Presenilin-1 and -2 (PS1, PS2) gene mutations appear to cause the majority of cases of early onset familial Alzheimer’s disease (EO-FAD). In this presentation Potter et al. (492.2) presented data that PS1 and PS2 (the PS's) have a nuclear membrane location and they may also reside, or are associated with related nuclear structures involved in cell division, chromosome segregation, nuclear apoptosis and chromosome destruction. Firstly, it was reviewed that Down's syndrome (DS) is associated with a triplicate chromosome 21 and virtually all individuals with DS develop AD pathology by age 30-40. Fibroblasts derived from FAD patients with mutant PS1 genes have often have chromosome 21 defects, including trisomy 21, and trisomy 21 is also associated with the potent cytokine IL-1 and Aβ overexpression.

Besides their putative roles in intercellular signaling and cell-fate determination, PS’s have also been shown to (1) induce apoptosis in the CNS and (2) to halt cell division in the G1 phase of the cell cycle (see Janicki and Monteiro, Am J Pathol 1999). Expression of the tumor supressor gene p53, localized to the centrosome, has been shown to decrease PS1 expression levels, and p53 mutations cause abnormal centrosome duplication and chromosome missegregation. PSs are thus implicated in the control of the cell cycle. Additional data in transgenic models showed that mutant PSs can induce chromosome mis-segregation. Taken together, the results suggested that AD is associated with a defect in the cell division cycle (at G1?) that ultimately leads to the mis-segregation of chromosomes and their disruption via the process of apoptosis and related nuclear destructive mechanisms.—Walter Lukiw
References: Session 492.2 Potter H, Geller LN, Wefes IM, Ma J. Chromosome segregation defects caused by Alzheimer presenilin mutations.


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