THESIS
2019
v, xiii, 104 pages : color illustrations ; 30 cm
Abstract
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...[
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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.
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