Hirano bodies differentially modulate cell death induced by tau and the amyloid precursor protein intracellular domain

Abstract

BackgroundHirano bodies are actin-rich paracrystalline inclusions found in brains of patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD), and in normal aged individuals. Although studies of post-mortem brain tissue provide clues of etiology, the physiological function of Hirano bodies remains unknown. A cell culture model was utilized to study the interactions of mutant tau proteins, model Hirano bodies, and GSK3β in human astrocytoma cells.ResultsMost tau variants showed co-localization with model Hirano bodies. Cosedimentation assays revealed this interaction may be direct, as recombinant purified forms of tau are all capable of binding F-actin. Model Hirano bodies had no effect or enhanced cell death induced by tau in the absence of amyloid precursor protein intracellular domain (AICD). In the presence of AICD and tau, synergistic cell death was observed in most cases, and model Hirano bodies decreased this synergistic cell death, except for forms of tau that caused significant cell death in the presence of Hirano bodies only. A role for the kinase GSK3β is suggested by the finding that a dominant negative form of GSK3β reduces this synergistic cell death. A subset of Hirano bodies in brain tissue of both Alzheimer’s disease and normal aged individuals was found to contain tau, with some Hirano bodies in Alzheimer’s disease brains containing hyperphosphorylated tau.ConclusionThe results demonstrate a complex interaction between tau and AICD involving activation of GSK3β in promoting cell death, and the ability of Hirano bodies to modulate this process.

Immununochemical Markers of the Amyloid Cascade in the Hippocampus in Motor Neuron Diseases

“…We also found increased expression of pho-TAU in the hippocampus in all cases. Although it has been suggested that increased TAU expression is linked to AICD production (63), we found no correlation between the two. It is therefore most likely due to increased intraneuronal Aβ expression.…”

De novoactin polymerization is required for model Hirano body formation inDictyostelium

“…Model Hirano bodies have been induced in Dictyostelium , mammalian cultured cells, and a range of complex physiological effects have been reported ( Davis et al, 2008 ; Furgerson et al, 2012 ; Ha et al, 2011a ; Maselli et al, 2002 , 2003 ; Spears et al, 2014 ). These results led to the effort to identify the proteins in these inclusions.…”

“…These altered forms exhibit gain-of-function activated F-actin binding ( Griffin et al, 2014 ; Maselli et al, 2002 , 2003 ). Proteins present in Hirano bodies in postmortem tissues were also found in model Hirano bodies ( Davis et al, 2008 ; Furgerson et al, 2012 ; Ha et al, 2011a ; Maselli et al, 2002 , 2003 ; Spears et al, 2014 ). These results prompted further investigation of some proteins found in brain specimens utilizing modern reagents in live cells expressing model Hirano bodies and have shed light on the possible physiological role(s) of Hirano bodies in neurodegenerative diseases.…”

“…The presence of model Hirano bodies protected cells from death induced by AICD (intracellular domain of the amyloid precursor protein) ( Furgerson et al, 2012 ; Ha et al, 2011a ). The presence of model Hirano bodies and AICD and/or various forms of tau either protected cells from cell death or enhanced cell death depending whether the form of tau had a propensity to aggregate through enhanced phosphorylation ( Spears et al, 2014 ). Since valuable information about the physiological role of Hirano bodies was obtained by re-examining proteins found to colocalize to Hirano bodies, we have developed a partial purification of model Hirano bodies and utilized mass spectrometry to elucidate the protein composition of model Hirano bodies in the model organism Dictyostelium .…”

The link between laughing death and Alzheimer's disease

“…8 The latter are actin-rich inclusions that seem to be associated with tau, the main component of neurofibrillar y tangles. 11,12 In the second patient, Aβ40 fibres were periodically twisted and varied in width. 8 'The predominant structures … are clearly different', the authors comment, adding that 'the structural specificity of brain-seeded Aβ40 fibrils … is remarkable'.…”