Cofilin Rods and Aggregates Concur with Tau Pathology and the Development of Alzheimer's Disease

Rahman, Tasnim; Davies, Danielle; Tannenberg, R. K.; Fok, Sandra; Shepherd, Claire E.; Dodd, Peter R.; Cullen, Karen M.; Goldsbury, Claire

doi:10.3233/jad-140393

Cited by 51 publications

(52 citation statements)

References 35 publications

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“…Tau neuropil threads and cofilin pathology are both present in AD brain, but their immunostaining at high magnification does not overlap [Rahman et al, 2014]. Because rods disrupt axonal microtubules Cichon et al, 2012], we suggest the release of tau following this disruption might be the source of tau initiating the hyperphosphorylation cascade (Fig.…”

Section: Nfts and Tauopathiesmentioning

confidence: 84%

“…In human AD brain, cofilin‐actin rods were first observed by immunohistochemistry in paraffin sections but were not found in similar sections from brains of cognitively normal subjects [Minamide et al, ]. A more recent study quantifying cofilin immunofluorescence showed rod‐like and aggregate cofilin pathology four‐fold greater in number and larger in area in human AD brain sections than in age‐matched controls [Rahman et al, ]. However, the question remains: are rods just a reporter of neurodegenerative stress or, as found in culture, a mediator of synapse loss?…”

Section: Bodymentioning

confidence: 99%

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Actin dynamics and cofilin‐actin rods in alzheimer disease

2016

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Cytoskeletal abnormalities and synaptic loss, typical of both familial and sporadic Alzheimer disease (AD), are induced by diverse stresses such as neuroinflammation, oxidative stress, and energetic stress, each of which may be initiated or enhanced by proinflammatory cytokines or amyloid-β (Aβ) peptides. Extracellular Aβ-containing plaques and intracellular phospho-tau-containing neurofibrillary tangles are postmortem pathologies required to confirm AD and have been the focus of most studies. However, AD brain, but not normal brain, also have increased levels of cytoplasmic rod-shaped bundles of filaments composed of ADF/cofilin-actin in a 1:1 complex (rods). Cofilin, the major ADF/cofilin isoform in mammalian neurons, severs actin filaments at low cofilin/actin ratios and stabilizes filaments at high cofilin/actin ratios. It binds cooperatively to ADP-actin subunits in F-actin. Cofilin is activated by dephosphorylation and may be oxidized in stressed neurons to form disulfide-linked dimers, required for bundling cofilin-actin filaments into stable rods. Rods form within neurites causing synaptic dysfunction by sequestering cofilin, disrupting normal actin dynamics, blocking transport, and exacerbating mitochondrial membrane potential loss. Aβ and proinflammatory cytokines induce rods through a cellular prion protein-dependent activation of NADPH oxidase and production of reactive oxygen species. Here we review recent advances in our understanding of cofilin biochemistry, rod formation, and the development of cognitive deficits. We will then discuss rod formation as a molecular pathway for synapse loss that may be common between all three prominent current AD hypotheses, thus making rods an attractive therapeutic target.

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Section: Nfts and Tauopathiesmentioning

confidence: 84%

Section: Bodymentioning

confidence: 99%

Actin dynamics and cofilin‐actin rods in alzheimer disease

2016

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“…Although punctate, the cells retained their branching processes (Figure b). To test whether other proteins also located to Iba1 puncta, cells were double labeled with actin‐associated protein cofilin (which is known to label microglia in AD brain) . This showed that some puncta contained both Iba1 and cofilin (Figure c, arrow).…”

Section: Resultsmentioning

confidence: 99%

“…Immunolabeling was performed as previously described with minor modifications . Sections were incubated in sodium citrate buffer pH6.0 at 100°C for 10 minutes for antigen retrieval, before permeablising, blocking and then incubating in primary antibodies (Cofilin 1:500 (Sigma, cat # C8736) or total tau 1:500 (Dako) and Iba‐1 1:50 (Millipore, cat # MABN92) for 3 hours.…”

Section: Methodsmentioning

confidence: 99%

Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer's disease

et al. 2016

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Changes in microglia function are involved in Alzheimer's disease (AD) for which ageing is the major risk factor. We evaluated microglial cell process morphologies and their gray matter coverage (arborized area) during ageing and in the presence and absence of AD pathology in autopsied human neocortex. Microglial cell processes were reduced in length, showed less branching and reduced arborized area with aging (case range 52-98 years). This occurred during normal ageing and without microglia dystrophy or changes in cell density. There was a larger reduction in process length and arborized area in AD compared to aged-matched control microglia. In AD cases, on average, 49%-64% of microglia had discontinuous and/or punctate Iba1 labeled processes instead of continuous Iba1 distribution. Up to 16% of aged-matched control microglia displayed discontinuous or punctate features. There was no change in the density of microglial cell bodies in gray matter during ageing or AD. This demonstrates that human microglia show progressive cell process retraction without cell loss during ageing. Additional changes in microglia occur with AD including Iba1 protein puncta and discontinuity. We suggest that reduced microglial arborized area may be an aging-related correlate of AD in humans. These variations in microglial cells during ageing and in AD could reflect changes in neural-glial interactions which are emerging as key to mechanisms involved in ageing and neurodegenerative disease.

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“…The actin cytoskeleton is highly impaired in AD, with actin accumulating in aggregates . The presence of these actin‐rich inclusions correlates with the extent of tau pathology in AD patients , and tau can be detected in a subset of these rods . Given the association of hBin1 with N‐WASP and the involvement of BAR‐domain proteins in regulating actin dynamics, we speculated that hBin1 could be involved in tau pathology by directly affecting actin dynamics.…”

Section: Introductionmentioning

confidence: 99%

Bin1 directly remodels actin dynamics through its BAR domain

et al. 2017

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Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect , where we observed that downregulation of Bin1 in a model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.

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Cofilin Rods and Aggregates Concur with Tau Pathology and the Development of Alzheimer's Disease

Abstract: Cofilin rods and aggregates signify events initiated early in the pathological cascade. Further definition of the mechanisms leading to their formation in the human brain will provide insights into the cellular causes of AD.

Cited by 51 publications

References 35 publications

Actin dynamics and cofilin‐actin rods in alzheimer disease

Actin dynamics and cofilin‐actin rods in alzheimer disease

Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer's disease

Bin1 directly remodels actin dynamics through its BAR domain

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