Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease.

TitleReduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2012
AuthorsMcIntire LBeth J, Berman DE, Myaeng J, Staniszewski A, Arancio O, Di Paolo G, Kim T-W
JournalJ Neurosci
Volume32
Issue44
Pagination15271-6
Date Published2012 Oct 31
ISSN1529-2401
KeywordsAlzheimer 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.

DOI10.1523/JNEUROSCI.2034-12.2012
Alternate JournalJ Neurosci
PubMed ID23115165
PubMed Central IDPMC3711720
Grant ListR01 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)

Weill Cornell Medicine
Department of Radiology
525 East 68th Street New York, NY 10065