Memory deficits correlate with tau and spine pathology in <scp>P</scp>301<scp>S <i>MAPT</i></scp> transgenic mice

Xu, Hong; Rösler, Thomas W.; Carlsson, Thomas; Andrade, Anderson de; Bruch, Julius; Höllerhage, Matthias; Oertel, Wolfgang H.; Höglinger, Günter U.

doi:10.1111/nan.12160

Cited by 45 publications

(60 citation statements)

References 31 publications

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“…Overall, our data lend direct support to the patho-physiological relevance of non-filamentous, oligomeric tau. Nevertheless, strong correlations with cognitive decline were also observed for conformational and phospho-tau as previously reported in humans [25, 30] and animal models [43, 44, 83]. Our data expand on the suggested disruptive role of monomeric phospho-tau [41], and suggest oligomerization caused by pathological modification of monomeric tau to play a key role.…”

Section: Discussionsupporting

confidence: 89%

Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline

et al. 2016

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Post-mortem investigations of human Alzheimer’s disease (AD) have largely failed to provide unequivocal evidence in support of the original amyloid cascade hypothesis, which postulated deposition of β-amyloid (Aβ) aggregates to be the cause of a demented state as well as inductive to tau neurofibrillary tangles (NFTs). Conflicting evidence suggests, however, that Aβ plaques and NFTs, albeit to a lesser extent, are present in a substantial subset of non-demented individuals. Hence, a range of soluble tau and Aβ species has more recently been implicated as the disease-relevant toxic entities. Despite the incorporation of soluble proteins into a revised amyloid cascade hypothesis, a detailed characterization of these species in the context of human AD onset, progression and cognitive decline has been lacking. Here, lateral temporal lobe samples (Brodmann area 21) of 46 human cases were profiled via tau and Aβ Western blot and native state dot blot protocols. Elevations in phospho-tau (antibodies: CP13, AT8 and PHF-1), pathological tau conformations (MC-1) and oligomeric tau (TOC1) agreed with medical diagnosis (non-AD cf. AD) and Braak stage classification (low, intermediate and high), alongside elevations in soluble Aβ species (MOAB-2 and pyro-glu Aβ) and a decline in levels of the amyloid precursor protein. Strong correlations were observed between individual Braak stages and multiple cognitive measures with all tau markers as well as total soluble Aβ. In contrast to previous reports, SDS-stable Aβ oligomers (*56) were not found to be reliable for all classifications and appeared likely to be a technical artefact. Critically, the robust predictive value of total soluble Aβ was dependent on native state quantification. Elevations in tau and Aβ within soluble fractions (Braak stage 2–3 cf. 0) were evident earlier than previously established in fibril-focused disease progression scales. Together, these data provide strong evidence that soluble forms of tau and Aβ co-localise early in AD and are closely linked to disease progression and cognitive decline.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1632-3) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 89%

Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline

et al. 2016

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“…In P301S Tau mice, the fraction of thin spines was found to be strongly reduced, whereas that of mushroom spines was found to be increased compared to controls [16]. Another study reported that, even at an early age, P301S Tau transgenic mice are characterized by a lower average spine density, length, area and volume compared with wild-type mice, concomitant with an impaired learning at this age in the Morris water maze [38]. Together with our findings this reveals that FTD mutant forms of Tau accumulate in the spine, which results in morphological changes and, subsequently, spine loss.…”

Section: Discussionmentioning

confidence: 91%

Pseudophosphorylation of Tau at distinct epitopes or the presence of the P301L mutation targets the microtubule-associated protein Tau to dendritic spines

Xia

Götz

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) and Tau in the brain. In mature neurons, Tau is concentrated in the axon and found at lower levels in the dendrite where it is required for targeting Fyn to the spines. Here Fyn mediates Aβ toxicity, which is vastly abrogated when Tau is either deleted or a truncated form of Tau (Tau(1-255)) is co-expressed. Interestingly, MAP2, a microtubule-binding protein with mainly dendritic localization that shares Fyn-binding motifs with Tau, does not mediate Aβ's synaptic toxicity in the absence of Tau. Here we show in hippocampal neurons that endogenous Tau enters the entire spine, albeit at low levels, whereas MAP2 only enters its neck or is restricted to the dendritic shaft. Based on an extensive mutagenesis study, we also reveal that the spine localization of Tau is facilitated by deletion of the microtubule-binding repeat domain. When distinct phosphorylation sites (AT180-T231/S235, 12E8-S262/S356, PHF1-S396/S404) were pseudophosphorylated (with glutamic acid, using alanine replacements as controls), Tau targeting to spines was markedly increased, whereas the pseudophosphorylation of the late phospho-epitope S422 had no effect. In determining the role physiological Fyn has in the spine localization of Tau, we found that neither were endogenous Tau levels reduced in Fyn knockout compared with wild-type synaptosomal brain fractions nor was the spine localization of over-expressed pseudophosphorylated or P301L Tau. This demonstrates that although Fyn targeting to the spine is Tau dependent, elevated levels of phosphorylated Tau or P301L Tau can enter the spine in a Fyn-independent manner.

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“…More importantly, compelling evidence indicates that tau pathology is closely associated with the severity of cognitive deficits in patients with AD or FTD (Giannakopoulos et al, 2003;Xu et al, 2014). In view of its critical role in the pathogenesis of these 2 diseases, more needs to be done to elucidate potential mechanisms affecting the formation and progression of tau pathology.…”

Section: Introductionmentioning

confidence: 98%

Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice

Jiang

Tan

Zhu

et al. 2015

Neurobiology of Aging

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Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice

Cited by 45 publications

References 31 publications

Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline

Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline

Pseudophosphorylation of Tau at distinct epitopes or the presence of the P301L mutation targets the microtubule-associated protein Tau to dendritic spines

Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice

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