Central and Peripheral apoE4 in Cognition and Dementia
Guojun Bu and Chia-Chen Liu Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). In the central nervous system (CNS), apoE4 inhibits the clearance and promotes the aggregation of amyloid-β (Aβ), and has several Aβ-independent effects including age-dependent inferior functions in transporting lipids, supporting synapses, and controlling neuroinflammation. ApoE is also abundantly expressed in peripheral tissues including liver where it mediates plasma lipid metabolism. APOE4 carriers have increased risk for hypercholesterolemia and atherosclerosis. To address apoE isoform-dependent functions in CNS and periphery, we developed cell type-specific and inducible apoE mouse models. Expression in the CNS was driven by astrocyte-specific GFAP-Cre and in the periphery by liver-specific Alb-Cre. These mice were further bred to the background of amyloid model APPSWE/PS1ΔE9 mice. When expressed by astrocytes, we found that expression of apoE3 but not apoE4 led to improved synaptic functions and memory performance, whereas expression of apoE4 but not apoE3 inhibited Aβ clearance and accelerated amyloid deposition. More interesting, expression of apoE4 prior to amyloid deposition had a greater impact on amyloid pathology than that during the rapid growth period. When apoE isoforms were expressed exclusively in the periphery in the Apoe-knockout background, apoE4 inhibited synaptic functions, impaired cognition, and was associated with compromised cerebrovascular integrity and increased Aβ pathology. These results provide mechanistic insights as to how apoE4 increases the risk for AD and how we should design apoE isoform-specific strategies for AD prevention and therapy. Funding: This work was supported by the National Institutes of Health grant R01AG046205 and a grant from the Cure Alzheimer's Fund.
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