Neurites containing the neurofilament-triplet proteins are selectively vulnerable to cytoskeletal pathology in Alzheimer’s disease and transgenic mouse models

Mitew, Stanislaw; Kirkcaldie, Matthew; Dickson, Tracey C.; Vickers, James C.

doi:10.3389/fnana.2013.00030

Cited by 19 publications

(26 citation statements)

References 57 publications

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“…The former method yielded smaller particle-size distributions, probably due both to the inclusion of objects that were not actually plaques and to underestimating the sizes of real plaques if only the plaque cores, but not the plaque peripheries, were above the threshold. Finally, yet another study [35] reported larger ThioS-positive plaques in 12-month Tg2576 and APP Swe PS1ΔE9 (gender unspecified) mice than we found here (mean areas ~ double those found in the current study). The discrepancies between the various studies point to the necessity of employing consistent methods when attempting quantitative comparisons.…”

Section: Discussioncontrasting

confidence: 66%

“…In that study, which examined the superior temporal sulcus, the ThioS plaque burden was 1.2 ± 0.2% (mean ± S.E.M., N = 62) [53]. Two smaller studies reported ThioS plaque burdens of 3.0 ± 0.3% (N = 6 [35]; N = 7 [54]) in inferior temporal gyrus. The latter study also measured ThioS plaque burdens in subjects with familial autosomal AD caused by Presenilin-1 mutations (8 subjects with 5 different mutations) and found that the burden in these subjects, 3.5 ± 0.3%, did not differ significantly from the burden in the subjects with sporadic AD.…”

Section: Discussionmentioning

confidence: 99%

“…Using stereology-based methods, we quantified dense-core plaque burdens (areal fraction occupied by plaques) in the cortex and hippocampus of young, middle-aged, and old mice, and compared these values with plaque burdens in the frontal, temporal, and parietal cortices of pathologically-confirmed AD cases. In addition, we measured plaque sizes in the mice, as microglial responses [34] and degree of plaque-associated neuritic abnormalities [35] have been reported to correlate with plaque size.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

Liu

Reichl

Rao

et al. 2017

JAD

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There exist several dozen lines of transgenic mice that express human amyloid-β precursor protein (AβPP) with Alzheimer’s disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ~4.5 times that of 21-month Tg2576 mice and ~15 times that of 21–24-month rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded those measured in the human cohort.

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Section: Discussioncontrasting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

Liu

Reichl

Rao

et al. 2017

JAD

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“…For instance, Map1b is critical for microtubule stabilization during axonal growth [114] and Ntn1 plays a role in axonal guidance [81], whereas Nfh is essential in maintaining axonal caliber and is dysregulated in human AD and animal models of the disease [42, 83]. Significant downregulation of these genes suggest that LC neurons may be undergoing an axonal degenerative process during prodromal stages, which progress to frank AD as evidenced by a significant increase in the cytoskeletal proteases Capn1 and Capn2 expression in AD neurons [92, 104].…”

Section: Discussionmentioning

confidence: 99%

Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease

Kelly

Perez

et al. 2017

acta neuropathol commun

236

230

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A major feature of Alzheimer’s disease (AD) is the loss of noradrenergic locus coeruleus (LC) projection neurons that mediate attention, memory, and arousal. However, the extent to which the LC projection system degenerates during the initial stages of AD is still under investigation. To address this question, we performed tyrosine hydroxylase (TH) immunohistochemistry and unbiased stereology of noradrenergic LC neurons in tissue harvested postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a putative prodromal AD stage), or mild/moderate AD. Stereologic estimates of total LC neuron number revealed a 30% loss during the transition from NCI to aMCI, with an additional 25% loss of LC neurons in AD. Decreases in noradrenergic LC neuron number were significantly associated with worsening antemortem global cognitive function as well as poorer performance on neuropsychological tests of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. Reduced LC neuron numbers were also associated with increased postmortem neuropathology. To examine the cellular and molecular pathogenic processes underlying LC neurodegeneration in aMCI, we performed single population microarray analysis. These studies revealed significant reductions in select functional classes of mRNAs regulating mitochondrial respiration, redox homeostasis, and neuritic structural plasticity in neurons accessed from both aMCI and AD subjects compared to NCI. Specific gene expression levels within these functional classes were also associated with global cognitive deterioration and neuropathological burden. Taken together, these observations suggest that noradrenergic LC cellular and molecular pathology is a prominent feature of prodromal disease that contributes to cognitive dysfunction. Moreover, they lend support to a rational basis for targeting LC neuroprotection as a disease modifying strategy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0411-2) contains supplementary material, which is available to authorized users.

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“…Desmin is highly expressed in muscle whereas GFAP is expressed in astrocytes. This tight regulation of IF subtype expression, which has the potential to give each cell type a “unique cytoskeletal architecture” (Chang & Goldman, ; Mitew, Kirkcaldie, Dickson, & Vickers, ), begs the question of what cell type‐specific functions the IF proteins carry out and to what degree IF proteins are functionally interchangeable.…”

Section: An Introduction To Intermediate Filamentsmentioning

confidence: 99%

Intermediate filaments in developing neurons: Beyond structure

Bott

Winckler

2020

Cytoskeleton

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Neuronal development relies on a highly choreographed progression of dynamic cellular processes by which newborn neurons migrate, extend axons and dendrites, innervate their targets, and make functional synapses. Many of these dynamic processes require coordinated changes in morphology, powered by the cell's cytoskeleton. Intermediate filaments (IFs) are the third major cytoskeletal elements in vertebrate cells, but are rarely considered when it comes to understanding axon and dendrite growth, pathfinding and synapse formation. In this review, we first introduce the many new and exciting concepts of IF function, discovered mostly in non‐neuronal cells. These roles include dynamic rearrangements, crosstalk with microtubules and actin filaments, mechano‐sensing and ‐transduction, and regulation of signaling cascades. We then discuss the understudied roles of neuronally expressed IFs, with a particular focus on IFs expressed during development, such as nestin, vimentin and α‐internexin. Lastly, we illustrate how signaling modulation by the unconventional IF nestin shapes neuronal morphogenesis in unexpected and novel ways. Even though the first IF knockout mice were made over 20 years ago, the study of the cell biological functions of IFs in the brain still has much room for exciting new discoveries.

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Neurites containing the neurofilament-triplet proteins are selectively vulnerable to cytoskeletal pathology in Alzheimer’s disease and transgenic mouse models

Cited by 19 publications

References 57 publications

Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease

Intermediate filaments in developing neurons: Beyond structure

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