Presenilin-1-immunoreactive neurons are preserved in late-onset Alzheimer's disease
    Recent studies have suggested that missense mutations in the presenilin-1 gene are causally related to the majority of familial early-onset Alzheimer's disease (AD). To examine the possible involvement of presenilin-1 in late-onset sporadic AD, a quantitative analysis of its distribution in the cerebral cortex    of nondemented and AD patients was performed using immunocytochemistry. Stereological analyses revealed that AD brains showed a marked neuronal loss in the CA1 field of the hippocampus and hilus of the dentate gyrus, subiculum, and entorhinal cortex. In these areas, however, the fraction of neurofibrillary tangle (NFT)-free neurons showing presenilin-1 immmunoreactivity was increased compared with nondemented controls. In contrast, cortical areas, which displayed no neuronal loss, did not short, any significant increase in the fraction of presenilin-1-positive neurons. Moreover, presenilin-1 immunoreactivity was reduced in NFT-containing neurons. Thus, in AD, the fraction of NFT-free neurons that contained presenilin-1 varied from 0.48 to 0.77, whereas the fraction of NFT-containing    neurons that were presenilin-1 positive varied from 0.1 to 0.24. Together, these observations indicate that presenilin-1 may have a neuroprotective role and that in AD low cellular expression of this protein may be associated with increased neuronal loss and NFT formation.
Mutant presenilins of Alzheimer's disease increase production of 42-residue    amyloid beta-protein in both transfected cells and transgenic mice

    The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta-42 peptide, peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid  beta-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels,  alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused   a highly significant increase in A beta-42 secretion in all mutant clones. Likewise, mutant but not  wild-type PS1 transgenic mice showed significant overproduction of A beta-42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta  generation. The extent of A beta-42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta-42  production, thus promoting cerebral beta-amyloidosis.