# Aβ plaques induce local pre-synaptic toxicity in human iPSC-derived neuron xenografts

## TL;DR

This study shows that Aβ plaques cause localized pre-synaptic damage in human neurons transplanted into mouse brains, offering a new model to study Alzheimer's.

## Contribution

A novel human iPSC-derived neuron xenograft model reveals localized pre-synaptic toxicity caused by extracellular Aβ plaques.

## Key findings

- Extracellular Aβ plaques induce local pre-synaptic loss in human neurons.
- Dystrophic neurites form in human neurons exposed to amyloid plaques.
- Synaptic damage is restricted to the plaque microenvironment without widespread degeneration.

## Abstract

Xenotransplantation enables the interrogation of human neuron-specific vulnerabilities to Alzheimer’s pathology within a physiologically relevant in vivo context. While amyloid-beta (Aβ) is known to disrupt synaptic integrity, it remains uncertain whether the synaptotoxicity observed in vitro accurately models the disease. Here, we establish a xenotransplantation paradigm in which human neurons integrate into the brains of amyloid precursor protein (APP) transgenic mice that develop amyloid plaques. Using a genetically encoded pre-synaptic reporter, we label human pre-synapses post engraftment to assess early-stage pathology. We demonstrate that extracellular Aβ plaques induce localized synaptic damage in human neurons, characterized by local pre-synaptic loss and the formation of dystrophic neurites. Notably, this pathology is restricted to the plaque microenvironment and does not result in widespread pre-synaptic degeneration. Our findings establish this human-mouse chimera model as a platform for dissecting Aβ-induced synaptic pathology and reveal that extracellular Aβ exerts compartmentalized yet impactful toxicity on human pre-synapses.

•Human pre-synapses are genetically tagged and quantified after xenotransplantation•Transplanted human neurons integrate and form synapses throughout the mouse brain•Amyloid plaques induce dystrophic neurite formation in human neurons•Extracellular Aβ plaques cause local loss of human pre-synaptic terminals

Human pre-synapses are genetically tagged and quantified after xenotransplantation

Transplanted human neurons integrate and form synapses throughout the mouse brain

Amyloid plaques induce dystrophic neurite formation in human neurons

Extracellular Aβ plaques cause local loss of human pre-synaptic terminals

Verstreken and colleagues provide a modified human iPSC line that enabled the visualization of human pre-synaptic terminals post engraftment in the mouse brain. This allowed for the evaluation of early-stage deficits induced by extracellular Aβ pathology, specifically pre-synaptic loss. They found the occurrence of dystrophic neurites in response to amyloid and a local plaque-specific pre-synaptic toxicity without observing overt pre-synaptic loss.