Related Experiment Video
Updated: Jun 15, 2026
Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
Mice knock out for the histone acetyltransferase p300/CREB binding protein-associated factor develop a resistance to
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.
Insights
p300/CREB binding protein-associated factor (PCAF) knockout mice are resistant to amyloid-beta peptide toxicity. PCAF influences proteins involved in amyloid-beta generation and degradation, suggesting new therapeutic targets for Alzheimer's disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Histone acetyltransferases, including p300/CREB binding protein-associated factor (PCAF), are implicated in amyloid-beta (Abeta) peptide toxicity.
- The specific role of PCAF in Alzheimer's disease pathogenesis remains largely unexplored.
Purpose of the Study:
- To investigate the sensitivity of PCAF knockout (KO) mice to Abeta(25-35) peptide-induced toxicity, a model for Alzheimer's disease.
- To elucidate the mechanisms underlying PCAF's role in Abeta toxicity.
Main Methods:
- Intracerebroventricular (i.c.v.) injection of Abeta(25-35) peptide or scrambled peptide into PCAF wild-type (WT) and KO mice.
- Assessment of hippocampal neuronal loss (CA1 pyramidal cells), oxidative stress, endoplasmic reticulum stress, apoptosis, and memory deficits (spontaneous alternation, water-maze, passive avoidance).
- Analysis of glutamate, acetylcholine, presenilins, neprilysin (NEP), and somatostatin (SRIH) in relation to Abeta generation and degradation.
Main Results:
- PCAF KO mice exhibited inherent CA1 cell loss and learning deficits, but were resistant to Abeta(25-35)-induced toxicity and exacerbation of deficits.
- This resistance was not mediated by alterations in glutamate or acetylcholine systems.
- PCAF KO mice showed altered transcription of presenilins and NEP activity, with an absence of Abeta(25-35)-induced NEP regulation, partly due to altered SRIH expression.
Conclusions:
- PCAF regulates proteins involved in Abeta generation and degradation, conferring resistance to amyloid toxicity in KO mice.
- Modulating PCAF's acetyltransferase activity presents a potential therapeutic strategy for Alzheimer's disease.
