A Two-Clone Approach to Study Signaling Interactions among Neuronal Cells in a Pre-clinical Alzheimer's Disease Model.

Catherine J Yeates,Madhuri Kango-Singh,Prajakta Deshpande,Amit Singh,Ankita Sarkar

doi:10.1016/j.isci.2020.101823

Catherine J Yeates, Madhuri Kango-Singh + Show 3 more

Open Access

https://doi.org/10.1016/j.isci.2020.101823

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Journal: iScience	Publication Date: Nov 18, 2020
Citations: 8	License type: cc-by

Affiliation: University of Dayton, Indiana State University

Abstract

SummaryTo understand the progression of Alzheimer's disease, studies often rely on ectopic expression of amyloid-beta 42 (Aβ42) throughout an entire tissue. Uniform ectopic expression of Aβ42 may obscure cell-cell interactions that contribute to the progression of the disease. We developed a two-clone system to study the signaling cross talk between GFP-labeled clones of Aβ42-expressing neurons and wild-type neurons simultaneously generated from the same progenitor cell by a single recombination event. Surprisingly, wild-type clones are reduced in size as compared with Aβ42-producing clones. We found that wild-type cells are eliminated by the induction of cell death. Furthermore, aberrant activation of c-Jun-N-terminal kinase (JNK) signaling in Aβ42-expressing neurons sensitizes neighboring wild-type cells to undergo progressive neurodegeneration. Blocking JNK signaling in Aβ42-producing clones restores the size of wild-type clones.

Highlights

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that is marked by widespread cell death throughout the brain and progressive impairments to memory and cognitive function (McKhann et al, 1984)
In order to understand how changes in cell-cell signaling downstream of amyloid-beta 42 (Ab42) accumulation contribute to the progressive neurodegeneration seen in AD, we have developed a two-clone approach
The FLP/FRT system triggers mitotic recombination mediated by Flippase (FLP) at Flippase Recognition Target (FRT) sites while the Gal4/UAS/Gal80 tissue-specific expression system can be used to introduce targeted misexpression of genes of interest, such as human Ab42 (Figure 1A) (Lee and Luo, 1999; Xu and Rubin, 1993)

Summary

Introduction

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that is marked by widespread cell death throughout the brain and progressive impairments to memory and cognitive function (McKhann et al, 1984). One of the hallmarks of AD is the accumulation of amyloid beta (Ab) peptides in extracellular plaques (Bonini and Fortini, 2003; Cline et al, 2018; Glenner and Wong, 1984; Hardy, 2009; Tare et al, 2011) These extracellular plaques are accompanied by the aggregation of intracellular neurofibrillary tangles (NFTs) made up of hyperphosphorylated tau protein (Grundke-Iqbal et al, 1986; Kosik et al, 1986; Wood et al, 1986). The neuropathology of AD results in accumulation of Ab42 plaques and NFTs, which triggers progressive neurodegeneration across brain regions (Braak and Braak, 1991; Palmqvist et al, 2017) It is not well understood how cellular changes contribute to the progression from an initial asymptomatic period into a phase of stark cognitive decline (Sperling et al, 2014). One possible point of failure in translation could be the difficulty in accurately modeling the local cellular context of the disease

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