Abstract
SummaryAlzheimer’s disease (AD) is the most common form of dementia, impairing cognitive and motor functions. One of the pathological hallmarks of AD is neuronal loss, which is not reflected in mouse models of AD. Therefore, the role of neuronal death is still uncertain. Here, we used a Drosophila AD model expressing a secreted form of human amyloid-β42 peptide and showed that it recapitulates key aspects of AD pathology, including neuronal death and impaired long-term memory. We found that neuronal apoptosis is mediated by cell fitness-driven neuronal culling, which selectively eliminates impaired neurons from brain circuits. We demonstrated that removal of less fit neurons delays β-amyloid-induced brain damage and protects against cognitive and motor decline, suggesting that contrary to common knowledge, neuronal death may have a beneficial effect in AD.
Highlights
Multicellular organisms have evolved mechanisms to maintain tissue homeostasis and integrity throughout development and aging
One of the pathological hallmarks of Alzheimer’s disease (AD) is neuronal loss, which is not reflected in mouse models of AD
We found that neuronal apoptosis is mediated by cell fitnessdriven neuronal culling, which selectively eliminates impaired neurons from brain circuits
Summary
Multicellular organisms have evolved mechanisms to maintain tissue homeostasis and integrity throughout development and aging. The elimination of potentially dangerous or abnormal cells based on their fitness status is known as cell competition. Recent findings prove cell competition is a broad biological process proposed to constitute a quality control mechanism against developmental malformations (de la Cova et al, 2004; Gibson and Perrimon, 2005; Moreno et al, 2002), tumorigenesis (Alexander et al, 2004; Hogan et al, 2009; Kajita and Fujita, 2015; Martins et al, 2014; Menendez et al, 2010), and aging (Merino et al, 2015). The cell competition machinery may be subverted by precancerous cells to acquire a super-fit status, enabling them to expand, kill, and invade surrounding wild-type tissue with a lower fitness status (Eichenlaub et al, 2016; Levayer et al, 2015; Moreno and Basler, 2004; Suijkerbuijk et al, 2016). Cell competition has not yet been investigated in the course of aging-associated disorders, in neurodegenerative diseases
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