Anales RANF

S3-03 ATP-DERIVED ADENOSINE CONTROLS SYNAPTIC AND MEMORY DYSFUNCTION IN β -AMYLOID MODELS OF ALZHEIMER’S DISEASE F.Q. Gonçalves 1 , H.B. Silva 1 , C. Lemos 1 , A.C. Silva 1 , N. Gonçalves 1 , A.R. Tomé 1 , S.G. Ferreira 1 , P.M. Canas 1 , D. Rial 1 , P.Agostinho 1,2 , R.A. Cunha 1,2 , J.P. Lopes 1 1 CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; 2 FMUC-Faculty of Medicine, University of Coimbra, Coimbra, Portugal Alzheimer's disease (AD) is characterized by an initial synaptic dysfunction and damage causing progressive cognitive impairment. Amyloid- β peptides (Aβ) have been proposed as culprits of AD, since their production is bolstered in AD and they can trigger synaptic and memory dysfunction. Epidemiological and animal studies have converged to show that the intake of caffeine, an adenosine receptor antagonist, prevents memory deficits caused by Aβ, an effect mimicked by blockade of adenosine A 2A receptors (A 2A R), which are mainly synaptic. Since ecto-5’-nucleotidase (CD73), controlling the formation of extracellular adenosine from released ATP, provides the adenosine activating A 2A R under physiological conditions, we now aimed to assess if tinkering with CD73 could rectify the synaptic and behavioural deficits triggered by Aβ. This was tackled using behavioural, neurochemical and slice electrophysiology approaches. We report that icv administration o f Aβ 1-42 (2 nmol, 14 days) increased the synaptic release of ATP, upregulated the levels of CD73 and A 2A R and blunted LTP amplitude in hippocampal synapses and impaired performance in memory tests. The genetic deletion of either CD73 (CD73-KO mice) or A 2A R (A 2A R-KO mice) counteracted this Aβ 1-42 -induced decrease of LTP and of memory. Similarly, direct exposure of naïf slices from wild type mice to oligomeric A β 1-42 (50 nM for 40 min) also decreased LTP amplitude. This acute effect of Aβ 1-42 was reverted by the CD73 inhibitor α,β -methylene- ADP (100 μM) or by the A 2A R antagonist SCH58261 (50 nM) and was prevented in slices from CD73- and A 2A R-KO mice. These results show that CD73 blockade prevents the impact of Aβ on synaptic function and memo ry; this confirms that the formation of ATP-derived adenosine through CD73 is responsible for A 2A R activation under pathological conditions, and prompts CD73 as a novel therapeutic target against the behavioural and synaptic deficits in early AD. Supported by Fundacion LaCaixa, Centro 2020 (CENTRO-01-0246-FEDER-000010) and through FCT (POCI-01-0145-FEDER-031274).