title: Model Hirano bodies protect against tau-independent and tau-dependent cell death initiated by the amyloid precursor protein intracellular domain.
abstract: The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP) and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has yet to be determined. We have established cell culture models to study the role of Hirano bodies in amyloid precursor protein and tau-induced cell death mechanisms. Exogenous expression of APP and either of its c-terminal fragments c31 or Amyloid Precursor Protein Intracellular Domain c58 (AICDc58) enhance cell death. The presence of tau is not required for this enhanced cell death. However, the addition of a hyperphosphorylated tau mimic 352PHPtau significantly increases cell death in the presence of both APP and c31 or AICDc58 alone. The mechanism of cell death induced by APP and its c-terminal fragments and tau was investigated. Fe65, Tip60, p53, and caspases play a role in tau-independent and tau-dependent cell death. In addition, apoptosis was determined to contribute to cell death. The presence of model Hirano bodies protected against cell death, indicating Hirano bodies may play a protective role in neurodegeneration.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Furgerson
authors.forename: Marcus
authors.initials: M
authors.lastname: Fechheimer
authors.forename: Ruth
authors.initials: R
authors.lastname: Furukawa
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D016159:Tumor Suppressor Protein p53; D016875:tau Proteins; D005047:Etoposide; D051548:Histone Acetyltransferases; D020169:Caspases