Alzheimerˇ¦s
Hum Mutat. 2006 Jul;27(7):686-95. Arch Neurol. 2006 Mar;63(3):370-6.
Mean age-of-onset of familial alzheimer disease caused by presenilin
mutations correlates with both increased Abeta42 and decreased Abeta40.
Kumar-Singh
S, Theuns
J, Van
Broeck B, Pirici
D, Vennekens
K, Corsmit
E, Cruts
M, Dermaut
B, Wang
R, Van
Broeckhoven C.
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics,
Flanders Interuniversity Institute of Biotechnology, University of Antwerp,
Antwerpen, Belgium. samir.kumarsingh@ua.ac.be
The varied ways in which mutations in presenilins
(PSEN1 and PSEN2) affect amyloid b precursor
protein (APP) processing in causing early-onset familial Alzheimer disease
(FAD) are complex and not yet properly understood. Nonetheless, one useful
diagnostic marker is an increased ratio of Ab42 to Ab40 (Ab42/Ab40) in
patients' brain and biological fluids as well as in transgenic mice and
cells. We studied Ab and APP processing for a set
of nine clinical PSEN mutations on a novel and highly reproducible
enzyme-linked immunosorbent assay (ELISA)-based
in vitro method and also sought correlation with brain Ab
analyzed by image densitometry and mass spectrometry. All mutations
significantly increased Ab42/Ab40 in vitro by significantly decreasing Ab40
with accumulation of APP C-terminal fragments, a sign of decreased PSEN
activity. A significant increase in absolute levels of Ab42 was observed
for only half of the mutations tested. We also showed that age-of-onset of
PSEN1-linked FAD correlated inversely with Ab42/Ab40 (r = -0.89; P = 0.001)
and absolute levels of Ab42 (r = -0.83; P = 0.006), but directly with Ab40
levels (r = 0.69; P = 0.035). These changes also partly correlated with
brain Ab42 and Ab40 levels. Together, our data suggested that Ab40 might be
protective by perhaps sequestering the more toxic Ab42 and facilitating its
clearance. Also, the in vitro method we describe here is a valid tool for
assaying the pathogenic potential of clinical PSEN mutations in a molecular
diagnostic setting.
PMID: 16752394 [PubMed - in process]
Lewy body pathology in familial Alzheimer disease:
evidence for disease- and mutation-specific pathologic phenotype.
Leverenz
JB, Fishel
MA, Peskind
ER, Montine
TJ, Nochlin
D, Steinbart
E, Raskind
MA, Schellenberg
GD, Bird
TD, Tsuang
D.
Parkinson's Disease, Mental Illness Research, Education, and Clinical
Centers, Veterans Affairs Puget Sound Health Care System, Seattle, Wash,
USA. leverenz@u.washington.edu
BACKGROUND: The origin and significance of Lewy
bodies and neurites (Lewy
body pathology [LBP]) in Alzheimer disease (AD) are poorly understood.
OBJECTIVE: To examine LBP in the brainstem, limbic cortex, and neocortex of a large number of familial AD cases with
mutations in 2 presenilin (PSEN) genes. METHODS:
Twenty-five familial AD cases with 9 known PSEN 1 mutations and 14 familial
AD cases with a single PSEN 2 mutation (N141I) were examined for LBP using
alpha-synuclein immunohistochemistry
and sampling of multiple brainstem and cortical regions. RESULTS: The amygdala was the most vulnerable site for LBP. In fact,
virtually all (24 [96%] of 25 cases) of the PSEN 1 mutation cases had LBP
in the amygdala. The PSEN 1 mutation cases also
had more frequent LBP in the amygdala and neocortex than those with the PSEN 2 mutation. However,
within families with a single mutation of either PSEN 1 or PSEN 2, there
was frequent variability of the LBP. CONCLUSION: These findings suggest
that there are genetic influences on the presence of LBP in familial AD as
demonstrated by the differences between PSEN 1 and PSEN 2 mutation cases.
PMID: 16533963 [PubMed - indexed for MEDLINE]