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P2‐339: Agonistic autoantibodies against the α1‐adrenoceptor in patients with Morbus Alzheimer and vascular dementia
Author(s) -
Kunze Rudolf
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1390
Subject(s) - autoantibody , medicine , chronotropic , vascular dementia , dementia , receptor , endocrinology , immunology , blood pressure , antibody , disease , heart rate
using transphosphatidylation reaction catalyzed by PLD in the presence of 1-butanol. LTP was evaluated in the CA1 region of hippocampal slices from Pld2 and Pld2 mice after treatment with Ab oligomers. Pld2 mutant mice were crossed with the Tg2576 (Swedish APP, SwAPP) line to generate transgenic mice lacking PLD2. Contextual fear conditioning and radial-arm-water-maze (RAWM) behavior was tested at 5-6 and 11-12 months of age, respectively. After the RAWM, forebrains were processed for biochemical analysis. ELISA was performed to measure the levels of soluble and insoluble Ab40/42. Lipidomics analysis of forebrain extracts was performed using high performance liquid chromatography coupled to electrospray ionization mass spectrometry. Results: We show that oligomeric Ab induces the internalization of GFP-PLD2 in PC12 cells. Acute treatments with oligomers enhance PLD activity in WT cultured neurons, but not in Pld2 mutant neurons. Oligomeric Ab fails to reduce LTP in PLD2-deficient hippocampi. Furthermore, Pld2 ablation rescues memory deficits in a transgenic model of AD despite a significant Ab load, suggesting PLD2 is necessary for the synaptotoxic action of Ab. A lipidomics analysis of Pld2 mutant brains in the presence or absence of the SwAPP transgene unmasks striking crosstalks between PA and other lipids, which have been previously implicated in AD pathogenesis. Finally, this lipid analysis shows an exquisite acyl chain specificity and plasticity in the perturbation of PA metabolism, with the notable elevation in SwAPP brains of a PLD product previously linked to degeneration. Conclusions: Collectively, our results point to specific molecular species of PA and interconnected lipid metabolic pathways as key mediators of AD pathogenesis and identify PLD2 as a novel potential target for therapeutics.