Research data for paper: Elevated amyloid beta disrupts the nanoscale organization and function of synaptic vesicle pools in hippocampal neurons

Data for paper published in Cerebral Cortex on 03/04/22

Files:

Biasettietal-VPools-TEM (Transmission electron microscope)-maps: TEM-based vesicle pool maps by synapse and condition, used to generate distance plots.

Biasettietal-SypHy-fractions: Fluorescence SypHy values used to calculate pool fractions by synapse and condition.

Biasettietal-iGluSNFR: iGluSnFR response values by synapse, experiment and condition.

Biasettietal-EMdistVtoAZ: Coordinates of each vesicle from TEM images measured as distances to nearest point on the active zone; this is used to generate mean distances for each pool class (PC+: photoconverted, PC-: non-photoconverted) and also to construct cumulative distance plots; measurements were collected for both WT (wild-type) and APPSwe/Ind mice.

Biasettietal-iGluSnFRrationale: Background dataset used to establish iGluSnFR protocol used in the paper

Biasettietal-abeta-time-conc-rationale: Supporting figure outlining the rationale for time and concentration used in this work.

Abstract

Alzheimer’s disease is linked to increased levels of amyloid beta (Aβ) in the brain, but the mechanisms underlying neuronal dysfunction and neurodegeneration remain enigmatic. Here, we investigate whether organizational characteristics of functional presynaptic vesicle pools, key determinants of information transmission in the central nervous system, are targets for elevated Aβ. Using an optical readout method in cultured hippocampal neurons, we show that acute Aβ42 treatment significantly enlarges the fraction of functional vesicles at individual terminals. We observe the same effect in a chronically elevated Aβ transgenic model (APPSw,Ind) using an ultrastructure-function approach that provides detailed information on nanoscale vesicle pool positioning. Strikingly, elevated Aβ is correlated with excessive accumulation of recycled vesicles near putative endocytic sites, which is consistent with deficits in vesicle retrieval pathways. Using the glutamate reporter, iGluSnFR, we show that there are parallel functional consequences, where ongoing information signaling capacity is constrained. Treatment with levetiracetam, an antiepileptic that dampens synaptic hyperactivity, partially rescues these transmission defects. Our findings implicate organizational and dynamic features of functional vesicle pools as targets in Aβ-driven synaptic impairment, suggesting that interventions to relieve the overloading of vesicle retrieval pathways might have promising therapeutic value.