Synergistic Interactions between Repeats in Tau Protein and Aβ Amyloids May Be Responsible for Accelerated Aggregation via Polymorphic States

Center for Cancer Research Nanobiology Program NCI-Frederick, Frederick, MD 21702, USA.
Biochemistry (Impact Factor: 3.02). 06/2011; 50(23):5172-81. DOI: 10.1021/bi200400u
Source: PubMed


Amyloid plaques and neurofibrillary tangles simultaneously accumulate in Alzheimer's disease (AD). It is known that Aβ and tau exist together in the mitochondria; however, the interactions between Aβ oligomers and tau are controversial. Moreover, it is still unclear which specific domains in the tau protein can interact with Aβ oligomers and what could be the effect of these interactions. Herein, we examine three different Aβ-tau oligomeric complexes. These complexes present interactions of Aβ with three domains in the tau protein; all contain high β-structure propensity in their R2, R3, and R4 repeats. Our results show that, among these, Aβ oligomers are likely to interact with the R2 domain to form a stable complex with better alignment in the turn region and the β-structure domain. We therefore propose that the R2 domain can interact with soluble Aβ oligomers and consequently promote aggregation. EM and AFM images and dimensions revealed highly polymorphic tau aggregates. We suggest that the polymorphic tau and Aβ-tau aggregates may be largely due to repeat sequences which are prone to variable turn locations along the tau repeats.

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Available from: Yifat Miller, Oct 06, 2015
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    • "It is known that aggregated A␤-based senile plaques and hyperphosphorylated tau-based neurofibrillary tangles do not colocalize in AD brains (e.g., [22]); that intracellular neurofibrillary tangles do not contain A␤ [39]; that monomeric as well as oligomeric A␤ peptides interact especially with phospho-tau in AD neurons, creating soluble complexes [23] [26]; that interactions with A␤ evoke phosphorylation and aggregation of tau in vitro (but they prevent A␤ self-aggregation); and that increased phosphorylation of tau subsequently reduces the extent of this binding [21] [22] [23]. Taken together, the available data may be interpreted as follows: i) extracellular A␤ plays a role especially in senile plaques and intracellular A␤ in interaction with tau, among others; ii) intracellular monomeric A␤ can bind to nonphospho-tau (tau protein could be a physiological intracellular carrier of intracellular A␤ peptides, preventing their oligomerization/aggregation [22], analogously to other protein/lipoprotein carriers [3–18], see, e.g., the high-affinity of A␤ for tau [23]); and finally iii) intracellular oligomeric A␤ peptides interact mainly with phospho-tau and so create soluble complexes [23] [26] [40], which could be one of the first pathological steps leading to neurofibrillary tangles containing aggregated hyperphospho-tau because subsequent phosphorylation promotes dissociation of the complexes [23]. Our results indicate that interactions of monomeric A␤ and tau probably occur also in healthy people and that soluble A␤-tau complexes can diffuse into CSF (see also the marked negative correlation between the complexes and MMSE score in the control group, Table 4). "
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    ABSTRACT: Background: Despite the physiological sequestration of amyloid-β (Aβ) peptides by various carriers, interactions between peptides and protein tau appear to be pathological and involved in the development of Alzheimer's disease (AD). A recent study reported increased Aβ-tau interactions in the neurons of AD patients. Objective: We investigated the possibility that levels of Aβ-tau complexes in cerebrospinal fluid could be a prospective biomarker of AD, with greater sensitivity and specificity than Aβ1-42, tau, or phospho-tau individually. Methods: By means of ELISA, we estimated levels of the complexes in 161 people (non-demented controls, people with mild cognitive impairment (MCI), probable AD or other types of dementia). Results: We found significant reductions in levels in people with MCI due to AD (down to 84.5%) or with AD (down to 80.5%) but not in other types of dementia. The sensitivity of the new biomarker to AD was 68.6%, the specificity 73.3% (compared to controls) or 59.1-66.1% (compared to other types of dementia). No significant correlations were observed between the complexes and the remaining biomarkers or between those and Mini-Mental State Examination score. Conclusion: We suppose that attenuated levels of complexes in cerebrospinal fluid reflect the accumulation of Aβ bound to tau in AD neurons and that changes start many years before symptom onset, analogously to those in Aβ1-42, tau, or phospho-tau. Unfortunately, these complexes are not a significantly better biomarker of AD than current biomarkers.
    Journal of Alzheimer's disease: JAD 03/2014; 42. DOI:10.3233/JAD-132393 · 4.15 Impact Factor
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    • "Recent experimental studies suggest that Aβ may interact directly or indirectly with tau to promote the formation of NFTs [19-22,62-68]. In light of the previous simulations of Miller et al. [24] showing that Aβ has a strong preference for interacting with the R2 repeat in the tau protein (rather than with repeats R1, R3 or R4) and of experimental studies showing that the mutation ΔK280 in the tau R2 repeat promotes aggregation (vis-à-vis wild-type tau R2 repeat) [3,14], we were motivated to investigate the mechanisms and the related interactions through which mutated tau and Aβ assemble to form preferred organizations of oligomeric complexes. "
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    ABSTRACT: One of the main hallmarks of the fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is the accumulation of neurofibrillary tangles in the brain as an outcome of the aggregation of mutated tau protein. This process occurs due to a number of genetic mutations in the MAPT gene. One of these mutations is the ∆K280 mutation in the tau R2 repeat domain, which promotes the aggregation vis-à-vis that for the wild-type tau. Experimental studies have shown that in Alzheimer's disease Aβ peptide forms aggregates both with itself and with wild-type tau. By analogy, in FTDP-17, it is likely that there are interactions between Aβ and mutated tau, but the molecular mechanisms underlying such interactions remain to be elucidated. Thus, to investigate the interactions between Aβ and mutated tau, we constructed fourteen ∆K280 mutated tau-Aβ17-42 oligomeric complexes. In seven of the mutated tau-Aβ17-42 oligoemric complexes the mutated tau oligomers exhibited hydrophobic interactions in their core domain, and in the other seven mutated tau-Aβ17-42 oligoemric complexes the mutated tau oligomers exhibited salt-bridge interactions in their core domain. We considered two types of interactions between mutated tau oligomers and Aβ oligomers: interactions of one monomer of the Aβ oligomer with one monomer of the mutated tau oligomer to form a single-layer conformation, and interactions of the entire Aβ oligomer with the entire mutated tau oligomer to form a double-layer conformation. We also considered parallel arrangements of Aβ trimers alternating with mutated tau trimers in a single-layer conformation. Our results demonstrate that in the interactions of Aβ and mutated tau oligomers, polymorphic mutated tau-Aβ17-42 oligomeric complexes were observed, with a slight preference for the double-layer conformation. Aβ trimers alternating with mutated tau trimers constituted a structurally stable confined β-structure, albeit one that was energetically less stable than all the other constructed models.
    PLoS ONE 08/2013; 8(8):e73303. DOI:10.1371/journal.pone.0073303 · 3.23 Impact Factor
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    • "DLB-3xtg-AD mice exhibit accelerated formation of αSyn and LB-like inclusions in the cortex and enhanced increase of p-tau deposits immunoreactive for antibody AT8 in the hippocampus, and neocortex provide further evidence that tau, αSyn, and Aβ interact in vivo to promote accumulation of each other and accelerate cognitive dysfunction, although accumulation of αSyn alone can significantly disrupt cognition [158, 159]. Polymorphic tau and Aβ-tau aggregates may be due to repeated sequences, which are prone to variable turn locations along the tau repeats, suggesting that synergistic interactions between repeats in tau protein and Aβ may be responsible for accelerated aggregation via polymorphic states [117]. These changes and common inflammatory mechanisms in these disorders [160] could be generated by the same stimulus, with the outcome possibly having an inverse relationship depending on genetic backgrounds and environmental factors. "
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    ABSTRACT: Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.
    The Scientific World Journal 10/2011; 11(2, article 5):1893-907. DOI:10.1100/2011/371893 · 1.73 Impact Factor
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