Phosphorylation of Tau protein correlates with changes in hippocampal theta oscillations and reduces hippocampal excitability in Alzheimer's model

Mondragón‐Rodríguez, Siddhartha; Salas-Gallardo, Anahí; González-Pereyra, Perla; Macías, Martín; Ordaz, Benito; Peña‐Ortega, Fernando; Aguilar-Vázquez, Azucena; Orta‐Salazar, Erika; Dı́az-Cintra, Sofı́a; Perry, George; Williams, Sylvain

doi:10.1074/jbc.ra117.001187

Cited by 66 publications

(58 citation statements)

References 37 publications

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“…Many recent studies suggest that in addition to amyloid‐β, tau protein may also play a significant role in the development of Alzheimer's disease and/or other neurodegenerative disorders . The neuropathological hallmarks of these diseases are related to the accumulation of amyloid‐β into senile plaques and of hyperphosphorylated tau into neurofibrillary tangles . Moreover, huge number of recent publications support that metal ions also play a crucial role in neurodegeneration .…”

Section: Introductionmentioning

confidence: 99%

“…[4,5] The neuropathological hallmarks of these diseases are related to the accumulation of amyloid-β into senile plaques and of hyperphosphorylated tau into neurofibrillary tangles. [6,7] Moreover, huge number of recent publications support that metal ions also play a crucial role in neurodegeneration. [8] The interactions of metal ions with prion protein and its peptide fragments and with amyloid-β peptide have been extensively studied and the most important results are summarized in several reviews.…”

Section: Introductionmentioning

confidence: 99%

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Copper(II) Coordination Abilities of the Tau Protein's N‐Terminus Peptide Fragments: A Combined Potentiometric, Spectroscopic and Mass Spectrometric Study

et al. 2019

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Copper(II) complexes of the N‐terminal peptide fragments of tau protein have been studied by potentiometric and various spectroscopic techniques (UV‐vis, CD, ESR and ESI‐MS). The octapeptide Tau(9‐16) (Ac−EVMEDHAG−NH2) contains the H14 residue of the native protein, while Tau(26‐33) (Ac−QGGYTMHQ−NH2) and its mutants Tau(Q26K‐Q33K) (Ac−KGGYTMHK−NH2) and Tau(Q26K‐Y29A‐Q33K) (Ac−KGGATMHK−NH2) include the H32 residue. To compare the binding ability of H14 and H32 in a single molecule the decapeptide Ac−EDHAGTMHQD−NH2 (Tau(12‐16)(30‐34)) has also been synthesized and studied. The histidyl residue is the primary metal binding site for metal ions in all the peptide models studied. In the case of Tau(9‐16) the side chain carboxylate functions enhance the stability of the M−Nim coordinated complexes compared to Tau(26‐33) (logK(Cu−Nim)=5.04 and 3.78, respectively). Deprotonation and metal ion coordination of amide groups occur around the physiological pH range for copper(II). The formation of the imidazole‐ and amide‐coordinated species changes the metal ion preference and the complexes formed with the peptides containing the H32 residue predominate over those of H14 at physiological pH values (90 %–10 %) and in alkaline samples (96 %–4 %).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Copper(II) Coordination Abilities of the Tau Protein's N‐Terminus Peptide Fragments: A Combined Potentiometric, Spectroscopic and Mass Spectrometric Study

et al. 2019

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“…Reduction in theta oscillation power has also been observed in other genetically modified AD mice models such as 3xTg (Mondragon-Rodriguez et al, 2018), CRND8 (Goutagny et al, 2013), and APP23 transgenic AD mice models (Ittner et al, 2014). However, in addition to the reduction of theta oscillation power, hypersynchrony and epileptic activities were also observed in transgenic AD mice models (Bezzina et al, 2015; Ittner et al, 2014; Palop and Mucke, 2010) which was absent in the AβO-injected mice in ours and other studies (Kalweit et al, 2015).…”

Section: Discussionmentioning

confidence: 82%

Optogenetic activation of SST-positive interneurons restores hippocampal theta oscillation impairment induced by soluble amyloid beta oligomersin vivo

Chung¹,

Park²,

Jang³

et al. 2018

Preprint

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Abnormal accumulation of amyloid β oligomers (AβO) is a hallmark of Alzheimer's disease (AD), which leads to learning and memory deficits. Hippocampal theta oscillations that are critical in spatial navigation, learning and memory are impaired in AD. Since GABAergic interneurons, such as somatostatin-positive (SST+) and parvalbumin-positive (PV+)interneurons, are believed to play key roles in the hippocampal oscillogenesis, we asked whether AβO selectively impairs these SST+ and PV+ interneurons. To selectively manipulate SST+ or PV+ interneuron activity in mice with AβO pathology in vivo, we coinjected AβO and adeno-associated virus (AAV) for expressing floxed channelrhodopsin-2 (ChR2) into the hippocampus of SST-Cre or PV-Cre mice. Local field potential (LFP) recordings in vivo in these AβO-injected mice showed a reduction in the peak power of theta oscillations and desynchronization of spikes from CA1 pyramidal neurons relative to theta oscillations compared to those in control mice. Optogenetic-activation of SST+ but not PV+ interneurons in AβO-injected mice fully restored the peak power of theta oscillations and resynchronized the theta spike phases to a level observed in control mice. In vitro whole-cell voltage-clamp recordings in CA1 pyramidal neurons in hippocampal slices treated with AβO revealed that short-term plasticity of SST+ interneuron inhibitory inputs to CA1 pyramidal neurons at theta frequency were selectively disrupted while that of PV+ interneuron inputs were unaffected. Together, our results suggest that dysfunction in inputs from SST+ interneurons to CA1 pyramidal neurons may underlie the impairment of theta oscillations observed in AβO-injected mice in vivo. Our findings identify SST+ interneurons as a target for restoring theta-frequency oscillations in early AD.

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“…These data agree with previous reports describing Aβ-associated dysfunction in hippocampal interneurons, and expand this hyperactivity phenotype to both putative interneurons and putative excitatory neurons in EC. Impaired neuronal network activity has been described in human AD 43 and in mouse models of AD pathology 44,45,46 . To investigate the effects of hAPP/Aβ and tau pathology on EC network activity in vivo, we examined the LFPs and compared oscillatory activity across genotypes ( Figure 3).…”

Section: Introductionmentioning

confidence: 99%

Attenuation of entorhinal cortex hyperactivity reduces Aβ and tau pathology

Rodriguez

Barrett

Duff

2018

Preprint

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13High levels of the amyloid-beta (Aβ) peptide have been shown to disrupt neuronal function and 14 induce hyperexcitability, but it is unclear what effects Aβ-associated hyperexcitability may have 15 on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to 16 model the impact of hAPP/Aβ accumulation on tauopathy in the entorhinal cortex-hippocampal 17(EC-HIPP) network, we demonstrate that hAPP aggravates EC tau aggregation and accelerates 18 pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for 19 hAPP/Aβ, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta 20 rhythmicity. Chronic chemogenetic attenuation of Aβ-associated hyperactivity led to reduced 21 hAPP/Aβ accumulation and reduced pathological tau spread into downstream hippocampus. 22These data strongly support the hypothesis that in Alzheimer's disease (AD), Aβ-associated 23 hyperactivity accelerates the progression of pathological tau along vulnerable neuronal circuits, 24and demonstrates the utility of chronic, neuromodulatory approaches in ameliorating AD 25 pathology in vivo. 26 Results 84 Aβ-associated acceleration of tau pathology in EC-Tau/hAPP mice in vivo 85Overexpression of mutant hAPP (Swedish/Indiana) in the hAPP/J20 mouse line leads to progressive 86Aβ plaque deposition throughout the hippocampus and neocortex, contributing to aberrant 87 network activity and cognitive deficits (21, 22). To test whether Aβ pathology alters the 88 progression of tau pathology along the EC-HIPP circuit, we generated the hAPP/J20 x EC-Tau 89 mouse line, hereafter referred to as EC-Tau/hAPP (described in Methods). At 16-months, EC-90Tau/hAPP mice exhibit robust amyloid deposition throughout the EC and HIPP using 6E10 91( Figure 1B), with no change in Aβ deposition compared to age-matched hAPP mice sampled. 92Diffuse amyloid accumulation made up the majority of the pathology, though small, compact Aβ 93 plaques and large, dense-core Aβ plaques were also present (arrows, Figure 1B). Mice 94 expressing hTau alone (EC-Tau) did not exhibit 6E10 immunoreactivity ( Figure 1A). 95Immunostaining for MC1 revealed a dramatic increase in abnormal, misfolded tau within the 96 somatodendritic compartments of EC and HIPP neurons of EC-Tau/hAPP mice compared to 97 EC-Tau littermates ( Figure 1C-D). This increase was over three-fold higher in EC cells (EC-98 Tau/hAPP: 131.00 ± 19.38 vs EC-Tau: 40.52 ± 7.24) and over ten-fold higher in DG granule 99 cells (EC-Tau/hAPP: 359.20 ± 109.40 vs EC-Tau: 30.67 ± 14.88) ( Figure 1E), suggesting that 100 hAPP/Aβ expression in the EC-HIPP network accelerates tau pathology along the classical 101 perforant pathway. MC1 immunostaining in 10-month EC-Tau/hAPP mice revealed mostly 102 diffuse tau in neuropil throughout the EC and in axons terminating in the middle-and outer-103 molecular layers of the DG ( Figure 1F). No somatodendritic MC1+ staining was detected in 104HIPP subregions at this age. By 16-months, it was clear that tau aggregation had not ...

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Phosphorylation of Tau protein correlates with changes in hippocampal theta oscillations and reduces hippocampal excitability in Alzheimer's model

Cited by 66 publications

References 37 publications

Copper(II) Coordination Abilities of the Tau Protein's N‐Terminus Peptide Fragments: A Combined Potentiometric, Spectroscopic and Mass Spectrometric Study

Copper(II) Coordination Abilities of the Tau Protein's N‐Terminus Peptide Fragments: A Combined Potentiometric, Spectroscopic and Mass Spectrometric Study

Optogenetic activation of SST-positive interneurons restores hippocampal theta oscillation impairment induced by soluble amyloid beta oligomersin vivo

Attenuation of entorhinal cortex hyperactivity reduces Aβ and tau pathology

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