Novel therapeutic approaches to target neurodegeneration

Ageing is the main risk factor common to most primary neurodegenerative disorders. Indeed, age-related brain alterations have been long considered to predispose to neurodegeneration. Although protein misfolding and the accumulation of toxic protein aggregates have been considered as causative events in neurodegeneration, several other biological pathways affected by brain ageing also contribute to pathogenesis. Here, we discuss the evidence showing the involvement of the mechanisms controlling neuronal structure, gene expression, autophagy, cell metabolism and neuroinflammation in the onset and progression of neurodegenerative disorders. Furthermore, we review the therapeutic strategies currently under development or as future approaches designed to normalize these pathways, which may then increase brain resilience to cope with toxic protein species. In addition to therapies targeting the insoluble protein aggregates specifically associated with each neurodegenerative disorder, these novel pharmacological approaches may be part of combined therapies designed to rescue brain function.We acknowledge funding from the Italian Ministry of University and Research (Ministero dell'Università e della Ricerca) (PRIN 202039WMFP to E.M. and 20202THZAW to M.D.L.); from Fondazione Cariplo (Grant No. 2018-0511) to E.M.; from Alzheimer Forschung Initiative (Grant No. 21019) and the Chica and Heinz Schaller Foundation (Chica and Heinz Schaller-Stiftung) to D.M.; from Instituto de Salud Carlos III (CP21/0032) and Spanish Science State Agency (PID2021-124465OA-I00) to A.G.d.l.F.; and from the BrightFocus Foundation (Grant A2019562S), the European Union (H2020 European Research Council Grants ERC-STG-2019-852086 and H2020-MSCA-IF-2017-797205), the Austrian Science Fund (Grant FWF-I5057), Clene Nanomedicine, the U.S. National Academy of Medicine (NAM), the Michael J. Fox Foundation for Parkinson's Research (MJFF), the Alzheimer’s Association (AARG-22-972303) and the NIH National Institute on Aging (Grant AG056306 and AG062429) to J.M.Open Access Funding provided by Universita degli Studi di Milano within the CRUI-CARE Agreement.Peer reviewe