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: 3.01). 06/2011; 50(23):5172-81. DOI: 10.1021/bi200400u
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Yifat Miller, Aug 17, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Growing evidence suggests that amyloid beta (Aβ) and tau pathologies are strongly associated with mitochondrial dysfunction and neuronal damage in Alzheimer's disease (AD). Extensive research of AD postmortem brains, mouse and fly models, including triple transgenic AD mice and mutant tau mice, and cell culture studies revealed that tau hyperphosphorylation is caused by multiple factors, including intraneuronal Aβ-oligomers, chronic oxidative stress, reduced insulin-like growth factor 1, and astrocytic mediated-Aβ and caspase activation. Overexpressed and phosphorylated tau appears to impair axonal transport of organelles causing synapse starvation, depletion of ATP, and ultimately neuronal damage. This article evaluates the role of tau in mitochondrial dysfunction and assesses how hyperphosphorylated tau impairs axonal transport of organelles in AD neurons.
    Brain research 07/2011; 1415:136-48. DOI:10.1016/j.brainres.2011.07.052 · 2.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.
    Annals of Neurology 10/2011; 70(4):532-40. DOI:10.1002/ana.22615 · 11.91 Impact Factor
Show more