CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

Abstract

AbstractTheAPOE4allele increases the risk for Alzheimer’s disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murineAPOEwith humanAPOE3orAPOE4, the latter show reduced neuronal dendritic complexity and impaired learning.APOE4TR mice also show reduced gamma oscillation power and sharp wave ripple (SWR) abundance, neuronal population activities important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power and SWR abundance, while attenuation of ECM can instead enhance these endpoints. In the present study we examine human cerebrospinal fluid (CSF) samples fromAPOE3andAPOE4individuals and brain lysates fromAPOE3andAPOE4TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples fromAPOE4individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased inAPOE4CSF as well as protein lysates fromAPOE4TR mice. Importantly, as compared to wildtype/APOE4heterozygotes, CCR5 knockout/APOE4heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target forAPOE4individuals.