ABSTRACT
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 (Abeta) 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 Abeta(25-35) peptide, a nontransgenic model of Alzheimer's disease. PCAF wild-type (WT) and KO mice received Abeta(25-35) (1, 3 or 9 nmol) or scrambled Abeta(25-35) (9 nmol) as control. After 7 days, Abeta(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, Abeta(25-35) injection failed to induce toxicity or worsen the deficits. This resistance to Abeta(25-35) toxicity did not involve changes in glutamate or acetylcholine systems. Examination of enzymes involved in Abeta generation or degradation revealed changes in transcription of presenilins, activity of neprilysin (NEP) and an absence of Abeta(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 Abeta generation and degradation, thus rendering PCAF KO insensitive to amyloid toxicity. Modulating acetyltransferase activity may offer a new way to develop anti-amyloid therapies.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/toxicity , Brain/metabolism , Drug Resistance/genetics , Genetic Predisposition to Disease/genetics , Peptide Fragments/toxicity , p300-CBP Transcription Factors/genetics , Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Animals , Apoptosis/drug effects , Apoptosis/genetics , Brain/physiopathology , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Memory Disorders/chemically induced , Memory Disorders/genetics , Memory Disorders/metabolism , Mice , Mice, Knockout , Neprilysin/drug effects , Neprilysin/genetics , Neprilysin/metabolism , Nerve Degeneration/chemically induced , Nerve Degeneration/genetics , Nerve Degeneration/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Oxidative Stress/drug effects , Oxidative Stress/genetics , Peptide Fragments/metabolism , Presenilins/drug effects , Presenilins/genetics , Presenilins/metabolism , Somatostatin/drug effects , Somatostatin/metabolismABSTRACT
We examined the potential protective effect of BDNF against beta-amyloid-induced neurotoxicity in vitro and in vivo in rats. In neuronal cultures, BDNF had specific and dose-response protective effects on neuronal toxicity induced by Abeta(1-42) and Abeta(25-35). It completely reversed the toxic action induced by Abeta(1-42) and partially that induced by Abeta(25-35). These effects involved TrkB receptor activation since they were inhibited by K252a. Catalytic BDNF receptors (TrkB.FL) were localized in vitro in cortical neurons (mRNA and protein). In in vivo experiments, Abeta(25-35) was administered into the indusium griseum or the third ventricle and several parameters were measured 7 days later to evaluate potential Abeta(25-35)/BDNF interactions, i.e. local measurement of BDNF release, number of hippocampal hilar cells expressing SRIH mRNA and assessment of the corpus callosum damage (morphological examination, pyknotic nuclei counting and axon labeling with anti-MBP antibody). We conclude that BDNF possesses neuroprotective properties against toxic effects of Abeta peptides.
