Abstract
IntroductionHirano bodies are actin-rich intracellular inclusions found in the brains of patients with neurodegenerative conditions such as Alzheimer's disease or frontotemporal lobar degeneration-tau. While Hirano body ultrastructure and protein composition have been well studied, little is known about the physiological function of Hirano bodies in an animal model system.ResultsUtilizing a Cre/Lox system, we have generated a new mouse model which develops an age-dependent increase in the number of model Hirano bodies present in both the CA1 region of the hippocampus and frontal cortex. These mice develop normally and experience no overt neuron loss. Mice presenting model Hirano bodies have no abnormal anxiety or locomotor activity as measured by the open field test. However, mice with model Hirano bodies develop age-dependent impairments in spatial working memory performance assessed using a delayed win-shift task in an 8-arm radial maze. Synaptic transmission, short-term plasticity, and long-term plasticity was measured in the CA1 region from slices obtained from both the ventral and dorsal hippocampus in the same mice whose spatial working memory was assessed. Baseline synaptic responses, paired pulse stimulation and long-term potentiation measurements in the ventral hippocampus were indistinguishable from control mice. In contrast, in the dorsal hippocampus, synaptic transmission at higher stimulus intensities were suppressed in 3 month old mice with Hirano bodies as compared with control mice. In addition, long-term potentiation was enhanced in the dorsal hippocampus of 8 month old mice with Hirano bodies, concurrent with observed impairment of spatial working memory. Finally, an inflammatory response was observed at 8 months of age in mice with Hirano bodies as assessed by the presence of reactive astrocytes.ConclusionThis study shows that the presence of model Hirano bodies initiates an inflammatory response, alters hippocampal synaptic responses, and impairs spatial working memory in an age-dependent manner. This suggests that Hirano bodies may promote disease progression. This new model mouse provides a tool to investigate how Hirano bodies interact with other pathologies associated with Alzheimer's disease. Hirano bodies likely play a complex and region specific role in the brain during neurodegenerative disease progression.
Highlights
Hirano bodies are actin-rich intracellular inclusions found in the brains of patients with neurodegenerative conditions such as Alzheimer’s disease or frontotemporal lobar degeneration-tau
To determine if expression of CT-GFP resulted in the production of Hirano bodies, hematoxylin and eosin staining was performed on paraffin sections of brains from 3 and 8 month old R26CT and R26CT-CRE mice
To verify that the eosinophilic inclusions found in the brains of R26CT-CRE animals have the same ultrastructure as Hirano bodies found in human brains, hippocampal samples from 8 month old mice were processed and viewed using transmission electron microscopy
Summary
Hirano bodies are actin-rich intracellular inclusions found in the brains of patients with neurodegenerative conditions such as Alzheimer’s disease or frontotemporal lobar degeneration-tau. Hirano bodies are differentiated from other types of actin inclusions based on their ultrastructure [14]. They have a distinct orientation and spacing of F-actin, the appearance of which changes based on the plane of section. In addition to actin-associated proteins, amyloid precursor protein intracellular domain (AICD) and tau are present in Hirano bodies, implicating these structures in the pathogenesis of Alzheimer’s disease [17,18,19]
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