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.

Highlights

  • Alzheimer’s disease is a growing, worldwide neurodegenerative disease affecting millions of elderly

  • Since tau co-localized with Hirano bodies and tau exhibits pathology in neurodegenerative diseases, we have studied the effect of tau in the presence of amyloid precursor protein (APP), Amyloid Precursor Protein Intracellular Domain c58 (AICDc58), and c31 and model Hirano bodies

  • Cells expressing model Hirano bodies and both APP/c31 showed a significant reduction in cell death levels (**p,0.01 compared to cells without model Hirano bodies)

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Summary

Introduction

Alzheimer’s disease is a growing, worldwide neurodegenerative disease affecting millions of elderly. The autopsied brains of AD patients reveal two hallmark neuropathological protein aggregates, amyloid-beta plaques and neurofibrillary tangles (reviewed in [1,2]) and have a higher frequency of intracellular F-actin-rich Hirano bodies than age matched normal subjects [2,3,4,5,6]. Investigating how these pathologies relate to molecular events leading to neurodegeneration is an extensive and often controversial area of research. It is thought that AICD can participate in signaling pathways (reviewed in [21,22,23])

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