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 anomaliesby perturbing intracellular signaling which, in turn, may underlie cognitive impairment. Aβ also alters lipid metabolism, notably causinga deficiency of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], a phospholipid that regulates critical neuronal functions. Haploinsufficiency of the gene encoding synaptojanin 1 (Synj1), a major PI(4,5)P2 phosphatase in the brain, provided protection against PI(4,5)P2 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)P2 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 maturespine 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.

Reduction of Synaptojanin 1 Accelerates Aβ Clearance and Attenuates Cognitive Deterioration in an Alzheimer Mouse Model

“…It should be also noted that in studies by McIntire et al, no alterations in A␤ levels were evident in 6-month-old Tg2576 mice with synj1 haploinsufficiency (6), despite the fact that they previously reported that A␤ biogenesis is modulated by PI(4,5)P 2 (11). They measured the whole brain lysates at 6 months of age, whereas we specifically quantified A␤ and amyloid plaque load from hippocampus in older mice (9 -10 months of age).…”

“…Synj1 has been linked to AD and Down's syndrome (5)(6)(7). It is a phosphatase that catalyzes the dephosphorylation of the signaling phospholipid PI(4,5)P 2 , which is shown to control clathrin-mediated endocytosis (40,41).…”

“…Interestingly, others reported that haploinsufficiency of synj1 protects against A␤-induced defects in long term potentiation (7) and ameliorates learning and memory deficits in a transgenic mouse model of AD (6). It was also suggested that increased PI(4,5)P 2 caused by down-regulation of synj1 suppresses A␤ oligomer-induced neurotoxic effects (5-7).…”

“…Synaptojanin 1 (synj1), a major negative regulator of the levels of PI(4,5)P 2 in the nervous tissue, has been implicated in the regulation of endocytic traffic at synapses (4). Trisomy of synj1 in Down syndrome mouse models causes a deficiency in PI(4,5)P 2 as well as learning deficits (5), whereas synj1 haploinsufficiency is protective against A␤-induced neurotoxicity in mouse models of AD (6,7). In the current study, we link synj1 to regulation of cellular A␤ clearance.…”

Modulation of Lipid Kinase PI4KIIα Activity and Lipid Raft Association of Presenilin 1 Underlies γ-Secretase Inhibition by Ginsenoside (20S)-Rg3

“…To explore the possible lipid-modulatory role of (20S)-Rg3, we examined the steady-state anionic phospholipid profile using conductance-based HPLC analysis (11,12,52). We found that treatment of mouse cortical neurons with (20S)-Rg3 led to increased levels of both PI(4)P and PI(4,5)P 2 (Fig.…”