23 September 2002. The Notch signaling pathway is of considerable interest to those studying Alzheimer's disease because the Notch receptor and the amyloid-β precursor protein (AβPP) are proteolytically processed much the same manner. γ-Secretase cleavage of these proteins results in the release of intracellular domains (NICD and AICD) that have profound cellular consequences (see ARF related news story and ARF related news story). Researchers at the Albert Einstein College of Medicine reveal in today’s online Nature Medicine that the Notch pathway may contribute to the progression of another neurodegenerative disease, multiple sclerosis (MS).
Because inflammation and reactive astrocytes have been implicated in the etiology of MS, first author Gareth John and colleagues, working with senior author Celia Brosnan, used microarray analysis to determine what genes may be switched on or off in astrocytes in response to the inflammatory cytokines interferon-g, interleukin 1b, and transforming growth factor b1 (TGF-b1). Among many genes repressed or induced by these cytokines, the authors found that Jagged1, a Notch ligand, was induced by TGF-b1, while Delta 1, another Notch ligand, was unaffected.
This specific effect is significant in that pre-myelinating oligodendrocytes are known to express the Notch receptor, and its activation induces expression of the transcription factor Hes5, which prevents the cells from maturing into myelinating oligodendrocytes. The TGF-b1, Jagged1, Notch relay may, therefore, prevent the essential remyelination of neurons.
In support of this theory, John et al., using autopsy tissue samples, found that the main players in this path of destruction, Jagged1, Notch1, and Hes5, are all present in MS lesions. Jagged1, however, was not found in remyelinating lesions, only in demyelinating ones, as would be predicted if it played a central role in disease progression.
What all this means for Alzheimer’s disease is unclear, but recent findings of white-matter atrophy in AD suggests that demyelination may be an important event in this disease as well. In any event, the potential role of the Notch pathway in an inflammatory response in the brain, which may or may not impact neuronal repair, seems worth investigating.-Tom Fagan
John GR, Shankar SL, Shafit-Zagardo B, Massimi A, Lee SC, Raine CS, Brosnan CF. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nature Medicine Online. 2002 September 23. (Abstract)