Signalling Pathways In Alzheimer Disease
Alzheimer disease is the most common neurodegenerative disease and the first cause of dementia in the elderly. It is characterized by memory impairment that leads to progressive loss of cognitive functions, and by extracellular deposits of β amyloid (Aβ) and neurofibrillary tangles (intracellular deposits).
A number of recent reports indicate the important role of circulating amyloid-beta oligomers in AD pathogenesis and more specifically in the cognitive impairment characterising AD patients. Yet again the intracellular signalling pathways, by which Aβ oligomers induce synaptic failure and consequently neuronal degeneration are poorly understood. Nevertheless increasing evidence indicate the involvement of kinases-dependent signalling pathways, and more specifically the JNK signalling pathway in these early degenerative events.
The JNK kinase phosphorylates APP (amyloid precursor protein) and its relevance in both neuronal death and brain plasticity is well established. We recently demonstrated, by using the specific cell penetrating JNK inhibitor peptide (D-JNKI1), that JNK is responsible for APP phosphorylation at Thr668, and that its specific inhibition reduced the βAPPs and Aβ fragments production in primary cortical neurons (Colombo et al., 2007). In addition, we could show that JNK inhibition leads to a shift from the amyloidogenic to the non-amyloidogenic pathway, a result with potentially important therapeutical implications (Colombo et al., 2008 in press).
Research Participants:
Tiziana Borsello
Xenia Antoniou, PhD
Alessio Colombo
Cristina Ploia
Alessandra Sclip
Alice Perego