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Abnormal Interaction of Oligomeric Amyloid-β with Phosphorylated Tau: Implications for Neuronal Damage in Alzheimer's Disease.

Neurogenetics Laboratory, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 04/2013; 36(2). DOI: 10.3233/JAD-130275
Source: PubMed

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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    • "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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    • "Hyperphosphorylation of Tau results in the formation of insoluble paired helical filaments which are the main constituents of NFTs, and the resulting loss of binding to microtubule leads to destabilization of axons and axonal degeneration, decline in a range of neuronal functions, and ultimately cell death (Iqbal and Grundke-Iqbal, 2008). While the relationship between Ab load and NFTs seems complex, and interactions between isoforms of the proteins are plausible (Roberson et al., 2007; Hyman, 2011; Desikan et al., 2012; Manczak and Reddy, 2013), the neurodegeneration and neurocognitive affection in AD may be more strongly related to NFTs than amyloid plaque load (Bennett et al., 2004). As Tau is found primarily in axons, and DTI is sensitive to axonal degeneration, this is supportive of microstructural changes as indexed by DTI playing a central role in the pathogenesis of AD. "
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    ABSTRACT: Alzheimer's Disease has traditionally been regarded as a disease of the gray matter (GM). However, the advent of diffusion tensor imaging (DTI) has contributed to new knowledge about how changes in white matter (WM) microstructure in vivo may be directly related to the pathophysiology of AD. It is now evident that WM is heavily affected in AD, even at early stages. Still, our knowledge about WM degeneration in AD is poor compared to what we know about GM atrophy. For instance, it has not been clear if WM can be directly affected in AD independently of GM degeneration, or whether WM changes mainly represent secondary effects of GM atrophy, e.g. through Wallerian degeneration. In this paper, we review recent studies using DTI to study WM alterations in AD. These studies suggest that microstructural WM affection at pre-AD stages cannot completely be accounted for by concomitant GM atrophy. Further, recent research has demonstrated relationships between increased cerebrospinal fluid levels of Tau proteins and changes in WM microstructure indexed by DTI, which could indicate that WM degeneration in pre-AD stages is related to ongoing axonal damage. We conclude that DTI is a promising biomarker for AD, with the potential also to identify subgroups of patients with especially high degree of WM affection, thereby contributing to more differentiated pre-AD diagnoses. However, more research and validation studies are needed before it is realistic to use this information in clinical practice with individual patients. This article is part of a Special Issue entitled: The CNS White Matter.
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    ABSTRACT: Considerable progress has been made in the past few years in the fight against Alzheimer's disease (AD) and Parkinson's disease (PD). Neuropathological studies in human brains and experimental in vivo and in vitro models support the notion that synapses are affected even at the earliest stages of the neurodegenerative process. The objective of this manuscript is to review some of the mechanisms of synaptic damage in AD and PD. Some lines of evidence support the notion that oligomeric neurotoxic species of amyloid β, α-synuclein, and Tau might contribute to the pathogenesis of synaptic failure at early stages of the diseases. The mechanisms leading to synaptic damage by oligomers might involve dysregulation of glutamate receptors and scaffold molecules that results in alterations in the axonal transport of synaptic vesicles and mitochondria that later on lead to dendritic and spine alterations, axonal dystrophy, and eventually neuronal loss. However, while some studies support a role of oligomers, there is an ongoing debate as to the exact nature of the toxic species. Given the efforts toward earlier clinical and preclinical diagnosis of these disorders, understanding the molecular and cellular mechanisms of synaptic degeneration is crucial toward developing specific biomarkers and new therapies targeting the synaptic apparatus of vulnerable neurons.
    Biochemical pharmacology 01/2014; 88(4). DOI:10.1016/j.bcp.2014.01.015 · 4.65 Impact Factor
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