Amyloid-Associated Transmembrane Proteins Promote Extracellular Tau Release Through Unconventional Mechanisms Restricted; Files Only

Abstract

Recent imaging and biomarker studies in Alzheimer’s disease (AD) have shown that amyloid-β (Aβ) deposition in the brain and soluble phosphorylated tau (p-tau) in cerebrospinal fluid emerge decades before clinical symptoms. This fact suggested that amyloid pathology may promote extracellular tau accumulation prior to widespread neurofibrillary tangle formation, but this process remains poorly understood. In this study, we aim to investigated how amyloid pathology may modulate extracellular tau accumulation. Using a cross-species proteomic comparison of human AD brain tissue with non-AD controls and CRND8 transgenic mice with non-transgenic controls, we identified a set of conserved amyloid-associated proteins. In these amyloid-associated proteins, a group of selected transmembrane proteins (STPs) was found to increase extracellular tau in the HEK293T cells functional screen without evidence of membrane damage. Further analysis showed that increased expression of these STPs was associated with higher extracellular tau levels and lower intracellular tau levels in a dose-dependent manner, consistent with the phenomenon of tau secretion. We also found that STP-associated extracellular tau secretion occurred across multiple tau constructs including phosphorylated tau species. Lastly, because tau is a cytosolic protein that lacks a classical signal peptide, we further investigate the underlying unconventional secretion mechanism. By comparing STP-associated tau release with the unconventional fibroblast growth factor-2 (Fgf2) secretion pathway, we found limiting evidence supporting overlap between their unconventional secretion pathway, suggesting a different mechanism for secretion. Together, these findings suggest that amyloid-induced membrane remodeling may contribute to extracellular tau secretion and identify STPs as candidate regulators linking amyloid pathology to early tau release in AD.

Table of Contents

Abstract 5

Introduction 6

Methods 8

Results 10

Cross-species proteomic analysis identifies selected transmembrane proteins (STPs) that increase extracellular tau without inducing cell death 10

Sdc4 expression alters intracellular and extracellular tau distribution in a dose-dependent relationship 12

STP-associated extracellular tau accumulation occurs across multiple tau variants and phosphorylated tau species 14

STP-associated extracellular tau accumulation shows minimal overlap with the Fgf2 unconventional secretion pathway. 16

Discussions 17

References 19

Acknowledgement 22

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Cell Biology, Molecular Biology, Neuroscience
Keyword	Unconventional secretion Proteomics Alzheimer's Disease Tau
Committee Chair / Thesis Advisor	Golde, Todd , Emory University
Committee Members	Gutekunst, Claire-Anne , Emory University Devineni, Anita, Emory University

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