An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience - Nature

MainThe hippocampus plays a crucial role in the registration of our experiences as episodic memories and includes the dentate gyrus (DG) subregion that contributes to memory formation by decreasing memory interference1. Furthermore, dysfunction in DG is considered to be a primary driver of aging-associated cognitive decline and a hallmark of mild cognitive impairment (MCI)2. Healthy cognitive aging depends on a balance of resilience and vulnerability factors that dictate the tempo of pathophysiological alterations, such as synapse loss3,4, lipid dysregulation5,6,7,8,9, emergence of maladaptive ‘inflammatory’ microglia6,10,11 and reactive astrogliosis12,13, oxidative stress14,15, loss of hippocampal neurogenesis16, and excitation–inhibition imbalance2,17,18. Disruption of this balance leads to a trajectory of cognitive decline and increased risk for MCI and Alzheimer’s disease (AD). A complementary perspective, first offered within the framework of cognitive reserve theory, posits that pathological cognitive decline reflects a failure to compensate for the progressive increase in pathophysiological alterations over time19 (Fig. 1a).