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Alzheimer Disease

The onset and progression of Alzheimer disease remain to be elucidated, although it appears that free radical damage and neuroinflammation are likely to play a significant role. In familial cases of AD, it was found that specific mutation in the precursor of amyloid protein generates a toxic protein fragment, i.e., beta-amyloid, which triggers inflammation. Subsequently, toxins — free radicals — are generated and could lead to the death of neurons, causing decreases in a vital brain chemical, the neurotransmitter acetylcholine, affecting memory and concentration, and developing into debilitating clinical symptoms that are most common in AD.


It has been suggested that loss of neurons could be due to vascular problems (silent strokes) and/or undetectable inflammation processes. Some theories in the development of Alzheimer disease have focused on the presence of beta-amyloid plaques and neurofibrillary tangles in the brain of AD patients. The only defense against these abnormal processes is to fight back, and, to do that, the brain activates immune cells, such as microglia. These reactive brain cells generate toxins, which under chronic conditions can become counterproductive.

Low-grade chronic inflammation (as opposed to acute), generally unnoticed, is believed to underlie the most serious neurodegenerative diseases. Consequently, anti-inflammatory drugs, such as the non-steroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin, ibuprofen, and acetaminophen) and the newer COX-2 inhibitors, are being investigated. Another main objective of Dr. Doré’s research is to understand the actions of cyclooxygenase and its metabolites, the prostaglandins.


In addition, in order to discover factors that could modulate the neuroprotective activities found to be associated with HO2, Dr. Doré and collaborators have performed a yeast-2-hybrid technique, which allows the identification of protein-protein interactions. They found that an amyloid-like precursor protein and its homologue, amyloid precursor proteins (APP), can directly bind to heme oxygenase and slightly decrease its activity. With Dr. Snyder’s laboratory, they identified that mutants associated with the familial AD would have higher affinity, suggesting that a possible chronically lower HO activity can be one of the factors contributing to the etiology of Alzheimer disease. Dr. Doré’s goal now is to further characterize this observation using in vivo and in vitro models.

Selected References:

  1. Doré S.Decreased activity of the anti-oxidant heme-oxygenase enzyme: implications in ischemia and in Alzheimer’s disease. Free Radical Res 32:1276-82, 2002.
  2. Doré S*, Takahashi M*, Ferris CD, Tomita T, Sawa A, Wolosker H, Borchelt DR, Iwatsubo T, Kim SH, Thinakanan G, Sissodia S, Snyder SH. Amyloid precursor proteins inhibit heme oxygenase activity and augment neurotoxicity in Alzheimer’s disease. Neuron 28:461-73, 2000