title: Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis.
abstract: 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.
authors.affiliation: Research & Development, James J. Peters VA Medical Center, Bronx, NY 10468; Department of Neurology, Alzheimer Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Westchester Medical Center, New York Medical College, Valhalla, NY 10595;
authors.forename: Minghao
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Research & Development, James J. Peters VA Medical Center, Bronx, NY 10468;
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Elder
authors.affiliation: Research & Development, James J. Peters VA Medical Center, Bronx, NY 10468; Department of Neurology, Alzheimer Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Mary
authors.initials: M
authors.lastname: Sano
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Research & Development, James J. Peters VA Medical Center, Bronx, NY 10468; Department of Neurology, Alzheimer Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
authors.affiliation: National Center of Excellence for the Medical Consequences of SCI, James J. Peters VA Medical Center, Bronx, NY 10468; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Christopher
authors.initials: C
authors.lastname: Cardozo
authors.affiliation: Department of Neurology, Alzheimer Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Robakis
authors.affiliation: Research & Development, James J. Peters VA Medical Center, Bronx, NY 10468; Department of Neurology, Alzheimer Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029; dongming.cai@mssm.edu.
authors.forename: Dongming
authors.initials: D
authors.lastname: Cai
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000150:complications* / Q000378:metabolism*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D055879:Gene Knock-In Techniques; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases
chemical_list: D053327:Apolipoprotein E4; D009419:Nerve Tissue Proteins; D018129:Phosphatidylinositol Phosphates; D010743:Phospholipids; C106336:phosphatidylinositol 3,5-diphosphate; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases
keywords: Alzheimer's disease; apolipoprotein E4; cognitive deficits; dysregulation; phospholipid