Title | Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | McIntire LBeth J, Berman DE, Myaeng J, Staniszewski A, Arancio O, Di Paolo G, Kim T-W |
Journal | J Neurosci |
Volume | 32 |
Issue | 44 |
Pagination | 15271-6 |
Date Published | 2012 Oct 31 |
ISSN | 1529-2401 |
Keywords | Alzheimer Disease, Amyloid beta-Peptides, Animals, Behavior, Animal, Blotting, Western, Cells, Cultured, Conditioning, Psychological, Cues, Dendritic Spines, Fear, Female, Genotype, Lipid Metabolism, Male, Maze Learning, Memory, Mice, Mice, Inbred Strains, Phosphatidylinositols, Phosphoric Monoester Hydrolases, Psychomotor Performance, Synapses |
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. |
DOI | 10.1523/JNEUROSCI.2034-12.2012 |
Alternate Journal | J Neurosci |
PubMed ID | 23115165 |
PubMed Central ID | PMC3711720 |
Grant List | R01 HD055457 / HD / NICHD NIH HHS / United States UL1 RR 024156 / RR / NCRR NIH HHS / United States P50 AG008702 / AG / NIA NIH HHS / United States UL1 RR024156 / RR / NCRR NIH HHS / United States R01 NS049442 / NS / NINDS NIH HHS / United States R01 NS074536 / NS / NINDS NIH HHS / United States NS049442 / NS / NINDS NIH HHS / United States AG033212 / AG / NIA NIH HHS / United States R01 NS056049 / NS / NINDS NIH HHS / United States HD055457 / HD / NICHD NIH HHS / United States MN015174 / MN / OMHHE CDC HHS / United States R03 AG033212 / AG / NIA NIH HHS / United States NS074536 / NS / NINDS NIH HHS / United States AG08702 / AG / NIA NIH HHS / United States |
Related Institute:
Brain Health Imaging Institute (BHII)