ECM regulation and neuronal plasticity in mice harboring a common risk allele for Alzheimer's

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Abstract The three human alleles of Apolipoprotein E (APOE) differentially impact individual risk for Alzheimer’s disease (AD), with the APOE4 allele significantly increasing risk in a dose dependent manner. The mechanisms by which APOE4 elevates AD risk are not fully understood. As compared to other alleles, APOE4 may reduce clearance of amyloid-β (Aβ) from the central nervous system. Moreover, in mice with targeted replacement (TR) of APOE or APOE3, APOE4 TR mice show a relative reduction in dendritic complexity and impaired learning. This is significant in that these mice do not deposit Aβ, suggesting that APOE4 might independently reduce cognitive reserve and thus enhance vulnerability to AD and cognitive decline. Consistent with this is a more recent study of sharp wave ripple (SWR) abundance, in which SWR abundance was reduced in APOE4 TR mice. SWRs are events in which assemblies of hippocampal neurons, sequentially activated as a function of time and place during a learning experience, are sequentially replayed in an accelerated fashion during quiet restfulness and slow wave sleep. Replay is critical to memory consolidation and to transfer of hippocampal encoded experience to cortical areas for long term storage. Accumulating evidence suggests that deficits in neuronal plasticity, including reduced pyramidal cell arborization and SWR abundance, may be due in part to alterations in brain extracellular matrix (ECM) including perineuronal nets (PNNs). PNNs are a specialized form of ECM predominantly localized to the soma and proximal dendrites of gamma aminobutyric acid (GABA) releasing parvalbumin (PV) expressing inhibitory interneurons, and they facilitate GABAergic inhibitory transmission to constrain excitatory neuroplasticity. Indeed, maturation of PNNs coincides with the closure of critical periods of enhanced physiological plasticity. Conversely, drugs that attenuate PNN abundance can increase long term potentiation (LTP) of hippocampal neurotransmission, plasticity of glutamatergic neurotransmission, cognitive flexibility and SWR abundance in adult rodents. In the present proposal, we outline plans to test the hypothesis that APOE4 is linked to a dysregulation of the balance between PNN deposition and proteolysis, and that it is this imbalance that leads to deficits including reduced SWR abundance. This hypothesis is based on published and preliminary data discussed in the background. In this proposal, we also outline plans to test the hypothesis that two FDA approved compounds, venlafaxine and maraviroc, will normalize ECM levels and physiological changes observed in APOE4 TR mice including reduced SWR abundance. Venlafaxine is an antidepressant medication with the potential to increase matrix metalloproteinase-9 (MMP-9) levels and attenuate the PNN, while maraviroc is instead an antagonist for CCR5, a hypothetical regulator of the ECM. The CCL5 receptor, CCR5, restricts LTP and post-stroke neuroplasticity, while both LTP and plasticity are instead increased in CCL5-receptor antagonist treated mice.