The concept of "aldehyde load" in neurodegenerative mechanisms: cytotoxicity of the polyamine degradation products hydrogen peroxide, acrolein, 3-aminopropanal, 3-acetamidopropanal and 4-aminobutanal in a retinal ganglion cell line.
In neurodegenerative diseases augmented polyamine metabolism results in the generation of hydrogen peroxide and a number of reactive aldehydes that participate in the death of compromised tissue. The major aldehydes produced by polyamine oxidase and amine oxidases include the 2-alkenal acrolein, the acetoamidoaldehyde 3-acetamidopropanal (3-AAP) and the aminoaldehydes 3-aminopropanal (3-AP) and 4-aminobutanal (4-AB). Using retinal ganglion cell (E1A-NR.3) cultures, we confirmed the cytotoxicity of acrolein and 3-AP. For the first time we also demonstrated the cytotoxicity of 4-AB and the lack of toxicity of 3-AAP. Our data with 3-AAP, a product of N-acetylspermine and N-acetylspermidine metabolism, indicate that the aldehyde function of aminoaldehydes is insufficient to express toxicity since the free amino group of aminoaldehydes is also required to gain access to lysosomes where their cytotoxic actions are expressed via leakage of cathepsins that compromise mitochondrial integrity. Metabolism of 3-AP to beta-alanine by aldehyde dehydrogenase was also evaluated in retinal ganglion cell cultures and found to proceed at a linear rate of 24.3+/-1 nmol/mg protein/h. These are the first data demonstrating the dynamic cellular detoxification of 3-AP by neural cells and support the concept that decrements in aldehyde elimination leading to an increase in "aldehyde load" may play pivotal roles in the development and progression of neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis and Parkinson's disease.
Wood
Paul L
PL
The Falk Center for Molecular Therapeutics, Dept. of Biomedical Engineering, McCormick School of Engineering and Applied Sciences, Northwestern University, 1801 Maple Ave., Suite 4306, Evanston, IL 60201, USA. p-wood@northwestern.edu
Khan
M Amin
MA
Moskal
Joseph R
JR
D000171:Acrolein / Q000378:metabolism / Q000633:toxicity; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism* / Q000633:toxicity; D001923:Brain Chemistry / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000633:toxicity; D008657:Metabolic Clearance Rate / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism* / Q000633:toxicity; D011437:Propylamines / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism*; D015091:beta-Alanine / Q000378:metabolism
D000447:Aldehydes; D015317:Biogenic Polyamines; D009498:Neurotoxins; D011437:Propylamines; D015091:beta-Alanine; D000171:Acrolein; D006861:Hydrogen Peroxide; D000444:Aldehyde Dehydrogenase; C050862:3-aminopropionaldehyde