Reversal of Neurofibrillary Tangles and Tau-Associated Phenotype in the rTgTauEC Model of Early Alzheimer's Disease

Polydoro, Manuela; Calignon, Alix de; Suárez‐Calvet, Marc; Sánchez, Laura; Kay, Kevin; Nicholls, Samantha B.; Roe, Allyson D.; Pitstick, Rose; Carlson, George A.; Gómez-Isla, Teresa; Spires‐Jones, Tara L.; Hyman, Bradley T.

doi:10.1523/jneurosci.0881-13.2013

Cited by 41 publications

(40 citation statements)

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“…At an age prior to synaptic loss or the appearance of NFT in the dentate gyrus, sensitive electrophysological and molecular markers demonstrate abnormalities in the presynaptic function of the perforant pathway projection to the hippocampal formation, implicating misfolded, but soluble tau in neural system failure (Polydoro et al, 2013b). Importantly, work on the rTgTauEC model indicates that lowering soluble tau levels by transgene suppression prevents synapse loss and trans-synaptic spread of mutant tau, and surprisingly allows reversal of existing neurofibrillary tangle pathology both in the dentate gyrus and entorhinal cortex (Polydoro et al, 2013a). This has implications for therapeutics as it implies reducing tau levels will prevent both the spread of the disease through the brain and the synapse loss that appears to contribute significantly to cognitive decline.…”

Section: A Role For Synapses In Disease Progressionmentioning

confidence: 99%

The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

Spires‐Jones

Hyman

2014

Neuron

888

723

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Summary The collapse of neural networks important for memory and cognition, including death of neurons and degeneration of synapses, causes the debilitating dementia associated with Alzheimer’s disease (AD). We suggest that synaptic changes are central to the disease process. Amyloid beta and tau form fibrillar lesions that are the classical hallmarks of AD. Recent data indicate that both molecules may have normal roles at the synapse, and that the accumulation of soluble toxic forms of the proteins at the synapse may be on the critical path to neurodegeneration. Further, the march of neurofibrillary tangles through brain circuits appears to take advantage of recently described mechanisms of trans-synaptic spread of pathological forms of tau. These two key phenomena, synapse loss and the spread of pathology through the brain via synapses, make it critical to understand the physiological and pathological roles of amyloid beta and tau at the synapse.

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Section: A Role For Synapses In Disease Progressionmentioning

confidence: 99%

The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

Spires‐Jones

Hyman

2014

Neuron

888

723

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“…The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of AD (Bellucci et al 2007;Polydoro et al 2013). The composition of NFTs is the microtubule-associated protein tau, in the form of filamentous aggregates.…”

Section: Rage:a Mediator Role Of Tau Hyperphosphorylation?mentioning

confidence: 99%

Role of RAGE in Alzheimer’s Disease

et al. 2015

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Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer's disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aβ depends on the balance between production and clearance. RAGE plays an important role in the Aβ clearance. RAGE acts as an important transporter via regulating influx of circulating Aβ into brain, whereas the efflux of brain-derived Aβ into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aβ generation via enhancing the activity of β- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE-Aβ interactions could inhibit Aβ neurotoxicity and promote Aβ clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aβ and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.

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“…Cells undoubtedly have evolved mechanisms to degrade amyloid structures. For example, in inducible mouse models, pre-existing amyloids will disappear once further protein production is stopped (Mallucci et al, 2007; Polydoro et al, 2013; Walker et al, 2015; Yamamoto et al, 2000). Finally, following amplification the seed must escape to enter a new cell and propagate an aggregated state throughout the nervous system using physiologic cell uptake mechanisms (Holmes and Diamond, 2012).…”

Section: Introductionmentioning

confidence: 99%

Prions and Protein Assemblies that Convey Biological Information in Health and Disease

Sanders

Kaufman

Holmes

et al. 2016

Neuron

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Prions derived from the prion protein (PrP) were first characterized as infectious agents that transmit pathology between individuals. However, the majority of cases of neurodegeneration caused by PrP prions occur sporadically. Proteins that self-assemble as cross-beta sheet amyloids are a defining pathological feature of infectious prion disorders and all major age-associated neurodegenerative diseases. In fact, multiple non-infectious proteins exhibit properties of template-driven self-assembly that are strikingly similar to PrP. Evidence suggests that like PrP, many proteins form aggregates that propagate between cells and convert cognate monomer into ordered assemblies. We now recognize that numerous proteins assemble into macromolecular complexes as part of normal physiology, some of which are self-amplifying. This review highlights similarities among infectious and non-infectious neurodegenerative diseases associated with prions, emphasizing the normal and pathogenic roles of higher-order protein assemblies. We propose that studies of the structural and cellular biology of pathological vs. physiological aggregates will be mutually informative.

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Reversal of Neurofibrillary Tangles and Tau-Associated Phenotype in the rTgTauEC Model of Early Alzheimer's Disease

Cited by 41 publications

References 50 publications

The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

Role of RAGE in Alzheimer’s Disease

Prions and Protein Assemblies that Convey Biological Information in Health and Disease

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