a(HBP:"amyloid-beta oligomers")
Early work on AD considered the fibrillar form to be the toxic species. However, a lack of correlation between plaque burden and cognitive score contrasted with a strong positive correlation between total soluble amyloid and cognitive decline pointing to soluble, oligomeric forms as the primary toxic factor (Walsh and Selkoe, 2007). PubMed:19293145
Early work on AD considered the fibrillar form to be the toxic species. However, a lack of correlation between plaque burden and cognitive score contrasted with a strong positive correlation between total soluble amyloid and cognitive decline pointing to soluble, oligomeric forms as the primary toxic factor (Walsh and Selkoe, 2007). PubMed:19293145
It has been demonstrated that cholinergic synapses are particularly affected by Aβ oligomers early neurotoxicity [218, 219] and that synaptic loss is the major correlate of cognitive impairment PubMed:26813123
The amount of Abeta was quantified, and following nicotine injections a reduction in Abeta, particularly in the oligomeric form, was found PubMed:25514383
In contrast, brain sections of animals treated with 10-nmol-aged Ab25–35 peptide demonstrated the presence of numerous and distinct extracellular amyloid deposits, widely disseminated throughout the brain (Fig. 5). PubMed:25881725
To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels. PubMed:22156579
The acidic environment in lysosomes is particularly favorable for the initial stages of Ab oligomerization (Peralvarez-Marin et al. 2008). PubMed:22908190
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
However, this appealing scenario is complicated by recent findings that beta-amyloid peptides directly modify alpha7 nAChR function (242, 278). PubMed:19126755
Early work on AD considered the fibrillar form to be the toxic species. However, a lack of correlation between plaque burden and cognitive score contrasted with a strong positive correlation between total soluble amyloid and cognitive decline pointing to soluble, oligomeric forms as the primary toxic factor (Walsh and Selkoe, 2007). PubMed:19293145
Early work on AD considered the fibrillar form to be the toxic species. However, a lack of correlation between plaque burden and cognitive score contrasted with a strong positive correlation between total soluble amyloid and cognitive decline pointing to soluble, oligomeric forms as the primary toxic factor (Walsh and Selkoe, 2007). PubMed:19293145
However, other naturally occurring oligomeric forms of Abeta are also toxic (Deshpande et al., 2006; Shankar et al., 2008), and evidence is accumulating that the capacity of Abeta, mutant Abeta, or fragments of Abeta to aggregate into oligomers is directly related to toxicity (Luheshi et al., 2007). PubMed:19293145
Which pathway is activated by Abeta depends upon the time of exposure to the amyloid peptide: chronic applications of oligomeric Abeta to hippocampal slice cultures activate the JNK/MAPK pathway but inhibit the ERK/MAPK pathway, whereas short-term applications of Abeta oligomers do not activate JNK (Bell et al., 2004). This may be one of the routes whereby Abeta impairs memory, because ERK-1 and ERK-2 play key roles in the signaling events central to memory (Satoh et al., 2007). PubMed:19293145
Which pathway is activated by Abeta depends upon the time of exposure to the amyloid peptide: chronic applications of oligomeric Abeta to hippocampal slice cultures activate the JNK/MAPK pathway but inhibit the ERK/MAPK pathway, whereas short-term applications of Abeta oligomers do not activate JNK (Bell et al., 2004). This may be one of the routes whereby Abeta impairs memory, because ERK-1 and ERK-2 play key roles in the signaling events central to memory (Satoh et al., 2007). PubMed:19293145
It has been demonstrated that cholinergic synapses are particularly affected by Aβ oligomers early neurotoxicity [218, 219] and that synaptic loss is the major correlate of cognitive impairment PubMed:26813123
These results confirm that the tau hyperphosphorylation stimulated by soluble ADDL preparations is indeed oligomer-induced. Tau hyperphosphorylation induced by 10M Abeta fibrils (Fig. 3N) was partially blocked (Fig. 3O), consistent with shared epitopes between oligomers and fibrils. PubMed:17403556
Importantly, pre-incubation of AD brain extracts with NU1 significantly blocked the increase in Thr231 phosphotau immunofluorescence (Fig. 6G), establishing the tau hyperphosphorylation was induced by Abeta oligomers in the AD brain extracts. NU1 also prevented the binding of brain-derived ADDLs to synaptic hot-spots (Fig. 6H and I). In NU1-treated cultures, the presence of large extracellular aggregates indicates that the antibody sequesters ADDLs and prevents their interactions with neurons (Fig. 6I). PubMed:17403556
Abetao exposure induced a translocation of tau into the PSD fraction (***p 0.0002, 2-tailed Student’s t test; control 20.12 1228 vs Abetao 29.74 1.748, N 12 independent culture). There was also an increase of PSD-95 (***p0.0006, 2-tailed Student’s t test; control 19.10 2.557 vs Abetao 33.3 2153, N 9 independent culture), GluA1 (**p 0.0078, 2-tailed Student’s t test; control 18.841.930 vs Abetao 26.221.475,N9 independent culture) and fyn (**p 0.0041, 2-tailed Student’s t test; control 19.42 1.337 vs Abetao 29.67 2.181, N 6 independent cultures; Fig. 6D). PubMed:24760868
After Abetao treatment, synaptic activation did not trigger any increase in synaptic markers and in fact decreased synaptic actin (***p 0.0009, 2-tailed Student’s t test; Abetao 29.64 1.495, Abetao Bic/4-AP 18.56 2.030, N 7 independent cultures; Fig. 7C), PSD-95 (***p0.0007, 2-tailed Student’s t test; Abetao 33.37 2.153, Abetao Bic/4-AP 19.25 2.550, N 7 independent cultures) and tau levels (**p0.0014, 2-tailed Student’s t test; Abetao 29.74 1.748, Abetao Bic/4-AP 20.68 1.751, N 12 independent cultures). PubMed:24760868
When we investigated Abetao-driven tau translocation to the synapse, we did not see any change in half-life recovery (4.729 s) from those measured with synaptic activation. However, the plateau value was drastically modified (71.20%), illustrating that, whereas Abetao induced tau translocation and subsequently its interaction with actin filament, the resulting synaptic tau is less stable. PubMed:24760868
Abetao exposure induced a translocation of tau into the PSD fraction (***p 0.0002, 2-tailed Student’s t test; control 20.12 1228 vs Abetao 29.74 1.748, N 12 independent culture). There was also an increase of PSD-95 (***p0.0006, 2-tailed Student’s t test; control 19.10 2.557 vs Abetao 33.3 2153, N 9 independent culture), GluA1 (**p 0.0078, 2-tailed Student’s t test; control 18.841.930 vs Abetao 26.221.475,N9 independent culture) and fyn (**p 0.0041, 2-tailed Student’s t test; control 19.42 1.337 vs Abetao 29.67 2.181, N 6 independent cultures; Fig. 6D). PubMed:24760868
After Abetao treatment, synaptic activation did not trigger any increase in synaptic markers and in fact decreased synaptic actin (***p 0.0009, 2-tailed Student’s t test; Abetao 29.64 1.495, Abetao Bic/4-AP 18.56 2.030, N 7 independent cultures; Fig. 7C), PSD-95 (***p0.0007, 2-tailed Student’s t test; Abetao 33.37 2.153, Abetao Bic/4-AP 19.25 2.550, N 7 independent cultures) and tau levels (**p0.0014, 2-tailed Student’s t test; Abetao 29.74 1.748, Abetao Bic/4-AP 20.68 1.751, N 12 independent cultures). PubMed:24760868
Abetao exposure induced a translocation of tau into the PSD fraction (***p 0.0002, 2-tailed Student’s t test; control 20.12 1228 vs Abetao 29.74 1.748, N 12 independent culture). There was also an increase of PSD-95 (***p0.0006, 2-tailed Student’s t test; control 19.10 2.557 vs Abetao 33.3 2153, N 9 independent culture), GluA1 (**p 0.0078, 2-tailed Student’s t test; control 18.841.930 vs Abetao 26.221.475,N9 independent culture) and fyn (**p 0.0041, 2-tailed Student’s t test; control 19.42 1.337 vs Abetao 29.67 2.181, N 6 independent cultures; Fig. 6D). PubMed:24760868
Abetao exposure induced a translocation of tau into the PSD fraction (***p 0.0002, 2-tailed Student’s t test; control 20.12 1228 vs Abetao 29.74 1.748, N 12 independent culture). There was also an increase of PSD-95 (***p0.0006, 2-tailed Student’s t test; control 19.10 2.557 vs Abetao 33.3 2153, N 9 independent culture), GluA1 (**p 0.0078, 2-tailed Student’s t test; control 18.841.930 vs Abetao 26.221.475,N9 independent culture) and fyn (**p 0.0041, 2-tailed Student’s t test; control 19.42 1.337 vs Abetao 29.67 2.181, N 6 independent cultures; Fig. 6D). PubMed:24760868
Preceded by 15 min Abetao treatment, synaptic activation disrupted LifeAct-RFP fluorescence, suggesting an alteration of F-actin organization and no additional EGFPtau recruitment at the synapse. PubMed:24760868
After Abetao treatment, synaptic activation did not trigger any increase in synaptic markers and in fact decreased synaptic actin (***p 0.0009, 2-tailed Student’s t test; Abetao 29.64 1.495, Abetao Bic/4-AP 18.56 2.030, N 7 independent cultures; Fig. 7C), PSD-95 (***p0.0007, 2-tailed Student’s t test; Abetao 33.37 2.153, Abetao Bic/4-AP 19.25 2.550, N 7 independent cultures) and tau levels (**p0.0014, 2-tailed Student’s t test; Abetao 29.74 1.748, Abetao Bic/4-AP 20.68 1.751, N 12 independent cultures). PubMed:24760868
Finally, we performed a phalloidin precipitation assay after a 15 min Abetao treatment on our neuron culture (Fig. 8A) and observed that tau/F-actin content was increased (**,*p 0.05 relative to control, #p 0.05 relative to Abetao, 1-way ANOVA; control 15.45 1.529, Abetao 32.90 3.181, Abetao Bic/ 4-AP 20.182671 for actin; control 16.342.618, Abetao 31.77 1.952, Abetao Bic/4-AP 17.704.080 for tau,N5 independent cultures Fig. 8B). A subsequent synaptic activation did alter tau interaction with F-actin. PubMed:24760868
When we investigated Abetao-driven tau translocation to the synapse, we did not see any change in half-life recovery (4.729 s) from those measured with synaptic activation. However, the plateau value was drastically modified (71.20%), illustrating that, whereas Abetao induced tau translocation and subsequently its interaction with actin filament, the resulting synaptic tau is less stable. PubMed:24760868
When we investigated Abetao-driven tau translocation to the synapse, we did not see any change in half-life recovery (4.729 s) from those measured with synaptic activation. However, the plateau value was drastically modified (71.20%), illustrating that, whereas Abetao induced tau translocation and subsequently its interaction with actin filament, the resulting synaptic tau is less stable. PubMed:24760868
Thr-205 phosphorylated tau was only increased under synaptic activation in the PSD fraction (control 24.57 0.9754 vs Bic/4-AP 38.90 1.936; Fig. 9E), whereas it was decreased after Abetao treatment (control 24.57 0.9754 vs Abeta 13.64 2.416). Synaptic activation after Abetao exposure did not produce any significant Thr-205 phosphorylation of tau (Abeta Bic/4-AP 22.892.796 vs Bic/ 4-AP 38.90 1.93 vs Abeta 13.642.50). PubMed:24760868
Conversely, only Abetao exposure promoted significant tau phosphorylation on Ser 404 (**p0.05, 1-way ANOVA; control 15.672.418 vs Abetao 32.65 3.76 vs Bic/4-AP 26.75 1.17 vs Abetao Bic/4-AP 24.97 4.48, N 4). These results revealed that, although synaptic activation or Abetao promote tau translocation to PSD fractions, the synaptic tau displays a different phosphorylation profile that may be responsible for the conditional tau properties observed. PubMed:24760868
Conversely, only Abetao exposure promoted significant tau phosphorylation on Ser 404 (**p0.05, 1-way ANOVA; control 15.672.418 vs Abetao 32.65 3.76 vs Bic/4-AP 26.75 1.17 vs Abetao Bic/4-AP 24.97 4.48, N 4). These results revealed that, although synaptic activation or Abetao promote tau translocation to PSD fractions, the synaptic tau displays a different phosphorylation profile that may be responsible for the conditional tau properties observed. PubMed:24760868
We observed that synaptic activation promoted EGFP-Tau T205A translocation to the spine but FRAP experiments revealed a shorter tau turnover time in the spine (Fig. 9B), whereas Abetao driven translocation to the spine was no longer observable in EGFP-Tau S404A-transfected neurons (Fig. 9F,G). These experiments highlight the pivotal role of these phosphorylations in tau translocation features to the spine. PubMed:24760868
Blocking proteasomes using Ab oligomers also effectively facilitates tau accumulation in AD mice (Tseng et al., 2008). PubMed:23528736
Blocking proteasomes using Ab oligomers also effectively facilitates tau accumulation in AD mice (Tseng et al., 2008). PubMed:23528736
Soluble oligomers of Ab42 serve as the prominent synapto- toxic form and induce tau hyperphosphorylation PubMed:22419736
To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels. PubMed:22156579
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.