minor amount, the fiber component would be of lesser importance since its toxicity is lower than that of oligomers (Klein et al., 2004; Ono et al., 2009).”

“An additional function of microtubules is to subtend cellular networks such as the ER and intermediate filament network, so that these networks collapse when microtubules or motors are inactivated or reversed in direction (Stamer et al., 2002; Eriksson et al., 2009).”

“These include loss of synapses and neurons, deficiency in neurotransmitters and metabolism, aggregation of amyloid- (A )-peptides into extracellular “amyloid plaques” and Tau protein into intracellular “neurofibrillary tangles” (Selkoe, 2004; Binder et al., 2005; Ballatore et al., 2007).”

“Lowering cytosolic Ca 2 would appear as prime target for intervention, but the decay of microtubules seems more targetable through microtubulestabilizing drugs (Mattson, 1992; Michaelis et al., 2005; Zhang et al., 2005).”

“In addition a change in MT dynamics alters their posttranslational modifications and thus perturbs polarized trafficking of cargo (Li and Gundersen, 2008; Conde and Cáceres, 2009; Konishi and Setou, 2009).”

“In addition a change in MT dynamics alters their posttranslational modifications and thus perturbs polarized trafficking of cargo (Li and Gundersen, 2008; Conde and Cáceres, 2009; Konishi and Setou, 2009).”

“This could explain the increase in activity of MARK, cdk5 and others; for example, CaMK-I activates MARK2 and this pathway contributes to neuronal differentiation (Biernat et al., 2002; Uboha et al., 2007; He et al., 2008; Wu et al., 2010).”

“6c); this kinase, like MARK, is involved in axonal differentiation (Kishi et al., 2005) and also belongs to the AMPK family of kinases.”

“The neurofibrillary changes follow a typical pathway of spreading which corresponds to clinical symptoms, hence Tau pathology is considered as one of the culprits in the disease (Braak and Braak, 1991; Spires-Jones et al., 2009).”

“Earlier experiments with overexpressed Tau had shown that dendritic Tau can cause traffic jams, resulting in transport inhibition of vesicles and organelles (e.g., mito- chondria), loss of ATP supply, and decay of synaptic spines (Thies and Mandelkow, 2007).”

“…have focused primarily on global effects of A on changes in Tau (e.g., phosphorylation, cleavage) and resulting cell death (Yankner et al., 1989; Mattson, 1990; Busciglio et al., 1995; Park and Ferreira, 2005; King et al., 2006), with less attention to the localized changes due to Tau…”

“This could explain the increase in activity of MARK, cdk5 and others; for example, CaMK-I activates MARK2 and this pathway contributes to neuronal differentiation (Biernat et al., 2002; Uboha et al., 2007; He et al., 2008; Wu et al., 2010).”

“…focused primarily on global effects of A on changes in Tau (e.g., phosphorylation, cleavage) and resulting cell death (Yankner et al., 1989; Mattson, 1990; Busciglio et al., 1995; Park and Ferreira, 2005; King et al., 2006), with less attention to the localized changes due to Tau redistribution.”

“and promotes their disassembly (Schliwa et al., 1981); this mechanism operates in addition to the Ca 2 -CaM-dependent”

“These include loss of synapses and neurons, deficiency in neurotransmitters and metabolism, aggregation of amyloid- (A )-peptides into extracellular “amyloid plaques” and Tau protein into intracellular “neurofibrillary tangles” (Selkoe, 2004; Binder et al., 2005; Ballatore et al., 2007).”

“This can be done in a variety of ways, and there is a debate on which is most appropriate for assessing A toxicity (Wogulis et al., 2005).”

“We also note that in our preparations we did not consistently observe a band at 56 kDa, a species that has been reported to be toxic for transgenic mice (Lesné et al., 2006) but can be visualized in certain conditions (Walsh et al., 2005; Ashe, 2006; Bernstein et al., 2009).”

“…Tau, but conversely Tau is considered necessary for the progression of neurodegeneration, as seen in cell and animal models (Rapoport et al., 2002; King et al., 2006; Roberson et al., 2007), and indeed the Tau pathology correlates well with clinical symptoms (Braak and Braak, 1991; Clavaguera et…”

“The results have not been uniform; increases in Tau phosphorylation have been observed in some cases, not in others (Davis et al., 1997; Lovell et al., 2004; Su et al., 2010).”

“The results have not been uniform; increases in Tau phosphorylation have been observed in some cases, not in others (Davis et al., 1997; Lovell et al., 2004; Su et al., 2010).”

“This type of phosphorylation causes the detachment of Tau from microtubules, makes them dynamic, and renders Tau highly diffusible and able to enter dendrites (Konzack et al., 2007).”

“Part of the problem is the definition of the toxic state of A , which may be monomeric, oligomeric (currently favored), or fibrillar (formerly favored) (Klein, 2006; Glabe, 2008; Roychaudhuri et al., 2009).”

“…polyclonal amyloid- (Cell Signaling Technology; 1:200); mAb 12E8 (1:500); mAb AT8 (1:100); polyclonal MARK phospho-T208 [prepared as described by Timm et al. (2008); 1:100]; phosphop70S6Kinase (pT389, clone 108D2, Cell Signaling Technology; 1:50); polyclonal BRSK1 (Acris, 1:100); phospho-MAPK…”

“…previously (Stamer et al., 2002; Hollenbeck and Saxton, 2005; Thies and Mandelkow, 2007), such mitochondrial traffic jams cause a local drop of energy (ATP) and consequently spine destruction through the perturbation of the actin network and loss of synaptic components (Whiteman et al., 2009).”

“Lowering cytosolic Ca 2 would appear as prime target for intervention, but the decay of microtubules seems more targetable through microtubulestabilizing drugs (Mattson, 1992; Michaelis et al., 2005; Zhang et al., 2005).”

“1b), whereas the general A antibody 6E10 (Pirttilä et al., 1994; Jung et al., 1999) reacted independently of the medium.”

“This could explain the increase in activity of MARK, cdk5 and others; for example, CaMK-I activates MARK2 and this pathway contributes to neuronal differentiation (Biernat et al., 2002; Uboha et al., 2007; He et al., 2008; Wu et al., 2010).”

“With regard to proline-directed kinases we tested MAPK, JNK, cdk5, and GSK3b, all considered to be involved in the pathological phosphorylation of Tau (Johnson, 2006).”

“Lowering cytosolic Ca 2 would appear as prime target for intervention, but the decay of microtubules seems more targetable through microtubulestabilizing drugs (Mattson, 1992; Michaelis et al., 2005; Zhang et al., 2005).”

“To confirm equal loading and successful blotting membranes were routinely stained using the CPTS staining method (Bickar and Reid, 1992), followed by standard Western blot procedure.”

“Glabe, University of California, Irvine, CA), that shows high specificity to amyloid oligomers (Kayed et al., 2007).”

“Proteasome activity was determined following (Flood et al., 2005).”

“Given this localized loss of microtubules, we hypothesized that this might lead to an impairment of mitochondrial trafficking with local dendritic energy deprivation (Yan et al., 2010).”

“This could explain the increase in activity of MARK, cdk5 and others; for example, CaMK-I activates MARK2 and this pathway contributes to neuronal differentiation (Biernat et al., 2002; Uboha et al., 2007; He et al., 2008; Wu et al., 2010).”

“1b), whereas the general A antibody 6E10 (Pirttilä et al., 1994; Jung et al., 1999) reacted independently of the medium.”

“Lowering cytosolic Ca 2 would appear as prime target for intervention, but the decay of microtubules seems more targetable through microtubulestabilizing drugs (Mattson, 1992; Michaelis et al., 2005; Zhang et al., 2005).”

“We also note that in our preparations we did not consistently observe a band at 56 kDa, a species that has been reported to be toxic for transgenic mice (Lesné et al., 2006) but can be visualized in certain conditions (Walsh et al., 2005; Ashe, 2006; Bernstein et al., 2009).”

“, 2007), and indeed the Tau pathology correlates well with clinical symptoms (Braak and Braak, 1991; Clavaguera et al., 2009).”

“Many studies employing supraphysiological concentrations of synthetic Ab peptides in oligomeric form (generally larger than dimers/ trimers) have also provided evidence of tau alteration (Zempel et al. 2010) and various neurotoxic effects.”