Alzheimer’s disease (AD) is an irreversible age-related neurodegenerative disorder clinically characterized by severe memory impairment, language deficits and cognitive decline. The major neuropathological hallmarks of AD include extracellular deposits of the β-amyloid (Aβ) peptides and cytoplasmic neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. The accumulation of plaques and tangles in the brain triggers a cascade of molecular events that culminate in neuronal damage and cell death. Despite extensive research, our understanding of the molecular basis of AD pathogenesis remains incomplete and a cure for this devastating disease is still not available. A growing body of evidence in different experimental models suggests that poly(ADP-ribose) polymerase-1 (PARP-1) overactivation might be a crucial component of the molecular network of interactions responsible for AD pathogenesis. In this work, we combined genetic, molecular and biochemical approaches to investigate the effects of two different PARP-1 inhibitors (olaparib and MC2050) in Drosophila models of Alzheimer’s disease by exploring their neuroprotective and therapeutic potential in vivo. We found that both pharmacological inhibition and genetic inactivation of PARP-1 significantly extend lifespan and improve the climbing ability of transgenic AD flies. Consistently, PARP-1 inhibitors lead to a significant decrease of Aβ42 aggregates and partially rescue the epigenetic alterations associated with AD in the brain. Interestingly, olaparib and MC2050 also suppress the AD-associated aberrant activation of transposable elements in neuronal tissues of AD flies

Neuroprotective effects of PARP inhibitors in Drosophila models of Alzheimer’s disease / Maggiore, Anna; Casale, Assunta Maria; Toscanelli, Walter; Cappucci, Ugo; Rotili, Dante; Grieco, Maddalena; Gagné, Jean-Philippe; Poirier, Guy G.; D’Erme, Maria; Piacentini, Lucia. - In: CELLS. - ISSN 2073-4409. - 11:8(2022). [10.3390/cells11081284]

Neuroprotective effects of PARP inhibitors in Drosophila models of Alzheimer’s disease

Maggiore, Anna;Casale, Assunta Maria;Toscanelli, Walter;Cappucci, Ugo;Rotili, Dante;Grieco, Maddalena;d’Erme, Maria;Piacentini, Lucia
2022

Abstract

Alzheimer’s disease (AD) is an irreversible age-related neurodegenerative disorder clinically characterized by severe memory impairment, language deficits and cognitive decline. The major neuropathological hallmarks of AD include extracellular deposits of the β-amyloid (Aβ) peptides and cytoplasmic neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. The accumulation of plaques and tangles in the brain triggers a cascade of molecular events that culminate in neuronal damage and cell death. Despite extensive research, our understanding of the molecular basis of AD pathogenesis remains incomplete and a cure for this devastating disease is still not available. A growing body of evidence in different experimental models suggests that poly(ADP-ribose) polymerase-1 (PARP-1) overactivation might be a crucial component of the molecular network of interactions responsible for AD pathogenesis. In this work, we combined genetic, molecular and biochemical approaches to investigate the effects of two different PARP-1 inhibitors (olaparib and MC2050) in Drosophila models of Alzheimer’s disease by exploring their neuroprotective and therapeutic potential in vivo. We found that both pharmacological inhibition and genetic inactivation of PARP-1 significantly extend lifespan and improve the climbing ability of transgenic AD flies. Consistently, PARP-1 inhibitors lead to a significant decrease of Aβ42 aggregates and partially rescue the epigenetic alterations associated with AD in the brain. Interestingly, olaparib and MC2050 also suppress the AD-associated aberrant activation of transposable elements in neuronal tissues of AD flies
Alzheimer; PARP; neurodegeneration
01 Pubblicazione su rivista::01a Articolo in rivista
Neuroprotective effects of PARP inhibitors in Drosophila models of Alzheimer’s disease / Maggiore, Anna; Casale, Assunta Maria; Toscanelli, Walter; Cappucci, Ugo; Rotili, Dante; Grieco, Maddalena; Gagné, Jean-Philippe; Poirier, Guy G.; D’Erme, Maria; Piacentini, Lucia. - In: CELLS. - ISSN 2073-4409. - 11:8(2022). [10.3390/cells11081284]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1628944
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