Abstract
Mutations in the presenilin genes account for the majority of familial Alzheimer disease (FAD) cases. In the present report we demonstrated that the FAD-linked presenilin 2 mutations (PS2 M239I and T122R) alter cystatin C trafficking in mouse primary neurons reducing secretion of its glycosylated form. These mutations showed a different impact on cystatin C: PS2 T122R had a much stronger effect determining a dramatic intracellular accumulation of cystatin C (native and glycosylated), followed by a reduction in the secretion of both forms. Several experimental evidences suggest that cystatin C exerts a protective role in the brain and favors stem cells proliferation. Confocal imaging showed that the effect of PS2 T122R mutation was a massive recruitment of cystatin C into the neuronal processes, in the presence of an intact cytoskeletal structure. The consequent reduction in the cystatin C extracellular levels might result in a failure of neuroregeneration. Understanding the interplay of PS2 and cystatin C in the pathogenesis of AD might highlight new therapeutic prospective.
Original language | English |
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Pages (from-to) | 371-376 |
Number of pages | 6 |
Journal | Neurobiology of Aging |
Volume | 28 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 2007 |
Keywords
- Cysteine protease
- Familial Alzheimer disease
- Glycosylated cystatin C
- Mutation
- Presenilin 2
- Protein secretion
ASJC Scopus subject areas
- Clinical Neurology
- Biological Psychiatry
- Developmental Neuroscience
- Neurology
- Psychology(all)