Presenilin: a role in neurogenesis via Notch? A different view on Alzheimer's disease pathology
Vries, E.M. de
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Alzheimer’s disease (AD) is a severe neurodegenerative disease characterized by the formation of amyloid plaques and neurofibrillary tangles. Familial Alzheimer’s disease (FAD) is an early onset form of AD and can be caused by mutations in three different genes; presenilin 1 (PS1) presenilin 2 (PS2) and amyloid precursor protein (APP). Presenilins are intramembranous proteins that are part of the -secretase complex. This proteolytic complex is responsible for the cleavage of several transmembrane proteins such as APP and Notch. Mutations in PS1 and PS2 are known to alter the ratio of two forms of amyloid, the soluble form (A40) and the more aggregation prone A42. This is thought to enhance plaque formation and cause neuronal degeneration and cognitive decline. Recently, the amyloid hypothesis is challenged by the fact that there can be neuronal degeneration without the presence of plaques. In addition, immunisation with A42 has beens shown to reduce plaque load, but has no effect on neurodegeneration and stage of dementia. This led to the idea that presenilin mutations could also enhance AD pathology via different mechanisms than increasing the A42/A40 ratio. One possible mechanism could be via altering neurogenesis. Neurogenesis is the formation of new neurons, and is limited to discrete zones in the adult mammalian brain. It could be a compensatory mechanism in response to injury and neurodegeneration. A shift from neurogenesis to gliogenesis could enhance the vulnerability of the brain to AD. The question in this thesis is whether AD presenilin mutations could alter neurogenesis via defective notch signalling. The evidence for this hypothesis shows to be hard to interpret. Data from human and animal studies seems to suggest that neurogenesis is impaired in AD, despite defective notch signalling. However, it is important not to rule out the other functions of presenilins, such as its role in Wnt signalling, apoptosis and synaptic functioning. More knowledge about the fundamental roles of all involved proteins is of crucial importance to be able to unravel all the critical steps in AD pathology.