| Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer
Research
Volume 5, Number 2, April 2008
Contents
Editorial:
Production and Fate of Amyloid Peptides: Recent Advances and
Perspectives Pp. 90-91
Frederic Checler
Processing of Amyloid Precursor Protein
and Amyloid Peptide Neurotoxicity Pp. 92-99
Pierrot Nathalie and Octave Jean-Noël
[Abstract]
BACE1 Structure and Function in Health and Alzheimer’s
Disease Pp. 100-120
Sarah L. Cole and Robert Vassar
[Abstract]
Memapsin 2 (Beta-Secretase) Inhibitors: Drug
Development Pp. 121-131
Arun K. Ghosh, Nagaswamy Kumaragurubaran, Ling Hong, Gerald
Koelsh and Jordan Tang
[Abstract]
Assembly, Maturation, and Trafficking of the
γ -Secretase
Complex in Alzheimer’s Disease Pp. 132-146
Daniel R. Dries and Gang Yu
[Abstract]
The Catalytic Core of γ
-Secretase: Presenilin Revisited Pp. 147-157
Harald Steiner
[Abstract]
γ
-Secretase Inhibition and Modulation for Alzheimer’s
Disease Pp. 158-164
Michael S. Wolfe
[Abstract]
ε-Secretase:
Reduction of Amyloid Precursor Protein ε-Site
Cleavage in Alzheimer’s Disease Pp. 165-171
Fuyuki Kametani
[Abstract]
From Presenilinase to γ-Secretase,
Cleave to Capacitate Pp. 172-178
Weiming Xia
[Abstract]
A Closer Look at α
-Secretase Pp. 179-186
Rolf Postina
[Abstract]
Part-Time α
-Secretases: The Functional Biology of ADAM 9, 10 and
17 Pp. 187-201
Miriam Deuss, Karina Reiss and Dieter Hartmann
[Abstract]
Regulation of β
APP and PrPc
Cleavage by α-Secretase:
Mechanistic and Therapeutic Perspectives Pp. 202-211
Bruno Vincent, Moustapha Alfa Cisse, Claire Sunyach, Marie-Victoire
Guillot-Sestier and Frédéric Checler
[Abstract]
Amyloid-Degrading Enzymes as Therapeutic Targets
in Alzheimer’s Disease Pp. 212-224
Natalia N. Nalivaeva, Lilia R. Fisk, Nikolai D. Belyaev
and Anthony J. Turner
[Abstract]
Neprilysin and Amyloid Beta Peptide Degradation
Pp. 225-231
Louis B. Hersh and David W. Rodgers
[Abstract]
Abstracts
[Back to top]
Editorial:
Production and Fate of Amyloid Peptides: Recent Advances and
Perspectives
Frederic Checler
[Back to top]
Processing of Amyloid Precursor Protein and Amyloid Peptide
Neurotoxicity
Pierrot Nathalie and Octave Jean-Noël
Alzheimer’s disease is characterized by the presence
of two types of lesions in brain: neurofibrillary tangles
and senile plaques. Intraneuronal neurofibrillary tangles
are made of paired helical filaments containing hyperphosphorylated
microtubule associated protein tau. Extracellular senile plaques
contain a core of beta-amyloid peptide (A
β ), which is produced by cleavage of the Amyloid
Precursor Protein (APP). Among the two catabolic pathways
of APP, the amyloi-dogenic pathway producing Aβ
peptides was intensively studied in different cellular models
expressing human APP. Differences in APP processing and in
toxicity resulting from Aβ
accumulation can be observed from one cell type to another.
In particular, primary cultures of neurons process APP differently
compared with other cultured cells including neuronal cell
lines. Neurons accumulate intraneuronal Aβ,
which is neurotoxic, and in these cells, APP can be phosphorylated
at specific residues. Recent studies suggest that APP phosphorylation
can play an important role in its amyloidogenic processing.
In addition, protein kinases that phosphorylate APP are also
able to phosphorylate the neuronal protein tau. Biochemical
analysis of these two proteins in primary cultures of neurons
show that phosphorylation of both APP and tau can be a factor
linking the two characteristic lesions of Alzheimer’s
disease.
[Back to top]
BACE1 Structure and Function in Health and Alzheimer’s
Disease
Sarah L. Cole and Robert Vassar
Amyloid plaques, hallmark neuropathological lesions in
Alzheimer’s disease (AD) brain, are composed of the
β-amyloid
peptide (Aβ).
Much evidence suggests that Aβ
is central to the pathophysiology of AD and is likely to play
an early role in this intractable neurodegenerative disorder.
Given the strong correlation between Aβ
and AD, therapeutic strategies to lower cerebral Aβ
levels should prove beneficial for AD treatment. Aβ
is derived from amyloid precursor protein (APP) via cleavage
by two proteases, β-
and γ-secretase.
The β-secretase
has been identified as a novel aspartic protease named BACE1
(β-site
APP Cleaving Enzyme 1) that initiates
Aβ
formation. Importantly, BACE1 appears to be dysregulated in
AD. As the rate-limiting enzyme in Aβ
generation, BACE1, in principle, is an excellent therapeutic
target for strategies to reduce the production of Aβ
in AD. While BACE1 knockout (BACE1-/-) mice have
been instrumental in validating BACE1 as the authentic β-secretase
in vivo, data indicates that complete abolishment of
BACE1 may be associated with specific behavioral and physiological
alterations. Recently a number of non-APP BACE1 substrates
have been identified. It is plausible that failure to process
certain BACE1 substrates may underlie some of the reported
abnormalities in the BACE1-/- mice. Here we review
the basic biology of BACE1, focusing on the regulation, structure
and function of this enzyme. We pay special attention to the
putative function of BACE1 during normal conditions and discuss
in detail the relationship that exists between key risk factors
for AD and the pathogenic alterations in BACE1 that are observed
in the diseased state.
[Back to top]
Memapsin 2 (Beta-Secretase) Inhibitors: Drug Development
Arun K. Ghosh, Nagaswamy Kumaragurubaran, Ling Hong, Gerald
Koelsh and Jordan Tang
Memapsin 2 (β-secretase,
BACE 1) processing of β-amyloid
precursor protein is the first step in the pathway leading
to the production of amyloid-β
, thus, it is a major target for the development of inhibitor
drug for the treatment of Alzheimers’s Disease. Although
there are distinctive advantages of this protease as a drug
target, the development of drug-like memapsin 2 inhibitors
has been somewhat slow since the cloning of the protease seven
years ago. Here we review the progress of memapsin 2 inhibitor
development using crystal structure-based design cycles. Recent
progress has evolved the inhibitors into sizes sufficiently
small to penetrate cell membranes and the blood-brain barrier
yet retain potency for the inhibition of Aβ
production in cultured cells and experimental animals. Such
progress lends optimism that clinically useful memapsin 2
inhibitors will eventually be developed.
[Back to top]
Assembly, Maturation, and Trafficking of the γ-Secretase
Complex in Alzheimer’s Disease
Daniel R. Dries and Gang Yu
In this review, we discuss the biology of γ-secretase,
an enigmatic enzyme complex that is responsible for the generation
of the amyloid-β
peptide that constitutes the amyloid plaques of Alzheimer’s
disease. We begin with a brief review on the processing of
the amyloid precursor protein and a brief discussion on the
family of enzymes involved in regulated intramembrane proteolysis,
of which γ-secretase
is a member. We then identify the four major components of
the γ-secretase
complex – presenilin, nicastrin, Aph-1, and Pen-2 –
with a focus on the identification of each and the role that
each plays in the maturation and activity of the complex.
We also discuss two new proteins that may play a role in modulating
the assembly and activity of the γ-secretase
complex. Next, we summarize the known subcellular locations
of each γ-secretase
component and the sites of
γ-secretase activity, as defined by the production
of A β.
Finally, we close by synthesizing all of the included topics
into an overarching model for the assembly and trafficking
of the γ-secretase
complex, which serves as a launching point for further questions
into the biology and function of γ-secretase
in Alzheimer’s disease.
[Back to top]
The Catalytic Core of γ-Secretase:
Presenilin Revisited
Harald Steiner
Mutations in the presenilin 1 (PS1) gene are the major
cause of familial Alzheimer´s disease (AD). They effect
an increased production of the highly neurotoxic 42 amino
acid variant of the amyloid-β
peptide (A β),which
is believed to initiate the disease. A
β is the product of two consecutive cleavages
of the β-amyloid
precursor protein (APP) by two proteases, β-secretase
and γ-secretase.
The latter enzyme has been identified as an intramembrane-cleaving
multiprotein complex that apart from APP cleaves a large number
of other type I transmembrane proteins. PS1 and its homologue
PS2 are essential for
γ-secretase cleavage and more than a decade after
their discovery it is now firmly established that they function
as catalytic subunits of γ-secretase.
This review recapitulates the findings that led to this conclusion
as well as the further progress made on the function of PS
as γ-secretase
since then.
[Back to top]
γ-Secretase Inhibition and Modulation for Alzheimer’s
Disease
Michael S. Wolfe
γ-Secretase
is a multi-protein complex that proteolyzes the transmembrane
region of the amyloid β
-peptide (Aβ)
precursor (APP),producing the A
β peptide implicated in the pathogenesis of Alzheimer’s
disease (AD). This protease has been a top target for AD,
and various inhibitors have been identified, including transitionstate
analogue inhibitors that interact with the active site, helical
peptides that interact with the initial substrate docking
site, and other less peptidelike, more drug-like compounds.
Although one γ-secretase
inhibitor has advanced into late-phase clinical trials, concerns
about inhibiting this protease remain. The protease complex
cleaves a number of other substrates, and in vivo
toxicities observed with γ-secretase
inhibitors are apparently due to blocking one particularly
important substrate, the Notch receptor. Thus, the potential
of γ-secretase
as therapeutic target likely depends on the ability to selectively
inhibit Aβ
production without hindering Notch proteolysis (i.e, modulation
rather than inhibition). The discovery of γ-secretase
modulators has revived γ-secretase
as an attractive target and has so far resulted in one compound
in late-phase clinical trials. The identification of other
modulators in a variety of structural classes raise the hope
that more promising agents will soon be in the pipeline.
[Back to top]
ε-Secretase:
Reduction of Amyloid Precursor Protein ε-Site
Cleavage in Alzheimer’s Disease
Fuyuki Kametani
The accumulation and deposition of fibrillar Aβ
is thought the primary cause of Alzheimer's disease (AD).
Aβ
is generated by sequential proteolytic processing involving
β-
and γ-secretase
on Amyloid β
protein precursor (APP). Recently, γ-secretase
was shown to cleave near the cytoplasmic membrane boundary
of APP, called ε-site
cleavage, as well as in the middle of the membrane domain,
called γ-site
cleavage. Recent findings indicate that γ-
and ε-site
cleavage are regulated independently. In this review, the
reduction of ε-site
cleavage in AD and the importance of ε
-site cleavage are discussed.
[Back to top]
From Presenilinase to γ-Secretase,
Cleave to Capacitate
Weiming Xia
Mutations in two genes, presenilin 1 (PS1) and its homologue
presenilin 2 (PS2), account for a majority of early onset
familial Alzheimer disease cases which are characterized by
intracellular neurofibrillary tangles and extracellular amyloid
fibrils composed of the amyloid β
protein (Aβ).
Aβ
is derived from sequential cleavages of Amyloid Precursor
Protein (APP) by β-secretase
and γ-secretase,
the latter is composed of four components, PS1, nicastrin
(NCT), presenilin enhancer 2 (PEN-2), and anterior pharynx
defective (APH-1). These components not only maintain the
stability of the γ-secretase
complex but also regulate the activity of presenilinase, the
protease responsible for the cleavage of full length PS1 into
N-terminal and C-terminal fragments (NTF/CTF). We have previously
shown that endoproteolysis of PS1 into NTF/CTF by presenilinase
requires two critical aspartate residues, suggesting that
PS1 may undergo autoproteolysis; full length PS1 complexes
with NCT, PEN-2, APH-1 and forms the presenilinase. While
these two aspartate residues are necessary for the endoproteolysis
of full length PS1, they are equally critical for the γ-secretase
cleavage of multiple substrates, and it is hypothesized that
the full length PS1/presenilinase is the zymogen of γ-secretase.
The inhibition profiles of presenilinase and γ-secretase
are illustrated by their biochemical similarity but are pharmacologically
distinct. Since the uncleaved PS1 loop may obstruct the entry
of γ
-secretase substrates to the docking site of the γ-secretase
complex, investigation of presenilinase inhibitors interfering
with substrate-docking may facilitate a novel approach to
identify APP specific γ-secretase
inhibitors.
[Back to top]
A Closer Look at α-Secretase
Rolf Postina
Accumulation of amyloid β
-peptides (Aβ)
in the brain is believed to contribute to the development
of Alzheimer disease (AD). Aβ,
a 40-42 amino acid-comprising proteolytical fragment of the
amyloid precursor protein (APP), is released from APP by sequential
cleavages via β-
and γ-secretases.
However, the predominant route of APP processing consists
of successive cleavages by α-
and γ-secretases.
Alpha secretase attacks APP inside the Aβ
sequence, and therefore prevents formation of neurotoxic Aβ.
After cleavage by α-secretase,
the solub N-terminal domain of APP, which possesses neurotrophic
and neuroprotective properties, is released. In AD patients,
a decrease in α
secretase processing of APP has been found and therefore,
strategies to improve α
-secretase activity are obvious.
Several years after descriptive reports on α-secretase,
the responsible enzymes have been identified to belong to
the family of A Disintegrin And Metalloproteinase (ADAM).
Three of these membrane-anchored zinc-dependent metalloproteinases,
ADAM10 as well as ADAM17 and presumably also ADAM9 display
α-secretase
activity. Since the individual knock-out of these proteinases
in neither case completely prevented α-secretase
processing of APP, it seems likely that different ADAMs are
compensating mutually, and under different conditions may
contribute to α-secretase
cleavage of APP. In addition to ADAMs, perhaps other membrane-associated
metalloproteinases contribute to the shedding of APP.
Stimulation of α-secretase
activities can be achieved via several signaling cascades
including phospholipase C, phosphatidylinositol 3 kinase and
serine/threonine-specific kinases such as protein kinases
C, and mitogen activated protein kinases. Direct activation
of protein kinase C and stimulation of distinct G protein-coupled
receptors are known to increase
α-secretase processing of APP. Agonists for M1
muscarinic acetylcholine receptors and serotonin 5-HT4 receptors
are currently in clinical trials to test their efficiency
in the treatment of AD.
[Back to top]
Part-Time α-Secretases:
The Functional Biology of ADAM 9, 10 and 17
Miriam Deuss, Karina Reiss and Dieter Hartmann
Disintegrin metalloproteases of the ADAM family form
a large (at present > 40 members in mammals) family of
multidomain membrane proteins that in their ectodomain combine
a cystein-rich, disintegrin and a zinc metalloprotease domain.
Via their metalloprotease domain, ADAMs are often implicated
in ectodomain shedding, either to release e.g. growth factors
or to initiate further intracellular signalling via regulated
intramembrane proteolysis. Mainly based upon overexpression
studies in vehicle cells, three of them, ADAMs 9, 10 and 17,
have been proposed to act as α-secretases
for amyloid precursor protein (APP). It is striking thereby
that this role has since then remained somewhat ill-defined,
as APP processing in ADAM9 deficient neurons is unaltered,
and also ADAM10 deficient murine embryonic fibroblasts exhibit
at best a highly variable reduction in α-secretase
activity.
However, during the past years, numerous other substrates
have been linked to all three sheddases, the cleavage of which
in some cases appears to be strikingly more important for
the organism than APP processing. Most notably, the perinatally
lethal phenotype of ADAM17 knockout mice is dominated by a
loss of growth factor shedding, while the even earlier fatal
effects of ADAM10 deficiency exhibit key features of disabled
Notch signalling and possibly also cadherin processing defects.
In this review, we will summarize the published data on the
“non-APP” functions of all three ADAMs, the further
evaluation of which may be crucial when attempting to treat
Alzheimer´s Disease by increasing their expression and/or
activity. As the knockouts of ADAM10 and ADAM17 are only informative
for their roles in (early) development, while a number of
recently assigned new substrates play crucial roles in the
normal and/or diseased adult organism as well, work on conditional
knockout models will be crucial to fully characterize both
the full functional portfolio of (candidate) α-secretases
as well as their clinical relevance, which may go way beyond
Alzheimer´s Disease.
[Back to top]
Regulation of βAPP
and PrPc
Cleavage by α-Secretase:
Mechanistic and Therapeutic Perspectives
Bruno Vincent, Moustapha Alfa Cisse, Claire Sunyach, Marie-Victoire
Guillot-Sestier and Frédéric Checler
Alzheimer's disease (AD) is by far the most common form
of dementia in the elderly and concerns one out of three individuals
over 85. Like other neurodegenerative disorders such as Parkinson,
Hungtington or prion diseases, AD is characterized by the
formation of amyloid plaques in the central nervous system.
In the brain of AD patients, the main component of these abnormal
deposits is an aggregated form of the so-called amyloid β-peptide
(Aβ),
which is produced from a large trans-membrane type-1 protein,
the β-amyloid
precursor protein (βAPP),
by the sequential action of the β
- and γ-secretases.
Beside these two amyloidogenic proteolytic attacks, β
APP is targeted by a third enzyme termed α-secretase.
Of utmost importance, this cleavage, which can be of constitutive
or regulated origin, occurs right in the middle of the Aβ
sequence, thus precluding its production. For this reason,
and because the sAPP
α-secreted fragment derived from this cleavage
displays beneficial effects, tremendous efforts have been
made recently in order to both identify the proteases involved
and the way they are regulated. More recently, it emerged
that α-secretase
was also responsible for the physiological processing of the
cellular prion protein (PrPc) in the middle of
its toxic 106-126 sequence. This review will focus on the
recent advances in the α-secretase
pathways regulation and will discuss the putative therapeutic
approaches that could be envisioned concerning the treatment
of two apparently distinct diseases that share common denominators
according to their metabolism.
[Back to top]
Amyloid-Degrading Enzymes as Therapeutic Targets in Alzheimer’s
Disease
Natalia N. Nalivaeva, Lilia R. Fisk, Nikolai D. Belyaev
and Anthony J. Turner
The steady state concentration of the Alzheimer's amyloid-β
peptide in the brain represents a balance between its biosynthesis
from the transmembrane amyloid precursor protein (APP), its
oligomerisation into neurotoxic and stable species and its
degradation by a variety of amyloid-degrading enzymes, principally
metallopeptidases. These include, among others, neprilysin
(NEP) and its homologue endothelin-converting enzyme (ECE),
insulysin (IDE), angiotensin-converting enzyme (ACE) and matrix
metalloproteinase-9 (MMP-9). In addition, the serine proteinase,
plasmin, may participate in extracellular metabolism of the
amyloid peptide under regulation of the plasminogen-activator
inhibitor. These various amyloid-degrading enzymes have distinct
subcellular localizations, and differential responses to aging,
oxidative stress and pharmacological agents and their upregulation
may provide a novel and viable therapeutic strategy for prevention
and treatment of Alzheimer's disease. Potential approaches
to manipulate expression levels of the key amyloid-degrading
enzymes are highlighted.
[Back to top]
Neprilysin and Amyloid Beta Peptide Degradation
Louis B. Hersh and David W. Rodgers
Neprilysin is a zinc metalloendopeptidase with relatively
broad substrate specificity. The enzyme is localized to the
plasma membrane of cells where it can function to degrade
extracellular peptides. Structural studies show that neprilysin
preferentially cleaves peptides on the amino side of hydrophobic
amino acids. Neprilysin has been implicated in the catabolism
of amyloid β
peptides in the brain and as such has received considerable
attention, particularly as a therapeutic target for Alzheimer’s
disease. An inverse relationship between neprilysin levels
and amyloid β
peptide levels and between neprilysin levels and amyloid plaque
formation has been observed in human brain. Neprilysin levels
decline with aging in the temporal and frontal cortex possibly
contributing to higher amyloid β
peptide levels. A number of studies have shown that increasing
neprilysin levels in the brain leads to a decrease in brain
amyloid β
peptide levels. Most recently a potential relationship between
amyloid β
peptide synthesis from the amyloid precursor protein and neprilysin
activity has been proposed.
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