Microglial Activation Under Hypoxic Conditions in Early Alzheimer's Disease: Can Natural SIRT1 Activators Be Therapeutic Allies in the Inflammation-Energy Axis?

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by a preclinical stage that typically lasts for decades. Early on during this time, microglia react to pathological changes and become protective and even transiently delay neurodegeneration. In contrast, microglia later acquire the typical pro-inflammatory features that contribute to neurodegeneration in advanced disease. Such decades-long time frame is marked by a significant vulnerability to any event able to tip the balance toward inflammatory microglia. Increasing evidence suggests that early life hypoxic events could be risk factors for AD by acting as early triggers of microglial phenotypic transition, especially affecting mitochondrial functions and energy balance. The NAD+-dependent deacetylase SIRT1 could be a valuable target in this context for its anti-inflammatory and anti-aging functions, which include direct modulation of mitochondrial homeostasis. Many natural compounds enriched in Mediterranean diet foods, such as citrus and olives, could prove protective by inducing SIRT1 and therefore both reducing neuroinflammation and promoting mitochondrial health. This would be in line with data reporting how the type of diet can affect AD risk. Based on these premises, we here discuss the links between hypoxia, neuroinflammation, energy imbalance and mitochondrial alterations. We will describe how SIRT1 can represent a key molecular link and an appealing target to harness microglial neuroprotective potential as a preventive strategy during the key time frame of pre-symptomatic AD. We conclude with a brief summary of the up-to-date evidence on the benefits of natural SIRT1 inducers that act on the inflammation-energy axis.