Engineered Hsp70 chaperones prevent Aβ42-induced memory impairments in a Drosophila model of Alzheimer's disease

Alfonso Martín-Peña, Diego E. Rincón-Limas, Pedro Fernandez-Fúnez

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Proteinopathies constitute a group of diseases in which certain proteins are abnormally folded leading to aggregation and eventual cell failure. Most neurodegenerative diseases belong to protein misfolding disorders and, among them, Alzheimer's disease (AD) is the most prevalent. AD is characterized by accumulation of the amyloid-β42 (Aβ42) peptide in the extracellular space. Hence, we genetically engineered a molecular chaperone that was selectively delivered to this cellular location. It has been reported that the heat shock protein 70 (Hsp70) binds Aβ42 preventing self-aggregation. Here, we employed two isoforms of the Hsp70, cytosolic and extracellular, to evaluate their potential protective effect against the memory decline triggered by extracellular deposition of Aβ42. Both Hsp70 isoforms significantly improved memory performance of flies expressing Aβ42, irrespective of their age or the level of Aβ42 load. Using olfactory classical conditioning, we established a Drosophila model of AD based on Aβ42 neurotoxicity and monitored memory decline through aging. The onset of the memory impairment observed was proportional to the cumulative level of Aβ42 in the Drosophila brain. These data support the use of this Drosophila model of AD to further investigate molecules with a protective activity against Aβ42-induced memory loss, contributing to the development of palliative therapies for AD.

Original languageEnglish (US)
Article number9915
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

Bibliographical note

Funding Information:
This work was supported by the National Institute of Health grants DP2 OD002721-01 to P.F.-F. and R21NS081356 to D.E.R.-L. We thank the Bloomington Drosophila Stock Center for fly strains (NIH P40OD018537) and Mercedes Arnes for technical support with Aβ42 immunodetection.

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