| First Author | McIntire LB | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 44 | Pages | 15271-6 |
| PubMed ID | 23115165 | Mgi Jnum | J:192294 |
| Mgi Id | MGI:5464264 | Doi | 10.1523/JNEUROSCI.2034-12.2012 |
| Citation | McIntire LB, et al. (2012) Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease. J Neurosci 32(44):15271-6 |
| abstractText | Decades of research have correlated increased levels of amyloid-beta peptide (Abeta) with neuropathological progression in Alzheimer's disease (AD) patients and transgenic models. Abeta precipitates synaptic and neuronal anomalies by perturbing intracellular signaling, which, in turn, may underlie cognitive impairment. Abeta 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 Abeta. Based on these data, we tested whether reduction of Synj1 could rescue cognitive deficits and Abeta-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 Abeta oligomer-induced changes in dendritic spines of cultured hippocampal neurons, sparing mature spine classes, which corroborates the protective role for Synj1 reduction against Abeta 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. |
