The axon initial segment (AIS) is a specialized neuronal structure that is strategically located between the somatodendritic and axonal domains of a neuron where it serves as a barrier to membrane and protein trafficking. The AIS also serves as the initiation site for an action potential with its size and distance from the soma serving to dramatically alter action potential firing. These essential functions make the AIS a vulnerable feature of any neural network. Indeed, disruption of AIS structural integrity is closely connected to cognitive dysfunction in many neurodegenerative diseases. In the current study we probe the response of the AIS to the progression of Alzheimer’s disease (AD). We examined the R1.40 transgenic mouse model of AD in which the entire human APP gene, wi...[ Read more ]

The axon initial segment (AIS) is a specialized neuronal structure that is strategically located between the somatodendritic and axonal domains of a neuron where it serves as a barrier to membrane and protein trafficking. The AIS also serves as the initiation site for an action potential with its size and distance from the soma serving to dramatically alter action potential firing. These essential functions make the AIS a vulnerable feature of any neural network. Indeed, disruption of AIS structural integrity is closely connected to cognitive dysfunction in many neurodegenerative diseases. In the current study we probe the response of the AIS to the progression of Alzheimer’s disease (AD). We examined the R1.40 transgenic mouse model of AD in which the entire human APP gene, with the Swedish mutation (APP_Swe), is inserted into the mouse genome. We found that in R1.40 neocortex and hippocampus the density AIS profiles was reduced as was AIS length. Similarly, in primary cultures, R1.40 neurons had axons with shorter AIS located at an increased distance from the cell body. This is in part a developmental problem as the appearance of the AIS of R1.40 neurons in culture is delayed. To confirm that this was a direct effect of APP itself, we showed that overexpression of APP or APP_Swe in wild type neurons also reduced AIS length; the reduction was greater with APP_Swe than with wild type. By contrast, treatment with fibrillar Aß or Aß oligomers had no effect on AIS properties. These effects appear to be partly calcium mediated. Blocking the calcium-dependent protease, calpain, improved but did not fully rescue the AIS phenotype following APP overexpression. To further explore the mechanistic basis of the APP/AIS interaction we showed with immunocytochemistry that APP localizes to the proximal end of the AIS. We also found that APP and Ankyrin G can be co-immunoprecipitated with each other from mouse brain. Additionally, APP intensity at the AIS elevated upon hyperactivity and paired with the AIS property changes. Taken together our findings suggest that rather than merely being a source of Aß, the APP holoprotein potentially fine tunes neuronal activity by dynamically regulating the length and position of the AIS. The implication is that in AD APP increases as neuronal damage increases dampening neuronal responsiveness. Finally, the AIS changes become irreversible and the resulting neuronal malfunctions contribute to the neurological symptoms of Alzheimer’s disease.