Reduction of Synaptojanin 1 Ameliorates Synaptic and Behavioral Impairments in a Mouse Model of Alzheimer's Disease

Decades of research have correlated increased levels of amyloid-beta peptide (A beta) with neuropathological progression in Alzheimer's disease (AD) patients and transgenic models. A beta precipitates synaptic and neuronal anomalies by perturbing intracellular signaling, which, in turn, may underlie cognitive impairment. A beta 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 A beta. Based on these data, we tested whether reduction of Synj1 could rescue cognitive deficits and A beta-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 A beta oligomer-induced changes in dendritic spines of cultured hippocampal neurons, sparing mature spine classes, which corroborates the protective role for Synj1 reduction against A beta 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.