MICE KNOCK OUT FOR THE HISTONE ACETYLTRANSFERASE P300/CREB BINDING PROTEIN-ASSOCIATED FACTOR DEVELOP A RESISTANCE TO AMYLOID TOXICITY

p300/CREB binding protein-associated factor (PCAF) regulates gene expression by acting through histone acetylation and as a transcription coactivator. Although histone acetyltransferases were involved in the toxicity induced by amyloid-beta (A beta) peptides, nothing is known about PCAF. We here analyzed the sensitivity of PCAF knockout (KO) mice to the toxic effects induced by i.c.v. injection of A beta(25-35) peptide, a nontransgenic model of Alzheimer's disease. PCAF wildtype (WT) and KO mice received A beta(25-35) (1, 3 or 9 nmol) or scrambled A beta(25-35) (9 nmol) as control. After 7 days, A beta(25-35) toxicity was measured in the hippocampus of WT mice by a decrease in CA1 pyramidal cells and increases in oxidative stress, endoplasmic reticulum stress and induction of apoptosis. Memory deficits were observed using spontaneous alternation, water-maze learning and passive avoidance. Non-treated PCAF KO mice showed a decrease in CA1 cells and learning alterations. However, A beta(25-35) injection failed to induce toxicity or worsen the deficits. This resistance to A beta(25-35) toxicity did not involve changes in glutamate or acetylcholine systems. Examination of enzymes involved in A beta generation or degradation revealed changes in transcription of presenilins, activity of neprilysin (NEP) and an absence of A beta(25-35)-induced regulation of NEP activity in PCAF KO mice, partly due to an altered expression of somatostatin (SRIH). We conclude that PCAF regulates the expression of proteins involved in A beta generation and degradation, thus rendering PCAF KO insensitive to amyloid toxicity. Modulating acetyltransferase activity may offer a new way to develop anti-amyloid therapies. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.