Autophagic processes in early- and late- onset Alzheimer's disease

Autophagy plays a fundamental role in maintaining intracellular homeostasis and cell survival by degrading damaged and unnecessary subcellular components via the lysosome. Impaired autophagy is evident in otherwise ‘normal’ elderly individuals and patients with neurodegenerative diseases, such as Alzheimer’s disease (AD). As the most common type of dementia, AD is an age-associated disease with memory loss as the primary clinical feature, as well as extracellular Aβ plaques and intracellular Tau tangles as disease-defining pathological features. Recent studies in animal models of AD, AD patient-derived stem cells, and AD post-mortem brain tissues suggest that compromised mitophagy/autophagy, plays a causative role in AD progression. Supporting this hypothesis, pharmacological approaches to induce mitophagy/autophagy, e.g., the use of the small natural molecule NAD+, slow down AD progression in animal models. This chapter reviews the extant literature on autophagy in AD, covers recent progress on the molecular mechanisms of NAD+-dependent mitophagy/autophagy regulation and mechanisms underlying the anti-AD potential of NAD+. Further studies to define the NAD+-mitophagy/autophagy axis may shed light on novel therapeutics to treat AD, and potentially provide insights into other neurodegenerative diseases.E.F.F. is supported by Helse Sør-Øst (#2017056, #2020001, #2021021), the Research Council of Norway (#262175 and #277813), the National Natural Science Foundation of China (#81971327), an Akershus University Hospital Strategic grant (#269901), and a Rosa Sløyfe grant (#207819) from the Norwegian Cancer Society. E.F.F., M.V., K.C. have received funding from the EEA/ Norway Grants 2014-2021 and the Technology Agency of the Czech Republic - project number TO0100021