New Theories of Presenilin Function
Chris Weihl led this live discussion on 12 December 2000. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
View Transcript of Live Discussion — Posted 30 August 2006
Among the numerous publications describing presenilin's
putative role in membrane trafficking, apoptosis, development,
signal transduction and the amyloid cascade, two sets
of papers have been published looking at novel pathogenic
mechanisms for the elusive 8 transmembrane domain protein
associated with familial Alzheimer's disease. One set
of papers deals with the role that presenilin may have
in the coordination of endoplasmic reticulum resident
chaperone proteins and their response to cellular stress
et al., 1999; Niwa
et al., 1999). The second set of papers looks at
the role of presenilin in synaptic plasticity using
neurophysiological paradigms associated with learning
et al., 2000; Parent
et al., 1999; Zaman
et al., 2000).
Presenilin and the Unfolded
Protein Response (UPR)
Ever since the discovery of presenilin-1 and its
homologue presenilin-2, researchers have attempted to
correlate its role with the phenotypic changes seen
in Alzheimer's patients. Several lines of evidence suggest
that PS plays an important role in amyloid production
and its subsequent deposition. Other investigators have
demonstrated that PS1 mutations associated with FAD
increase a cells susceptibility to apoptosis and neuronal
cell death. Two recent studies attempt to link these
two phenomenon by investigating the role of PS in a
novel cellular signaling pathway associated with the
unfolded protein response (UPR) (Katayama
et al., 1999; Niwa
et al., 1999).
What is the UPR?
In brief, when a cell's endoplasmic reticulum (the
place where proteins are synthesized) is overloaded
with misfolded proteins, as in times of stress, the
UPR allows for an increase in the transcription of resident
ER chaperone proteins such as GRP78/Bip. The upregulation
of these chaperones aid in the maintenance of protein
tertiary structure, diminishing the load of detrimental
"junk" ER misfolded protein. This pathway,
while not essential for the cell's everyday function,
is invaluable under times of cellular stress and instrumental
in cellular survival (for review see Welihinda
et al., 1999).
What Are the Molecular Mechanisms
Involved in the UPR
The UPR was initially characterized in yeast, but
several homologous pathways have now been described
in mammalian cells. In yeast the pathway involves two
proteins, an ER transmembrane protein (Ire1) and a nuclear
transcription factor (Hac1). Hac1 recognizes UPR elements
on promoters for GRP78/Bip and other molecular chaperones.
In yeast, the ER lumenal domain of Ire1 senses the level
of free GRP78/Bip. When free GRP78/Bip is low as in
times of stress (presumably because GRP78/Bip is complexed
with misfolded protein in the ER lumen), Ire1 dimerizes,
autophosphorylates and becomes an RNA endonuclease.
The Ire1 endonuclease then splices a constitutively
produced but inactive Hac1 mRNA into an actively translated
mRNA. Once the newly spliced Hac1 mRNA is translated,
the Hac1 protein then enters the nucleus and activates
specific UPR elements on molecular chaperone genes.
The upregulation of ER molecular chaperones such as
GRP78/Bip is the final result of the UPR.
In mammals this process is less well characterized. While hIre1·
and hIre1, maintain RNA endonuclease function in vitro, they do not appear
to function this way in vivo. Current data suggests that after hIre1·
and hIre1, autophosphorylation, they are cleaved and transported to the
nucleus where they can help in the trans-activation of Hac1 homologues.
This process again results in an upregulation of ER molecular chaperones.
Does Mutant PS1 Perturb the UPR in
Katayama and colleagues initially looked at the susceptibility
of mutant PS1 stably expressing neuroblastoma cells
to "ER stressors." These stressors included
tunicamycin (which prevents protein glycosylation) and
the calcium ionophore, A23187 (which depletes ER stores
of calcium). As expected the mutant PS1 expressing cells
were more susceptible to these stresses as suggested
by earlier investigators (Guo
et al., 1996; Guo
et al., 1999b).
In order to characterize the cellular response to these stressors in
mutant PS1-expressing neuroblastoma cells, Katayama looked at the mRNA expression
levels of a specific ER resident molecular chaperone, GRP78/Bip, that is
known to be upregulated with the application of these ER stressors. While
basal levels of GRP78/Bip were unaltered amongst the expressed transgenes,
6 hours after the application of tunicamycin a 50-30% decrease in GRP78
expression was seen in mutant PS1 expressing cell lines. This data was further
reproduced in transiently expressing HEK293 cells and knock-in mice expressing
To determine whether this decrease was due to a defect in the cells'
unfolded protein response, Katayama performed gel shift assays with lysates
from PS1-WT or PS1 mutant expressing cells. They demonstrated that there
was a decrease in the activation of the UPR promoter element on GRP78/Bip.
Niwa and colleagues performed a similar set of experiments using fibroblasts
from PS1 knockout mice. The level of GRP78/Bip mRNA was decreased ~40% in
the PS1 knockout cells 7 hours after the ER stressor tunicamycin was added.
Katayama also demonstrated a significant decrease in the levels of GRP78/Bip
in the brains of sporadic and familial AD patients when compared with unaffected
What Role Does PS1 Play in the Unfolded
Protein Response Pathway?
Katayama demonstrates the colocalization of PS1 with
Ire1 and co-immunoprecipitates full-length wild type
and mutant PS1 with overexpressed Ire1 in vivo. These
data suggest a putative interaction between PS1 and
the most upstream element of the UPR pathway, Ire1.
Furthermore, Katayama show that the phosphorylation
and presumable activation of Ire1 is diminished in PS1-mutant
expressing cells. Katayama and colleagues speculate
that PS1 may serve as a molecular tether between Ire1
oligomers and phosphatases associated with Ire1 regulation.
This hypothesis is reminiscent of other proposed mechanism
for PS1. Takashima et al. suggested that PS1 binds GSK3-beta
as well as its substrates, tau and beta-catenin. By
tethering a kinase with its substrate, PS1 modulates
the phosphorylation of tau and the phosphorylation and
subsequent degradation of beta-catenin (Takashima
et al., 1998; Zhang
et al., 1998).
Niwa further extends these studies by demonstrating that PS1 knockout
fibroblasts have a decrease in their ability to cleave and subsequently
transport the C-terminus of hIre1 to the nucleus from the ER when compared
with PS1-WT expressing controls. They speculate that PS1 regulates the activity
of, or serves as, the gamma-secretase responsible for the cleavage of hIre1
since its cleavage site is within the ER membrane. This hypothesis is similar
to the proposed role of PS1 as the gamma-secretase involved in the processing
of APP, and Notch (Haass
and Mandelkow, 1999).
How Do Changes in the UPR Pathway Result in AD and Amyloid
It is intriguing to speculate that the neuronal cell
loss seen in FAD patients may be due to an impaired
UPR. Perhaps neurons are more sensitive to specific
environmental insults (or ER stressors) that may precipitate
the neuronal cell loss seen in FAD patients expressing
mutant PS1. Furthermore, several studies have demonstrated
an increase in multi-ubiquitinated protein inclusions
in AD patient brain tissue suggesting an overload of
misfolded proteins (Alves-Rodrigues
et al., 1998). It is interesting that overexpression
of GRP78/Bip rescues PS1-mutant expressing cells from
the ER stressors tunicamycin and calcium ionophore,
et al., 1999). A similar study overexpressed HSP70,
a cytosolic molecular chaperone, and rescued cells from
cell death induced by mutations in Cu/Zn superoxide
dismutase-1 (SOD-1) that are associated with familial
ALS patients (Bruening
et al., 1999). Moreover this same study demonstrated
a decrease in HSP70 chaperoning function in transgenic
mice expressing mutant SOD-1 (Bruening
et al., 1999).
Another study found that APP transiently associated with the GRP78/Bip
as it moved through the secretory pathway. Overexpression of GRP78/Bip decreased
the amyloidogenic phenotype of the APP Swedish mutation by lowering the
ratio of A-beta1-42/1-40 (Yang
et al., 1998). The authors speculated that an increase in APP's association
with GRP78/Bip decreased the likelihood of gamma-secretase cleavage. Moreover,
a decrease in the cells UPR would result in a decrease in GRP78/Bip and
may allow for APP to be conformationally more susceptible to gamma-secretase
et al., 1998).
Addendum (4 December 2000)
Since the cloning of the presenilins (PSs) in 1995,
the functional role of these proteins and the deleterious
effects of their familial Alzheimer disease (FAD) associated
mutations has been steeped in controversy. While it appears
to be incontrovertible that mutant PS has a clear role
in amyloid deposition, by increasing A-beta 1-42, the
mechanism by which this event occurs remains unclear.
To date, several investigators have proposed novel mechanisms
by which these mutations cause FAD (discussed above).
The current discussion (also above) addresses two novel
roles for PS in the pathogenesis of FAD: 1) alterations
in synaptic transmission using FAD transgenic mice and
2) alterations in the ER stress response in FAD expressing
cells, mice and human patients .
A new paper by Sato and colleagues casts doubt on the putative role of
PS and its mutations in the ER stress response. This paper, in the December
2000 Nature Cell Biology, uses similar strategies as the antecedent
investigations by Katayama and Niwa (see above) to explore the role of PS
and FAD associated mutant PS in the unfolded protein response (UPR). Contrary
to these previous studies, Sato finds no difference in the UPR between PS1-WT,
PS1 knockout or FAD mutant PS1 expressing cells, mice or FAD patients.
This addendum will attempt to highlight the major differences between the
studies placing special emphasis on the results and experimental design.
Sato and colleagues comprehensively address the role of PS1 in the UPR.
However, contrary to Niwa et al., Sato finds no difference in the UPR using
PS1 knockout fibroblasts, as well as, PS1/PS2 knockout cells after measuring
the levels of GRP78/Bip and CHOP mRNA and protein levels following tunicamycin
treatment. Moreover, Sato also finds no difference in the activity of IRE1
in PS1 deficient cells. However, Niwa's study addressed the translocation
of IRE1 from the cytosol to the nucleus, whereas Sato's study used immunoblots
to assess the phosphorylation state of the IRE1 protein. While this difference
seems trivial, Niwa and colleagues speculate that PS1 has a direct role
in the cleavage and hence transport of the IRE1 protein, not the phosphorylation
state. This difference in technique and concomitant result is reminiscent
of studies investigating the translocation vs. the stability of beta-catenin
in similar cell lines (see previous panel discussion). However, in support
of Sato, the most downstream event in the UPR pathway, GRP78/Bip mRNA levels,
is tested and no difference was found between the treatment groups.
Using several different cell lines and transgenic mice that express FAD
associated mutant PS1, Sato and colleagues again challenge the previous
studies of Katayama. Sato demonstrates no difference in the levels of GRP78/Bip
mRNA/protein levels or the phosphorylation state of IRE1 following ER stress
in mutant expressing cell lines. However, Katayama assessed the activity
of IRE1 differently in the initial study. They used gel shift assay to
assess the functional activation of the UPR in stimulated cells. It remains
to be determined if subtle changes in experimental design may confound the
distinct differences in these two papers. Sato also contradicts the initial
study of Katayama and finds no difference in basal GRP78/Bip protein levels
from FAD patient and transgenic mouse tissue.
Finally, a recent paper by Sato, Imaizumi, et al. demonstrates that a
splice variant of PS2, which is enriched in sporadic AD brains, can associate
with IRE1 and plays a direct role in the UPR by downregulating GRP78/Bip
expression . This study further unifies the hypothesis that PS increases
the susceptibility of FAD patient brains to specific stresses that modulate
the ER stress response.
The role of the UPR in Alzheimer's disease and amyloid production is
intriguing. The papers by Katayama and Niwa propose a novel mechanism of
action for PS1 and its mutations that unify the current phenotypes of enhanced
cell death and A-beta production.
Presenilin and Synaptic Plasticity
The pathology seen in PS1 mutant expressing transgenic
mice has been disappointing. Although the mice do demonstrate
an increase in the ratio of A-beta1-42/1-40, they do
not develop appreciable amyloid plaques even when co-expressed
with human APP. This is in contrast to the APP mutant
expressing transgenic mice, which do demonstrate amyloid
plaque deposition (presumably because of the high level
of mutant APP expression). In an effort to investigate
the role of PS1 on more subtle phenotypes such as synaptic
plasticity, three independent groups investigated the
neurophysiologic properties of neurons from FAD transgenic
et al., 2000; Parent
et al., 1999; Zaman
et al., 2000).
The role of PS1 at the synapse has not been fully investigated. While
most studies demonstrate that PS1 and its fragments are localized to nuclear,
ER and golgi membranes, some groups have shown that PS1 is present on synaptic
vesicles and at pre- and post-synaptic terminals (Beher
et al., 1999; Efthimiopoulos
et al., 1998; Georgakopoulos
et al., 1999; Lah
et al., 1997). The role of PS1 in the development of neuronal pathways
has also not been appropriately addressed by investigators. PS1 knockout
mice have significant perturbations in embryonic pattern formation (Shen
et al., 1997). Moreover, one study using double transgenic mice expressing
both mutant PS1 and mutant APP demonstrated a reorganization of the synaptic
terminals of the basal forebrain suggesting that mutations associated with
FAD altered the anatomical structure of the developing brain (Wong
et al., 1999). These studies suggest that PS1 may alter synaptic plasticity
in PS1 mutant transgenic mice by directly participating in synaptic transmission
or by altering the brains neuronal architecture.
The simplest form of learning and memory occurs between two neurons,
one pre-synaptic and another post-synaptic. Synaptic stimulation using the
correct frequency, amplitude and duration can create a lasting response
in the post-synaptic neuron. Neuronal plasticity involves multiple mechanisms
including membrane potential, receptor density, calcium release and gene
transcription. More complex mechanisms of learning have been described that
involve several pre- and post-synaptic neurons. The most well characterized
neurophysiologic mechanism of higher learning is long-term potentiation
(LTP) in the CA1 and CA3 regions of the mammalian hippocampus. In this paradigm,
tetanic stimulation of post-synaptic neurons by the pre-synaptic neuron
can produce a prolonged potentiation of the post-synaptic neurons response
to future stimulation that can last for several hours. Neurophysiologists
presume that alterations in these simple learning paradigms might result
in higher learning deficits in animals.
Does Mutant PS1 Alter Synaptic
In order to address whether mutations in PS1 alter the
neurophysiology of mammalian brains, three independent
groups explored the synaptic plasticity in FAD transgenic
et al., 2000; Parent
et al., 1999; Zaman
et al., 2000). Each group studied well-characterized
neurophysiologic paradigms using hippocampal brain slices
from unique mutant PS1 expressing mice (PS1A246E, PS1deltaE9,
Parent and colleagues measured several neurophysiologic parameters in
their experiments using field excitatory postsynaptic potential (fEPSP)
at the Schaffer collateral-CA1 synapse in hippocampal slices. They found
no difference in the basal synaptic transmission including maximum fEPSP
slope, maximum fEPSP amplitude or the basal synaptic strength. However upon
high frequency stimulation used to elicit long-term potentiation (LTP),
mutant PS1 expressing animals had a larger initial amplitude that was more
persistent than PS1-WT and non-transgenic control littermates.
Barrow and colleagues examined similar parameters using intracellular
recordings from CA3 pyramidal neurons. Their data demonstrated that following
a train of 10 action potentials there was significant increase in the amplitudes
of the after-hyperpolarizations. Moreover they also found that mutant PS1
expressing animals had a larger amplitude and more persistent response to
LTP induction when compared with controls. Barrow and colleagues speculated
that this may be due to a change in the release of ER stores of intracellular
calcium as previously demonstrated (Guo
et al., 1996). Using PS1-mutant expressing hippocampal pyramidal cell
neurons they showed an increase in the rise and rate of intracellular calcium
release following neuronal depolarization. Their data demonstrates that
mutant PS1 may alter the intracellular ER calcium stores and hence increase
its release upon depolarization. Increased ER calcium release may contribute
to the enhanced neuronal plasticity seen in PS1 mutant transgenic brain
Zaman and colleagues confirmed the prior two studies. They found enhanced
and elevated LTP in PS1-mutant expressing brain slices at CA1 pyramidal
neurons. In addition, they propose that the increase in synaptic plasticity
due to enhanced calcium release may alter GABAA inhibitory input at the
CA1 hippocampal neuron. Zaman used pharmacologic manipulation to either
inhibit or enhance GABAA inhibitory transmission. Normally, in non-transgenic
mice brain slices, when GABAA is inhibited by picrotoxin, LTP is enhanced
and when GABAA is potentiated with a benzodiazepine, LTP is decreased. However
in PS1 mutant transgenic mice brain slices, GABAA inhibition produced no
effect and GABAA potentiation restored LTP to wild-type controls. This finding
suggested that GABAA inhibition was upregulated in PS1 mutant expressing
mice to compensate for the enhanced synaptic excitatory activity.
How Do Changes in Synaptic Plasticity
Contribute to AD?
On the simplest level it is easy to speculate that alterations
in LTP, either increased or decreased, could lead to
alterations of learning and memory that are associated
with the progression of AD in patients. Another possible
scenario proposed by Zaman and colleagues postulates
that the constant increase in intracellular calcium
during neuronal stimulation may burden the neurons causing
them to die or improperly function. Support for this
hypothesis is found in a paper by Mattson and colleagues
describing an increased sensitivity of FAD transgenic
mice to glutamate mediated excitotoxicity (Guo
et al., 1999a). Finally, as shown by Zaman, the
neuronal architecture may be altered so as to compensate
for the changes associated with mutant PS1 expression.
Zaman proposes that pharmacologic agents aimed at decreasing
the synaptic activity, such as benzodiazapines, may
be protective in AD. This thought is intriguing in light
of a clinical study that showed a decrease in the incidence
of AD in patients chronically using benzodiazipines
for sleep (Fastbom et al., 1998).
It is important for researchers to continue to search
for mechanisms by which mutations in PS1 and PS2 cause
familial Alzheimer's Disease. An increase in apoptosis
or changes in amyloid production are only phenotypes.
While therapies can be aimed at rescuing these phenotypes,
it is also prudent to explore therapies targeted at
the underlying mechanisms related to these phenotypic
changes. The aforementioned papers suggesting roles
for PS1 in the unfolded protein response or synaptic
transmission shed new light onto potential roles for
PS in AD.
Questions for Discussion and Future Investigation
- Does mutant PS1 increase FAD patient brains' susceptibility to ER stresses,
even though this may not occur through the UPR pathway?
- Can experimental design account for the differences between the reports
- How does a gain of function mutation in PS1 result in the same phenotype
as PS1 knockouts?
- Can one unified global function of PS be attributed to its effects
on amyloid production, apoptosis, signal transduction, synaptic transmission
- Assuming that PS is the gamma secretase, how will future treatments
such as gamma secretase inhibitors affect PS's function on other cellular
- Describe future treatments that may be aimed at correcting the defect
in these newly identified roles of PS?
- What directions are you currently pursuing in regards to your initial
- Do your results agree with the other sets of investigator's papers?
- Is Alzheimer's Disease research too narrowly limited to the amyloid
hypothesis? Do you have other hypotheses related to your own work?
Alves-Rodrigues, A., L. Gregori, and M.E. Figueiredo-Pereira. 1998. Ubiquitin,
cellular inclusions and their role in neurodegeneration. Trends Neurosci.
1998 Dec;21(12):516-20. Abstract.
Barrow, P.A., R.M. Empson, S.J. Gladwell, C.M. Anderson, R. Killick,
X. Yu, J.G. Jefferys, and K. Duff. 2000. Functional phenotype in transgenic
mice expressing mutant human presenilin-1. Neurobiol Dis. 2000 Apr;
Beher, D., C. Elle, J. Underwood, J.B. Davis, R. Ward, E. Karran, C.L.
Masters, K. Beyreuther, and G. Multhaup. 1999. Proteolytic fragments of
Alzheimer's disease-associated presenilin 1 are present in synaptic organelles
and growth cone membranes of rat brain. J Neurochem. 199 Apr; 72:1564-73.
Bruening, W., J. Roy, B. Giasson, D.A. Figlewicz, W.E. Mushynski, and
H.D. Durham. 1999. Up-regulation of protein chaperones preserves viability
of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated
with amyotrophic lateral sclerosis. J Neurochem. 1999 Feb;72:693-9.
Efthimiopoulos, S., E. Floor, A. Georgakopoulos, J. Shioi, W. Cui, S.
Yasothornsrikul, V.Y. Hook, T. Wisniewski, L. Buee, and N.K. Robakis. 1998.
Enrichment of presenilin 1 peptides in neuronal large dense-core and somatodendritic
clathrin-coated vesicles. J Neurochem. 1998 Dec; 71:2365-72. Abstract.
Fastbom, J., Y. Forsell, and B. Winblad. 1998. Benzodiazepines may have
protective effects against Alzheimer disease. Alzheimer Dis Assoc Disord.
12:14-7. No abstract available.
Georgakopoulos, A., P. Marambaud, S. Efthimiopoulos, J. Shioi, W. Cui,
H.C. Li, M. Schutte, R. Gordon, G.R. Holstein, G. Martinelli, P. Mehta,
V.L. Friedrich, Jr., and N.K. Robakis. 1999. Presenilin-1 forms complexes
with the cadherin/catenin cell-cell adhesion system and is recruited to
intercellular and synaptic contacts. Mol Cell.1999 Dec; 4:893-902.
Guo, Q., K. Furukawa, B.L. Sopher, D.G. Pham, J. Xie, N. Robinson, G.M.
Martin, and M.P. Mattson. Alzheimer's PS-1 mutation perturbs calcium homeostasis
and sensitizes PC12 cells to death induced by amyloid beta-peptide. Neuroreport.
1996 Dec 20; 8:379-83. Abstract.
Guo, Q., W. Fu, B.L. Sopher, M.W. Miller, C.B. Ware, G.M. Martin, and
M.P. Mattson. 1999a. Increased vulnerability of hippocampal neurons to excitotoxic
necrosis in presenilin-1 mutant knock-in mice. Nat Med. 1999 Jan;5:101-6.
Guo, Q., L. Sebastian, B.L. Sopher, M.W. Miller, C.B. Ware, G.M. Martin,
and M.P. Mattson. Increased vulnerability of hippocampal neurons from presenilin-1
mutant knock-in mice to amyloid beta-peptide toxicity: central roles of
superoxide production and caspase activation. J Neurochem. 1999 Mar;
Haass, C., and E. Mandelkow. Proteolysis by presenilins and the renaissance
of tau. Trends Cell Biol. 1999 Jun; 9:241-4. Abstract.
Katayama, T., K. Imaizumi, N. Sato, K. Miyoshi, T. Kudo, J. Hitomi, T.
Morihara, T. Yoneda, F. Gomi, Y. Mori, Y. Nakano, J. Takeda, T. Tsuda, Y.
Itoyama, O. Murayama, A. Takashima, P. St George-Hyslop, M. Takeda, and
M. Tohyama. Presenilin-1 mutations downregulate the signalling pathway of
the unfolded-protein response. Nat Cell Biol. 1999 Dec;1:479-485.
Lah, J.J., C.J. Heilman, N.R. Nash, H.D. Rees, H. Yi, S.E. Counts, and
A.I. Levey. Light and electron microscopic localization of presenilin-1
in primate brain. J Neurosci. 1997 Mar; 17:1971-80. Abstract.
Niwa, M., C. Sidrauski, R.J. Kaufman, and P. Walter. A role for presenilin-1
in nuclear accumulation of Ire1 fragments and induction of the mammalian
unfolded protein response. Cell. 1999 Dec 23; 99:691-702. Abstract.
Parent, A., D.J. Linden, S.S. Sisodia, and D.R. Borchelt. Synaptic transmission
and hippocampal long-term potentiation in transgenic mice expressing FAD-linked
presenilin 1. 1999 Feb; Neurobiol Dis. 6:56-62. Abstract.
Sato, N., Imaizumi, K., Manabe, T., Taniguchi, M., Hitomi, Y., Takagi,
T., Kudo, T., Tsuda, T., Itoyama, Y., Makifuchi, T., Fraser, P., St. George-Hyslop,
P., and Tohyama, M. (2000). Increased production of b-amyloid and vulnerability
to ER stress by an aberrant spliced form of presenilin-2. J Biol Chem. 2000
Oct 12 . Abstract.
Sato, N., Urano, F., Leem, J.-Y., Kim, S.-H., Li, M., Donoviel, D., Bernstein,
A., Lee, A., Ron, D., Veselits, M., Sisodia, S., and Thinakaran, G. (2000).
Upregulation of BiP and CHOP by the unfolded-protein response is independent
of presenilin expression. Nature Cell Biol Dec 2000. 2 (12) 863-870. Abstract.
Shen, J., R.T. Bronson, D.F. Chen, W. Xia, D.J. Selkoe, and S. Tonegawa.
Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997
May 16; 89:629-39. Abstract.
Takashima, A., M. Murayama, O. Murayama, T. Kohno, T. Honda, K. Yasutake,
N. Nihonmatsu, M. Mercken, H. Yamaguchi, S. Sugihara, and B. Wolozin. Presenilin
1 associates with glycogen synthase kinase-3beta and its substrate tau.
Proc Natl Acad Sci U S A. 1998 Aug 4; 95:9637-41. Abstract.
Welihinda, A.A., W. Tirasophon, and R.J. Kaufman. 1999. The cellular
response to protein misfolding in the endoplasmic reticulum. Gene Expr.
Wong, T.P., T. Debeir, K. Duff, and A.C. Cuello. 1999. Reorganization
of cholinergic terminals in the cerebral cortex and hippocampus in transgenic
mice carrying mutated presenilin-1 and amyloid precursor protein transgenes.
J Neurosci. 19:2706-16. Abstract.
Yang, Y., R.S. Turner, and J.R. Gaut. 1998. The chaperone BiP/GRP78 binds
to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion.
J Biol Chem. 273:25552-5. Abstract.
Zaman, S.H., A. Parent, A. Laskey, M.K. Lee, D.R. Borchelt, S.S. Sisodia,
and R. Malinow. 2000. Enhanced synaptic potentiation in transgenic mice
expressing presenilin 1 familial Alzheimer's disease mutation is normalized
with a benzodiazepine. Neurobiol Dis. 7:54-63. Abstract.
Zhang, Z., H. Hartmann, V.M. Do, D. Abramowski, C. Sturchler-Pierrat,
M. Staufenbiel, B. Sommer, M. van de Wetering, H. Clevers, P. Saftig, B.
De Strooper, X. He, and B.A. Yankner. 1998. Destabilization of beta-catenin
by mutations in presenilin-1 potentiates neuronal apoptosis. Nature.
Submit a Comment on this Live Discussion