Presenilin
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.