Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 38; pp. 11965 - 11970
• Main Authors: Zhu, Li, Zhong, Minghao, Elder, Gregory A., Sano, Mary, Holtzman, David M., Gandy, Sam, Cardozo, Christopher, Haroutunian, Vahram, Robakis, Nikolaos K., Cai, Dongming
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.09.2015; National Acad Sciences
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - etiology; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Astrocytes - metabolism; Biological Sciences; Brain; Brain - metabolism; Brain - pathology; Cognition Disorders - complications; Cognition Disorders - metabolism; Cognitive ability; Cohort Studies; Disease Progression; Female; Gene Knock-In Techniques; Homeostasis; Humans; Lipids; Male; Mice; Nerve Tissue Proteins; Neurons; Neurons - metabolism; Pathogenesis; Phosphatidylinositol Phosphates - metabolism; Phospholipids - metabolism; Phosphoric Monoester Hydrolases; dysregulation; cognitive deficits; phospholipid; Alzheimer's disease; apolipoprotein E4
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1510011112

The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer’s disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP₂) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP₂-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP₂ levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.