Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease

Pooler, Amy M.; Polydoro, Manuela; Maury, Eduardo A.; Nicholls, Samantha B.; Reddy, Snigdha; Wegmann, Susanne; William, Christopher; Saqran, Lubna; Cagsal‐Getkin, Ozge; Pitstick, Rose; Beier, David R.; Carlson, George A.; Spires‐Jones, Tara L.; Hyman, Bradley T.

doi:10.1186/s40478-015-0199-x

Cited by 190 publications

(197 citation statements)

References 29 publications

(43 reference statements)

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“…Compact, congophilic Aβ deposits, induced or spontaneously formed in APP tg animals, are surrounded by degenerating neuritic boutons in which hyperphosphorylated tau has accumulated [76]. Human mutated APP and human mutated tau tg mice have been crossed to study the interaction of Aβ and tau pathologies [100]. Neurofibrillary tangles are initially found in the entorhinal cortex in tg mice expressing P301L human tau predominantly in that area (rTgTauEC) [135].…”

Section: In Animalsmentioning

confidence: 99%

Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

Eisele

Duyckaerts

2015

Acta Neuropathol

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In brains of patients with Alzheimer's disease (AD), Aβ peptides accumulate in parenchyma and, almost invariably, also in the vascular walls. Although Aβ aggregation is, by definition, present in AD, its impact is only incompletely understood. It occurs in a stereotypical spatiotemporal distribution within neuronal networks in the course of the disease. This suggests a role for synaptic connections in propagating Aβ pathology, and possibly of axonal transport in an antero- or retrograde way-although, there is also evidence for passive, extracellular diffusion. Striking, in AD, is the conjunction of tau and Aβ pathology. Tau pathology in the cell body of neurons precedes Aβ deposition in their synaptic endings in several circuits such as the entorhino-dentate, cortico-striatal or subiculo-mammillary connections. However, genetic evidence suggests that Aβ accumulation is the first step in AD pathogenesis. To model the complexity and consequences of Aβ aggregation in vivo, various transgenic (tg) rodents have been generated. In rodents tg for the human Aβ precursor protein, focal injections of preformed Aβ aggregates can induce Aβ deposits in the vicinity of the injection site, and over time in more distant regions of the brain. This suggests that Aβ shares with α-synuclein, tau and other proteins the property to misfold and aggregate homotypic molecules. We propose to group those proteins under the term "propagons". Propagons may lack the infectivity of prions. We review findings from neuropathological examinations of human brains in different stages of AD and from studies in rodent models of Aβ aggregation and discuss putative mechanisms underlying the initiation and spread of Aβ pathology.

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Section: In Animalsmentioning

confidence: 99%

Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

Eisele

Duyckaerts

2015

Acta Neuropathol

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“…The temporal dynamics of these neuropathologic processes may be one explanation for the close correlation between tau pathology and dementia severity, whereas A β shows no additive predictive value 2. Interestingly, animal studies – more appropriate to investigate the temporal relationship of protein accumulation than postmortem studies – recently suggested a synergistic effect of A β ‐mediated tau propagation and neuronal loss 3. However, the relative contributions of A β and tau pathology to AD‐related neurodegeneration in humans remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Impact of tau and amyloid burden on glucose metabolism in Alzheimer's disease

Bischof

Jessen

Fließbach

et al. 2016

Ann Clin Transl Neurol

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In a multimodal PET imaging approach, we determined the differential contribution of neurofibrillary tangles (measured with [18F]AV‐1451) and beta‐amyloid burden (measured with [11C]PiB) on degree of neurodegeneration (i.e., glucose metabolism measured with [18F]FDG‐PET) in patients with Alzheimer's disease. Across brain regions, we observed an interactive effect of beta‐amyloid burden and tau deposition on glucose metabolism which was most pronounced in the parietal lobe. Elevated beta‐amyloid burden was associated with a stronger influence of tau accumulation on glucose metabolism. Our data provide the first in vivo insights into the differential contribution of Aβ and tau to neurodegeneration in Alzheimer's disease.

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“…Interestingly, the rTgTauEC/APP/PS1 mice also showed increased tau-induced neuronal loss [142]. There is still debate and discrepancy in the field as to the toxic species of tau, with oligomeric species emerging as an attractive candidate for both toxicity and seeding, although it should be noted they are not the only species to show efficacious seeding, but have been shown to be upregulated following transgenic lysate and EV injection in our studies [146,154].…”

Section: Discussionmentioning

confidence: 59%

“…Tat accelerated the speed and trajectory of tau spreading [142]. However, when isolating specific mechanisms involved in seeding it is preferable to begin to establish roles, such as those of extracellular vesicles, in simpler models first.…”

Section: Discussionmentioning

confidence: 99%

“…propagation to more distal sites and display increased cell loss, suggesting Aβ pathology amplifies tau spreading [142] Other approaches have utilised stereotaxic injection to target the delivery of potential seeds to specific brain areas. Injection of mouse brain lysates from the FTDP-17 tau mutation (P301S) and human brain lysates from AD patients into young ALZ17 mice show acceleration of tau pathology and seeding of NFTs at the injection site and in neighbouring regions [143,144].…”

Section: In Vivo Supportmentioning

confidence: 99%

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Investigating in vivo the principles governing the spread of tau phosphorylation and amyloid-beta excitotoxicity

Baker¹

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Alzheimers disease (AD) is a devastating neurodegenerative disease which presents clinically with progressive loss of memory, executive function and cognitive abilities.Traditionally AD is diagnosed post-mortem by presence of two hallmark lesions, extracellular plaques comprised of amyloid-beta (Aβ) and intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated microtubule-associated protein tau.The current available therapies for the treatment of AD only provide mild symptomatic relief and cannot halt the ongoing disease progression. Therefore, the research presented focuses on the mechanisms underlying disease propagation specifically that of hyperphosphorylated tau pathology, and understanding potential disease modifying therapeutics targeting known mechanisms, specifically TatNR2b9c peptide induced neuroprotection against Aβ induced excitotoxicity.Current approaches to investigate tau propagation have utilised tau transgenic recipient mice, mutant tagged tau constructs and whole brain lysates to establish tau seeding and spreading in vitro. To circumvent caveats of this technique and progress our understanding of tau seeding events we proposed a two-pronged approach.Firstly, we created an endogenous model of tau hyperphosphorylation by inhibiting tau dephosphorylation with the unilateral injection of the inhibitor okadaic acid. By keeping the concentration and volume low we were able to show by ELISA that the spread of the inhibitor could be restricted, and this single exposure was sufficient to induce tau hyperphosphorylation, increases in insolubilty and thioflavin-S NFT-Like immunoreactivity at both the injection site and anatomically distinct non-exposed brain regions. Secondly, we injected exosome and large extracellular vesicle fractions derived from tau transgenic mice into human tau expressing mice and compared there seeding ability to brain lysate. Under our experiment parameters we did not observe any NFT positivity and could not recreate previous seeding using brain lysates. Interestingly, both brain lysates and exosomes increased AT8 phosphorylation and oligomeric tau deposition in the hippocampus, whereas large extracellular vesicles did not.To address whether the Tat-NR2b9c peptide can provide long-term protection against Aβ induced excitotoxicity we treated mutant amyloid precursor protein 3 transgenic mice at both young and old age and investigated amyloid levels and NMDA receptor subunit expression in synaptic and extrasynaptic zones.Unfortunately, lack of a robust behavioural deficit in our aged APP23 cohort prevented us from performing a therapeutic intervention study. However, biochemical analysis of aged Tat-NR2b9c revealed a similar effect on synaptic redistribution of NMDA receptor subunits as that observed in young treated mice, indicating that the peptide may be a viable therapeutic prospect for late stage intervention in AD.This work demonstrates that mechanisms underlying tau spreading may also be studied by using endogenous mouse tau models. An avenue whic...

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Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease

Cited by 190 publications

References 29 publications

Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

Impact of tau and amyloid burden on glucose metabolism in Alzheimer's disease

Investigating in vivo the principles governing the spread of tau phosphorylation and amyloid-beta excitotoxicity

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