This is the readme for NEURON and MATLAB model code for the paper

Peng Yuan, Mengyang Zhang, Lei Tong, Thomas M. Morse, Robert A. McDougal, Hui Ding, Diane Chan, Yifei Cai, Jaime Grutzendler (2022) PLD3 impacts axonal spheroids and network defects in Alzheimer’s disease. Nature

The NEURON code was written by Tom Morse and the MATLAB code by Peng (Paul) Yuan and Tom Morse.

To run the NEURON code download and extract this archive and compile the mod files with nrnivmodl. If you need more help than provided here please consult https://senselab.med.yale.edu/ModelDB/NEURON_DwnldGuide for more help.

### Extended Data Figures 2a,b

please run the mosinit.hoc with a command like

nrngui mosinit.hoc

The PAAS (plaque-associated axonal spheroid(s)) is represented in the model by a compartment called Can (as in tomato soup can) which is connected to the middle of an axon via a short process called Stick and these morphologies are displayed in a zoomed in shape plot above a voltage plot. A current clamp connected to the left end of the axon evokes one or more action potentials (APs). The voltage plot displays the AP(s) that is/are evoked in the left end of the dendrite (green voltage trace) and these propagate and are transmitted through the dystrophy or blocked. The voltage on the right end of the axon is displayed in purple. The left, middle, and right extended data figure 2a single AP examples can be generated by pressing the appropriate button which automatically sets the PAAS diameter to 1e-7 (normal), 29 (delayed), and 40 (blocked) for the single AP cases. For 2b the spheroid diameter example is set to 53 um, which would also block a single AP, however will generate a delayed AP transmitted after multiple APs when supplied with a 20 Hz AP train input.

Normal diam=1e-3 (only the connecting shaft to the dystrophy protrudes from the axon in the above)

Delayed diam=29

Blocked diam=40

Blocked then delayed transmission during 20 Hz AP input diam=53

### Extended Data Figure 2e top

Run the following program which takes about a day (or skip ahead to use provided stored results)

nrngui alz_axon_serial_one_AP.hoc

When finished run the following MATLAB command which will gather the results into MATLAB matricies

load_data

or you can start with the results that alz_axon_serial_one_AP.hoc would generate by reading in the workspace that was saved after we previously ran load_data, saved, and included that mat file in this archive

load results/one_AP_input_results.mat

then execute the graphics program

[delaytime, apcount] = PlotAP(active_results, 0.15);

which generates two figures, the second figure of which is similar to extended data figure 2e top

### Extended Data Figure 2e bottom

Run the following program which takes about a day (or skip ahead to use provided stored results)

nrngui alz_axon_serial_20Hz.hoc

When finished run the following MATLAB command which will gather the results into MATLAB matricies

load_data

or you can start with the results that alz_axon_serial_20Hz.hoc would generate by reading in the workspace that was saved after we previously ran load_data, saved, and included that mat file in this archive

load results/20Hz_input_results.mat

then execute the graphics program

[delaytime, apcount] = PlotAP(active_results, 0.15);

which generates two figures, the second figure of which is similar to extended data figure 2e bottom