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Lamp1 proximity labeling proteomics in 5XFAD mice

ABSTRACT: Plaque-associated axonal spheroids (PAAS) are frequently observed around amyloid deposits in Alzheimer's disease (AD) and are known to impair axonal electrical conduction, disrupt neural circuits, and correlate with AD severity. Despite their significance, the mechanisms underlying PAAS formation remain largely unknown. To explore this, we developed a proximity labeling proteomics approach to identify the PAAS proteome in human postmortem brains and mice. Additionally, we established a human iPSC-derived AD model allowing structural, optical electrophysiology, and mechanistic investigation of PAAS pathology. This approach revealed the molecular architecture of PAAS and identified dysregulated biological processes, including protein turnover, cytoskeleton dynamics, and lipid transport. Activated PI3K/AKT/mTOR pathway, which regulates these processes, was expressed in PAAS and strongly correlated with AD severity in humans. Inhibition of mTOR in human iPSC-derived neurons and in mice led to a marked reduction in PAAS. Our study provides a multidisciplinary toolkit for investigating axonal pathology and identifying novel targets for neurodegeneration.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Yifei Cai

LAB HEAD: Jaime Grutzendler

PROVIDER: PXD048097 | Pride | 2025-02-20

REPOSITORIES: Pride

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			Action	DRS
	QEp20-1611_Cai_371_Control.msf	Msf
	QEp20-1611_Cai_371_Control.raw	Raw
	QEp20-1616_Cai_375_Control.msf	Msf
	QEp20-1616_Cai_375_Control.raw	Raw
	QEp20-1621_Cai_377_Control.msf	Msf

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