Abnormal Interaction of Oligomeric Amyloid-β with Phosphorylated Tau: Implications for Neuronal Damage in Alzheimer's Disease.
ABSTRACT Alzheimer's disease (AD) is a progressive neurodegenerative mental illness characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. The purpose of our study was to determine the interaction between monomeric and oligomeric amyloid-β (Aβ) and phosphorylated tau in AD neurons. Using postmortem brains from AD patients at different stages of disease progression and control subjects, and also from AβPP, AβPPxPS1, and 3xTg-AD mice, we studied the physical interaction between Aβ and phosphorylated tau. Using immunohistological and double-immunofluorescence analyses, we also studied the localization of monomeric and oligomeric Aβ with phosphorylated tau. We found monomeric and oligomeric Aβ interacted with phosphorylated tau in neurons affected by AD. Further, these interactions progressively increased with the disease process. These findings led us to conclude that Aβ interacts with phosphorylated tau and may damage neuronal structure and function, particularly synapses, leading to cognitive decline in AD patients. Our findings suggest that binding sites between Aβ and phosphorylated tau need to be identified and molecules developed to inhibit this interaction.
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ABSTRACT: Alzheimer's disease (AD) is a devastating disease characterized by synaptic and neuronal loss in the elderly. Compelling evidence suggests that soluble amyloid-beta peptide (Abeta) oligomers induce synaptic loss in AD. Abeta-induced synaptic dysfunction is dependent on overstimulation of N-methyl-D-aspartate receptors (NMDARs) resulting in aberrant activation of redox-mediated events as well as elevation of cytoplasmic Ca2+, which in turn triggers downstream pathways involving phospho-tau (p-tau), caspases, Cdk5/dynamin-related protein 1 (Drp1), calcineurin/PP2B, PP2A, Gsk-3beta, Fyn, cofilin, and CaMKII and causes endocytosis of AMPA receptors (AMPARs) as well as NMDARs. Dysfunction in these pathways leads to mitochondrial dysfunction, bioenergetic compromise and consequent synaptic dysfunction and loss, impaired long-term potentiation (LTP), and cognitive decline. Evidence also suggests that Abeta may, at least in part, mediate these events by causing an aberrant rise in extrasynaptic glutamate levels by inhibiting glutamate uptake or triggering glutamate release from glial cells. Consequent extrasynaptic NMDAR (eNMDAR) overstimulation then results in synaptic dysfunction via the aforementioned pathways. Consistent with this model of Abeta-induced synaptic loss, Abeta synaptic toxicity can be partially ameliorated by the NMDAR antagonists (such as memantine and NitroMemantine). PSD-95, an important scaffolding protein that regulates synaptic distribution and activity of both NMDA and AMPA receptors, is also functionally disrupted by Abeta. PSD-95 dysregulation is likely an important intermediate step in the pathological cascade of events caused by Abeta. In summary, Abeta-induced synaptic dysfunction is a complicated process involving multiple pathways, components and biological events, and their underlying mechanisms, albeit as yet incompletely understood, may offer hope for new therapeutic avenues.Molecular Neurodegeneration 11/2014; 9(1):48. · 5.29 Impact Factor
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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; · 3.61 Impact Factor
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ABSTRACT: Alzheimer's disease is a complex disease characterized by overlapping phenotypes with different neurodegenerative disorders. Oligomers are considered the most toxic species in amyloid pathologies. We examined human AD brain samples using an anti-oligomer antibody generated in our laboratory and detected potential hybrid oligomers composed of amyloid-β, prion protein, α-synuclein, and TDP- 43 phosphorylated at serines 409 and 410. These data and in vitro results suggest that Aβ oligomer seeds act as a template for the aggregation of other proteins and generate an overlapping phenotype with other neuronal disorders. Furthermore, these results could explain why anti amyloid-β therapy has been unsuccessful.Neurobiology of Disease 08/2014; · 5.20 Impact Factor