The central role of peroxisomes in ROS and lipid metabolism and their importance in brain functioning are well established. The aim of this work was to study the modulation of peroxisomal and peroxisome-related proteins in cortical neurons in vitro challenged with chronic or acute Aβ treatment, in order to investigate whether peroxisomes represent one of the cellular target of Aβ in these cells. The expression of peroxisomal (PMP70, catalase, acyl-CoA oxidase and thiolase), peroxisome-related (PPARα, insulin-degrading enzyme) and anti-oxidant (SOD1, SOD2, GSTP1) proteins was studied. The results obtained, demonstrating an early upregulation of the peroxisomal proteins during the chronic challenge, followed by their dramatic impairment after acute challenge, suggest that peroxisomes represent one of the first line of defence against Aβ-mediated oxidative injury. Our results support the notion that substances able to activate PPARα and/or to induce peroxisomal proliferation may constitute a novel preventive and/or therapeutic tool against neurodegenerative diseases.