Herrup, Karl and Benosman, Benjamin
(2020)
Alzheimer's disease and the axon initial segment: a powerful new disease model.
In: Pitt Momentum Fund 2020, University of Pittsburgh, Pittsburgh, Pa.
(Unpublished)
Abstract
The dominant hypothesis of Alzheimer's disease initiation and progression is known as the amyloid cascade hypothesis. The core of this hypothesis is that the amyloid precursor protein (APP) is cleaved by two proteases (the b- and g-secretases) to produce a small peptide known as b-amyloid, which aggregates and serves as a disease causing agent. One of the strongest arguments supporting the amyloid cascade hypothesis is that mutations in either APP or the g-secretase are fully penetrant disease genes that lead to aggressive, early-onset forms of Alzheimer's disease. While the genetics identify APP, not b-amyloid per se, the field has nonetheless accepted the amyloid connection. We have preliminary evidence that offers a much more direct connection to APP that does not involve b-amyloid. We propose a cross-disciplinary set of experiments to test one aspect of this new idea. Specifically, we find that APP interacts with the two main structural proteins of the axon initial segment (AIS) – bIV-spectrin and AnkyrinG. The AIS is the specialized part of the axon where voltage sensitive ion channels are concentrated, allowing the generation of an action potential, the unit of neuronal activity. When APP levels rise the AIS is shifted away from the cell body and shortens, thus reducing neuronal excitability, potentially mimicking the condition of the AD brain. We propose to use state of the art network analysis hardware and software to analyse the functioning of neural networks in dissociated cortical cell cultures. We will then transfect APP-expressing plasmids into the cells of the culture and monitor the changing network dynamics. This will allow the altered AIS geometry to be directly linked to altered network function. With these preliminary data in hand we will be in a strong position to submit and R01 application to the NIH for enhanced funding.
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