The impact of Hirano bodies on Alzheimer's disease progression
Furgerson, Matthew Chase
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Alzheimer’s disease is a neurodegenerative condition characterized by three pathological hallmarks: amyloid beta plaques composed of amyloid beta (a fragment of the amyloid precursor protein), neurofibrillary tangles composed of tau, and Hirano bodies composed of filamentous actin (F-actin) and actin binding proteins (1). While both amyloid beta plaques and neurofibrillary tangles have been well studied, relatively little is known about Hirano bodies because of the absense of a model system. We have established cell culture models to study the role of Hirano bodies in amyloid precursor protein and tau-induced cell death. Exogenous expression of the amyloid precursor protein (APP) plus its c-terminal fragment C31, or expression of amyloid precursor protein intracellular domain (AICDc58, AICD) alone, initiates cell death. The addition of a hyperphosphorylated tau mimic 352PHPtau (2,3) or FTLD-tau mutants significantly increases cell death in the presence of both APP and C31 or AICDc58 alone. The mechanism of cell death induced by APP, its c-terminal fragments, and tau was investigated. Fe65, Tip60, p53, and caspases play a role in both 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 initiated by some forms of tau and increased cell death initiated by others. Further investigation of the physiological role of Hirano bodies in a mouse model indicates that Hirano bodies initiate an inflammatory response in the brain as measured by reactive astrocytes. In addition, mice with Hirano bodies show a deficit in spatial working memory as measured using an 8-arm radial maze, while electrophysiological measurements of both short-term and long-term plasticity appear unaffected. These studies suggest that Hirano bodies can be either protective or detrimental and likely play a dynamic and complex role in neurodegeneration.