Alzheimer's disease (AD) is the most common form of late-onset dementia. Growing evidence suggests that cerebral elevation and accumulation of amyloid-beta peptide (Abeta) mediate many aspects of the disease's pathogenesis. While brains from AD patients generally contain amyloid plaques that consist of insoluble aggregates of Abeta, the levels of the soluble oligomeric forms of Abeta better correlate with cognitive decline and/or disease progression in animal models and individuals with AD. Accordingly, Abeta oligomers have been recently shown to cause synaptic defects in the hippocampus, at least in part through their ability to modulate cell surface levels of glutamate receptor-channels, actin dynamics and calcium homeostasis. Recently, we have investigated the relationship between Abeta and phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2], a key signaling phospholipid that is concentrated at the plasma membrane where it controls multiple processes. We have found that treatment of primary cortical neurons with soluble Abeta oligomers significantly decreases PtdIns(4,5)P2 levels without marked effects on cell viability. PtdIns(4,5)P2 downregulation is reversible, requires extracellular Ca2+ and is partially blocked by glutamate (NMDA) receptor antagonists. To test for the relevance of this phenomenon in the synapse-impairing actions of Abeta, we have utilized a mouse genetic model in which the main pathway leading to the elimination of PtdIns(4,5)P2 at synapses has been targeted. These mice lack one copy of Synj1, a gene encoding the PtdIns(4,5)P2 phosphatase synaptojanin 1. We have found that Abeta oligomers fail to downregulate PtdIns(4,5)P2 in cultured neurons derived from Synj1+/- mice. Furthermore, the inhibitory effect of Abeta on hippocampal long-term potentiation is strongly suppressed in slices from Synj1+/- mice. Altogether, our findings suggest a novel hypothesis whereby PtdIns(4,5)P2 dyshomeostasis may underlie major early neurotoxic effects of Abeta at synapses and that Synj1 haploinsufficiency may confer protection against the actions of this peptide. While our biochemical and electrophysiology data from neuronal cultures and slice preparations point to a central role of PtdIns(4,5)P2 in Abeta-induced synaptic dysfunction, a fundamental question is whether this phenomenon is relevant for the pathophysiology of AD and, in particular, for the cognitive decline associated with this disorder. To begin to address this issue and validate our hypothesis in vivo, we plan to test whether Synj1 haploinsufficiency confers neurobehavioral benefits in animal models for AD. More specifically, we will generate double transgenic mice expressing familial AD-linked mutant versions of APP and presenilin 1 (""""""""PSAPP mice"""""""") that are haploinsufficient for Synj1 and test whether these animals exhibit reduced age-dependent cognitive deficits relative to PSAPP mice using tests, such as fear conditioning, the radial-arm water maze and the Morris water maze.

Public Health Relevance

Alzheimer's disease (AD) is the most common form of late-onset dementia. Growing evidence suggests that cerebral elevation and accumulation of amyloid-beta peptide (Abeta) mediate many aspects of the disease's pathogenesis. Recently, we have found that Abeta decreases the levels of phosphatidylinositol-4,5- bisphosphate [PtdIns(4,5)P2], a major bioactive intracellular lipid. The goal of this proposal is to assess whether genetically decreasing the catabolism of PtdIns(4,5)P2 in the brain of AD mouse models can ameliorate learning and memory deficits in various behavioral tasks.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
5R03AG033212-02
Application #
7788084
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Refolo, Lorenzo
Project Start
2009-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$70,056
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Frere, Samuel G; Chang-Ileto, Belle; Di Paolo, Gilbert (2012) Role of phosphoinositides at the neuronal synapse. Subcell Biochem 59:131-75
McIntire, Laura Beth J; Berman, Diego E; Myaeng, Jennifer et al. (2012) Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease. J Neurosci 32:15271-6
Di Paolo, Gilbert; Kim, Tae-Wan (2011) Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci 12:284-96