Culling less fit neurons protects against amyloid-β-induced brain damage and cognitive and motor decline

Abstract

Alzheimer'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 show 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 show that removal of less fit neurons delays amyloid-β42-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.

Characterising the Modulatory Role of Ikebana in Flower-Dependent Cell Competition

“…We then tested an Alzheimer's disease model scenario where we expected more loser cells (Coelho et al 2018). Intriguingly, in this scenario, removing ikebana did not further increase the number of loser cells in the optic lobe (Figure 3J).…”

“…2 Cell competition has been documented across various tissues in organisms ranging from Drosophila and mice to zebrafish and humans, with implications in neurodegenerative diseases and cancer biology (Akieda et al 2019;Coelho et al 2018;Eisenhoffer et al 2012;Madan et al 2019;Oliver et al 2004;Villa del Campo et al 2014;Walderich et al 2016). The prevailing consensus in the field identifies three major mechanisms of cell competition.…”

“…Second, mechanical cell competition, where cells compete for space, and the resistance to mechanical forces determines their fate, as seen in the elimination of cells converging to the midline in the Drosophila thorax (Brás-Pereira and Moreno 2018; Levayer, Dupont, and Moreno 2016;Moreno et al 2019). Lastly, cells may compete based on their fitness state, influenced by factors such as ageing (Merino et al 2015) or exposure to toxic environments (Coelho et al 2018). This leads to the elimination of suboptimal cells (losers) and their potential replacement by fitter cells when in the vicinity of healthier (winner) cells.…”

“…The differential expression of these isoforms determines the fate of a cell as a winner or loser. The expression of flower lose isoforms in Drosophila causes the elimination of suboptimal cells in various contexts, including during eye development (Merino et al 2013), in response to traumatic brain injury (Moreno et al 2015), and in an Alzheimer's disease model (Coelho et al 2018;Moreno 2019, 2020). The significance of Flower extends beyond Drosophila, with orthologues described in mice and humans (Madan et al 2019;Petrova et al 2012).…”