title: Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease.
abstract: Decades of research have correlated increased levels of amyloid-β peptide (Aβ) with neuropathological progression in Alzheimer's disease (AD) patients and transgenic models. Aβ precipitates synaptic and neuronal anomalies by perturbing intracellular signaling, which, in turn, may underlie cognitive impairment. Aβ also alters lipid metabolism, notably causing a deficiency of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], a phospholipid that regulates critical neuronal functions. Haploinsufficiency of the gene encoding synaptojanin 1 (Synj1), a major PI(4,5)P(2) phosphatase in the brain, provided protection against PI(4,5)P(2) breakdown and electrophysiological deficits attributable to Aβ. Based on these data, we tested whether reduction of Synj1 could rescue cognitive deficits and Aβ-induced morphological alterations of synapses. We found that hemizygous deletion of Synj1 in the context of a mouse model expressing the Swedish mutant of amyloid precursor protein rescues deficits in learning and memory without affecting amyloid load. Synj1 heterozygosity also rescued PI(4,5)P(2) deficiency in a synaptosome-enriched fraction from the brain of Tg2576 mice. Genetic disruption of Synj1 attenuated Aβ oligomer-induced changes in dendritic spines of cultured hippocampal neurons, sparing mature spine classes, which corroborates the protective role for Synj1 reduction against Aβ insult at the synapse. These results indicate that Synj1 reduction ameliorates AD-associated behavioral and synaptic deficits, providing evidence that Synj1 and, more generally, phosphoinositide metabolism may be promising therapeutic targets. Our work expands on recent studies identifying lipid metabolism and lipid-modifying enzymes as targets of AD-associated synaptic and behavioral impairment.
authors.affiliation: Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Laura Beth J
authors.initials: LB
authors.lastname: McIntire
authors.forename: Diego E
authors.initials: DE
authors.lastname: Berman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Myaeng
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Staniszewski
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000502:physiology; D003463:Cues; D049229:Dendritic Spines / Q000502:physiology; D005239:Fear / Q000502:physiology; D005260:Female; D005838:Genotype; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D010716:Phosphatidylinositols / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000502:physiology*; D011597:Psychomotor Performance / Q000502:physiology; D013569:Synapses / Q000473:pathology*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D016229:Amyloid beta-Peptides; D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases