| Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer
Research
Volume 4, Number 5, December 2007
Contents
Drug Discovery for
Alzheimer’s Disease: Filling the Pipeline
Guest Editors: Antony R. Horton and Howard M. Fillit
Section I – Neuroprotection
Editorial:
Drug Discovery for Alzheimer’s Disease:
Filling the Pipeline Pp. 501-502
Antony R. Horton and Howard M. Fillit
Small Molecule Neurotrophin Receptor Ligands: Novel Strategies
for Targeting Alzheimer’s Disease Mechanisms
Pp. 503-506
Frank M. Longo, Tao Yang, Juliet K. Knowles,
Youmei Xie, Laura A. Moore and Stephen M. Massa
[Abstract]
NAP, A Neuroprotective Drug Candidate in Clinical Trials,
Stimulates Microtubule Assembly in the Living Cell Pp.
507-509
Illana Gozes and Inna Divinski
[Abstract]
Regeneration in a Degenerating Brain: Potential of Allopregnanolone
as a Neuroregenerative Agent Pp. 510-517
Jun Ming Wang, Ronald W. Irwin, Lifei Liu, Shuhua Chen and
Roberta Diaz Brinton
[Abstract]
Oligomers of β-Amyloid
Peptide Inhibit BDNF-Induced Arc Expression in Cultured Cortical
Neurons Pp. 518-521
Valentine Echeverria, Diego E. Berman and Ottavio Arancio
[Abstract]
Novel Multifunctional Anti-Alzheimer Drugs with
Various CNS Neurotransmitter Targets and Neuroprotective Moieties
Pp. 522-536
Cornelis J. Van der Schyf, Silvia Mandel, Werner J. Geldenhuys,
Tamar Amit, Yael Avramovich, Hailin Zheng, Mati Fridkin, Shunit
Gal, Orly Weinreb, Orit Bar Am, Yotam Sagi and Moussa B.H.
Youdim
[Abstract]
Detrimental Effects of Apolipoprotein E4: Potential
Therapeutic Targets in Alzheimer’s Disease
Pp. 537-540
Robert W. Mahley, Yadong Huang and Karl H. Weisgraber
[Abstract]
APP Based Neuroprotective Strategies Pp.
541-543
Dale E. Bredesen and Shahrooz Rabizadeh
[Abstract]
Section II – Anti-Tangles and Other Mechanisms
Inhibition of Tau Aggregation in Cell Models of Tauopathy
Pp. 544-546
Inna Khlistunova, Marcus Pickhardt, Jacek Biernat, Yipeng
Wang, Eva-Maria Mandelkow and Eckhard. Mandelkow
[Abstract]
New Approaches to the Discovery of cdk5 Inhibitors
Pp. 547-549
Marcie A. Glicksman, Gregory D. Cuny, Min Liu, Brittany Dobson,
Kenneth Auerbach, Ross L. Stein and Kenneth S. Kosik
[Abstract]
Perispinal Etanercept for Treatment of Alzheimer’s
Disease Pp. 550-552
Edward Tobinick
[Abstract]
Section III – Anti-Amyloid
Memory Improvement with Docosahexaenoic Acid
Study (MIDAS)-Brief Review Pp. 553-555
Karin Yurko-Mauro
[Abstract]
Is Alpha-Synuclein Pathology
a Target for Treatment of Neurodegenerative Disorders?
Pp. 556-561
Manfred Windisch, Hans-Jörg Wolf, Birgit Hutter-Paier
and Robert Wronski
[Abstract]
Discovery of ADDL-Targeting Small Molecule Drugs
for Alzheimer’s Disease Pp. 562-567
Gary C. Look, Jasna Jerecic, Diana B. Cherbavaz, Todd R. Pray,
Jean-Claude R. Breach, Walter J. Crosier, Lev Igoudin, Catherine
M. Hironaka, Raymond M. Lowe, Michele McEntee, Lily Ruslim-Litrus,
Hsiu-Mei Wu, Sue Zhang, Susan M. Catalano, William F. Goure,
David Summa and Grant A. Krafft
[Abstract]
Nogo Receptor Interacts with Brain APP and Aβ
to Reduce Pathologic Changes in Alzheimer’s Transgenic
Mice Pp. 568-570
James H. Park and Stephen M. Strittmatter
[Abstract]
γ-Secretase
Modulators Pp. 571-573
Michael S. Wolfe
[Abstract]
Section IV – Cognitive Enhancement
A New Model for Academics Based Drug Discovery
Pp. 574-576
Ross L. Stein
[Abstract]
M1 Muscarinic Agonists Target Major Hallmarks
of Alzheimer's Disease – an Update Pp.
577- 580
Abraham Fisher
[Abstract]
Cytotoxicity of Aβ1-42,
RAGE23-54, and An Aβ-RAGE
Complex in PC-12 Cells Pp. 581-586
Shyamala Mruthinti, Nicholas Capito, Ajay Sood and Jerry J.
Buccafusco
[Abstract]
Abstracts
[Back to top]
Small Molecule Neurotrophin Receptor Ligands:
Novel Strategies for Targeting Alzheimer’s Disease Mechanisms
Frank M. Longo, Tao Yang, Juliet K. Knowles, Youmei Xie, Laura
A. Moore and Stephen M. Massa
A number of factors limit the therapeutic application
of neurotrophin proteins, such as nerve growth factor (NGF)
and brain-derived growth factor (BDNF), for Alzheimer’s
and other neurodegenerative diseases. These factors include
unfavorable pharmacological properties typical of proteins
and the pleiotropic effects mediated by protein-ligand interactions
with p75NTR
Trk, and sortilin neurotrophin receptors. Targeted modulation
of p75NTR
provides a strategy for preventing degeneration without promoting
TrkA-mediated deleterious effects, and targeted activation
of TrkB might achieve more favorable neurotrophic effects
than those achieved by concomitant activation of p75NTR
and TrkB. The discovery of small molecules functioning as
ligands at specific neurotrophin receptors has made possible
for the first time approaches for modulating selected components
of neurotrophin signaling processes for the purpose of modulating
underlying Alzheimer’s disease mechanisms.
[Back to top]
NAP, A Neuroprotective Drug Candidate
in Clinical Trials, Stimulates Microtubule Assembly in the
Living Cell
Illana Gozes and Inna Divinski
NAP (NAPVSIPQ), derived from activity-dependent
neuroprotective protein (ADNP) provides neuroprotection in
vitro and in vivo against a wide variety of
neurotoxic substances. To further understand the mechanism
by which NAP provides broad neuroprotection it was essential
to find NAP’s binding partners. Previous results, using
affinity chromatography coupled with mass spectrometry, identified
tubulin, the subunit protein of microtubules, as the major
NAP binding protein in neurons and glial cells. Here, following
microtubule depolymerization in the presence of nocodazole,
NAP treatment enhanced rapid microtubule assembly and stimulated
neurite outgrowth. Nocodazole is an established inhibitor
of axoplasmic transport and cell division that exerts its
effect by depolymerizing microtubules. NAP shows selectivity
in interacting with brain tubulin and does not affect dividing
cells. This data demonstrates that NAP functions as a neuroprotectant,
at least in part, through its interaction with tubulin with
a resulting increase in microtubule assembly.
[Back to top]
Regeneration in a Degenerating Brain:
Potential of Allopregnanolone as a Neuroregenerative Agent
Jun Ming Wang, Ronald W. Irwin, Lifei Liu, Shuhua Chen and
Roberta Diaz Brinton
Confronting the efficacy of a regenerative therapeutic
is the degenerative environment that is characterized by neuronal
loss, physical plague and glial scar barriers and inflammation.
But perhaps more fundamental from a regenerative perspective,
are changes in the biochemical milieu of steroid and peptide
growth factors, cytokines and neurotransmitter systems. Data
from multiple levels of analysis indicate that gonadal steroid
hormones and their metabolites can promote neural health whereas
their decline or absence are associated with decline in neural
health and increased risk of neurodegenerative disease including
Alzheimer’s. Among the steroids in decline, is allopregnanolone
(APα)
a neurosteroid metabolite of progesterone, which was found
to be reduced in the serum [1,2] and plasma [3] and brain
of aged vs. young subjects [4]. Further, Alzheimer disease
(AD) victims showed an even further reduction in plasma and
brain levels of APα
relative to age-matched neurologically normal controls [1,4,5].
Our earlier work has shown that APα
is a neurogenic agent for rodent hippocampal neural progenitors
and for human neural progenitor cells derived from the cerebral
cortex [6]. Our ongoing research seeks to determine the neurogenic
potential of APα
in the triple transgenic mouse model of Alzheimer’s
disease (3xTgAD) as AD related pathology progresses from imperceptible
to mild to severe. Initial analyses suggest that neurogenic
potential changes with age in nontransgenic mice and that
the neurogenic profile differs between non-transgenic and
3xTgAD mice. Comparative analyses indicate that APαmodifies
neurogenesis in both non-transgenic and 3xTgAD mice. Preliminary
data suggest that APα
may modify Alzheimer’s pathology progression. Together
the data indicate that APα
may maintain the regenerative ability of the brain and modify
progression of AD related pathology. Challenges for efficacy
of regenerative agents within a degenerative milieu are discussed.
[Back to top]
Oligomers of β-Amyloid
Peptide Inhibit BDNF-Induced Arc Expression in Cultured Cortical
Neurons
Valentine Echeverria, Diego E. Berman and Ottavio Arancio
The progressive memory loss observed in Alzheimer’s
disease (AD) is accompanied by an increase in the levels of
amyloid-β
peptide (Aβ)
and a block of synaptic plasticity. Both synaptic plasticity
and memory require changes in the expression of synaptic proteins
such as the activity-regulated cytoskeleton-associated protein,
Arc (also termed Arg3.1). Using a model of synaptic plasticity
in which BDNF increases Arc expression in cultured cortical
neurons, we have found that an oligomeric form of Aβ
strongly inhibits the BDNF-induced increase of Arc expression.
Given that Aβ
oligomers are likely to be involved in the synaptic dysfunction
and cognitive impairment observed in amyloid depositing mouse
models, we hypothesize that inhibition of Arc induction by
BDNF contributes to the synaptic and memory deficits at early
stages of AD.
[Back to top]
Novel Multifunctional Anti-Alzheimer Drugs
with Various CNS Neurotransmitter Targets and Neuroprotective
Moieties
Cornelis J. Van der Schyf, Silvia Mandel, Werner J. Geldenhuys,
Tamar Amit, Yael Avramovich, Hailin Zheng, Mati Fridkin, Shunit
Gal, Orly Weinreb, Orit Bar Am, Yotam Sagi and Moussa B.H.
Youdim
Traditionally, drug design programs are focused
on optimizing the specificity of lead compounds against a
carefully selected drug target. Disappointingly, this approach
to discover a “magic bullet” drug has not met
with the expected success for CNS disorders. Transcriptomics
and proteomic profiling of neurodegenerative diseases have
indicated that they are poly-etiological in origin and that
the processes leading to neuronal death are multifactorial.
An emerging concept is the design of drug ligands that modulate
multiple drug targets identified for a particular disease.
In this review we explore some examples of multifunctional
drugs which may be useful in the treatment of neurodegenerative
diseases, such as Alzheimer’s and Parkinson’s
disease.
[Back to top]
Detrimental Effects of Apolipoprotein E4:
Potential Therapeutic Targets in Alzheimer’s Disease
Robert W. Mahley, Yadong Huang and Karl H. Weisgraber
As the major genetic risk factor for Alzheimer’s
disease, the apolipoprotein (apo) E4 isoform is a promising
therapeutic target. ApoE4 likely contributes to Alzheimer’s
disease pathology by interacting with multiple factors through
various pathways. Interactions with the amyloid β
peptide and the amyloid cascade, for example, may lead to
cognitive decline and neurodegeneration. Alternatively, apoE4
might act independently of the amyloid β
peptide. Our working hypothesis is that apoE has isoform-specific
effects on neuronal repair and remodeling. One or more injurious
agents could result in neuronal damage, requiring neuronal
repair or remodeling. The injurious agents (or “second
hits”) may be genetic, metabolic, or environmental.
Potential therapeutic strategies include changing the structure
of apoE4 to be more apoE3-like, inhibiting the protease that
cleaves apoE4 into toxic fragments, and protecting mitochondria
from apoE4 toxicity. Structural features that distinguish
apoE4 and apoE3 determine their functional differences and
hold the key to understanding how apoE4 is involved in Alzheimer’s
disease.
[Back to top]
APP Based Neuroprotective Strategies
Dale E. Bredesen and Shahrooz Rabizadeh
While much of the focus on Alzheimer’s disease
therapeutics has been directed at beta-amyloid peptide or
at cholinergic synaptic transmission, recent data suggest
that targeting signal transduction by the amyloid precursor
protein (APP) itself may be an alternative approach with significant
potential [1]. Here we discuss the possibility that APP-mediated
signal transduction, downstream from amyloid-beta peptide
production itself, may be an appropriate therapeutic target
in Alzheimer’s disease.
[Back to top]
Inhibition of Tau Aggregation in Cell Models
of Tauopathy
Inna Khlistunova, Marcus Pickhardt, Jacek Biernat, Yipeng
Wang, Eva-Maria Mandelkow and Eckhard. Mandelkow
The pathological aggregation of tau into paired
helical filaments is a hallmark of several neurodegenerative
diseases, including Alzheimer's disease. We have generated
cell models of tau aggregation in order to study mechanisms
involving abnormal changes of tau. In the cell models the
repeat domain of tau (tauRD)
and some of its variants are expressed in a regulated fashion,
e.g. the 4-repeat domain of tau with the wild-type sequence,
the repeat domain with the ΔK280
mutation ("pro-aggregation mutant"), or the repeat
domain with additional proline mutations ("anti-aggregation
mutant"). The aggregation of tauRD
is toxic to the cells, but aggregation and toxicity can be
prevented by low molecular weight compounds identified by
a screen for inhibitors. Thus the cell models are suitable
for developing aggregation inhibitor drugs and testing their
cellular roles.
[Back to top]
New Approaches to the Discovery of cdk5
Inhibitors
Marcie A. Glicksman, Gregory D. Cuny, Min Liu, Brittany Dobson,
Kenneth Auerbach, Ross L. Stein and Kenneth S. Kosik
Cyclin-dependent kinase 5 (cdk5) is a member of
the serine-threonine kinase family of cyclin-dependent kinases.
This family is known for its role in the cell cycle, but cdk5
differs due to its interaction with activators p35 or p39,
both abundant in post-mitotic neurons. Cdk5 is not known to
have a role in cell cycle regulation at all, but is known
to be an important modulator of neuronal activity. Cdk5 has
been an attractive target for CNS diseases for a number of
years. Among its attractions is the possibility that inhibitors
will prevent the pathological phosphorylation of tau and neurofibrillary
pathology in both Alzheimer’s disease and tauopathies.
More recently, there has been evidence that cdk5 is involved
in the processing of pain and therefore inhibitors would also
have potential therapeutic value for acute pain. Several classes
of potent chemical inhibitors for cdk5 have been identified
but most are competitive with the ATP binding site, resulting
in a lack of specificity among the other cyclin-dependent
kinases as well as other ATP-dependent kinases. We are working
to discover specific inhibitors that might disrupt the interaction
of tau and cdk5 at sites other than the ATP binding site.
We are screening our compound library of 110,000 compounds
using the full length tau as a substrate and will separate
ATP competitive from non-competitive binders. In addition,
we are taking a computational approach with virtual screening
to identify non-ATP-competitive binders. These two approaches
may lead to the discovery of site-specific inhibitors for
tau and cdk5 interactions rather than competitive inhibitors
for ATP binding. The hope is that non-ATP competitive compounds
will more likely be selective and will be better therapeutics.
[Back to top]
Perispinal Etanercept for Treatment of
Alzheimer’s Disease
Edward Tobinick
Background: Increasing basic science and
clinical evidence implicates inflammatory processes and resulting
glial activation in the pathogenesis of Alzheimer’s
Disease. Excess TNF-alpha, a cytokine with pleotropic effects
in the CNS, has been suggested to be involved in the pathogenesis
of AD. In addition to its pro-inflammatory effects, TNF-alpha
affects synaptic transmission; and glutamate, NMDA, and amyloid
pathways. More specifically, TNF-alpha, produced by glia,
has been shown to affect both synaptic strength and to mediate
synaptic scaling, a homeostatic mechanism important to the
control of neural networks. A recently published small, open-label
pilot study suggested that inhibition of the inflammatory
cytokine TNF-alpha utilizing the perispinal administration
of etanercept may lead to sustained cognitive improvement
for six months in patients with mild, moderate, and severe
Alzheimer’s disease. Results: Continued open-label
clinical experience with this new treatment modality, now
for more than two years, suggests that weekly maintenance
treatment with perispinal etanercept may have a sustained
positive effect. In addition, rapid clinical improvement,
within minutes of dosing, has been observed on a repeated
basis in multiple patients. Discussion: It is hypothesized
that perispinal administration of etanercept may enable rapid
delivery to the CNS via the cerebrospinal venous system, resulting
in improvement in synaptic mechanisms which have been dysregulated
by excess TNF-alpha. TNF-alpha modulation in Alzheimer’s
disease may also act by influencing glutamate, NMDA, amyloid
and other inflammatory pathways. Methods of perispinal administration,
as described in the pilot study, may prove useful for delivering
other therapeutics, particularly large molecules, to the CNS.
Further study in randomized, placebo-controlled clinical trials
and in basic science studies is merited.
[Back to top]
Memory Improvement with Docosahexaenoic
Acid Study (MIDAS)-Brief Review
Karin Yurko-Mauro
A decline in memory and cognitive function is considered
to be a normal consequence of aging in humans. Age-related
cognitive decline is a term used to describe “older
persons with objective memory declines relative to their younger
years, but cognitive functioning that is normal relative to
their age peers.”1
Age-related cognitive decline (as defined in DSM-IV[1]) is
considered part of the normal aging process whereby individuals
may experience problems remembering names or difficulty solving
complex problems but is not attributable to a specific medical
or neurological condition. It is therefore different from
Mild Cognitive Impairment (MCI) which displays impairments
in neurocognitive functioning due to a general medical condition
and represents a decline from one’s previous level of
functioning, “is more severe or consistent … and
may indicate the early stages of a condition such as dementia.”2
The U.S. prevalence of age-related cognitive decline has been
estimated by one source at 144 million adults 40 years of
age and older.3 Given the
high prevalence of this condition and the impact which it
can have on one’s life, memory loss is a prominent health
concern for many Americans aged 55 and older. A recent national
survey released by the Alzheimer’s Association shows
that Americans 55-64 years old rank brain and memory health
as their second greatest health concern as they age, with
heart health being their top health concern.4
While some dietary and herbal supplements have been linked
to reducing the risks of cognitive dysfunction, the need for
a well-characterized, safe and effective nutritional product
for age-related cognitive decline remains great. Data from
various studies show a definite trend in increased supplement
use by individuals over age 60 in the last 15 years with higher
use among individuals with healthier lifestyles.5
Martek Biosciences Corporation (Martek) is investigating
docosahexaenoic acid (DHA, 22:6n-3), a long-chain omega-3
fatty acid, as a potential nutritional neuroprotective agent
for use in age-related cognitive decline. DHA plays an important
role in neural and visual development and cardiovascular health[2,
3] [4-7]. Dietary sources of DHA include fatty fish (e.g.
salmon, herring, tuna), organ meats (e.g. beef and chicken
liver), eggs, and nutritional oil supplements. A minor portion
of DHA is synthesized from its precursor, α-linolenic
acid (18:3n-3), but the majority of DHA utilized by the human
body comes from the diet. The average intake of DHA in the
American Western diet (~70mg/d) is relatively low compared
to many other countries [8].
[Back to top]
Is Alpha-Synuclein Pathology a Target for
Treatment of Neurodegenerative Disorders?
Manfred Windisch, Hans-Jörg Wolf, Birgit Hutter-Paier
and Robert Wronski
Since the discovery that mutations of alpha-synuclein
(AS) gene are responsible for rare forms of familiar Parkinson’s
disease this synaptic protein attracted increased interest.
AS is the main constituent of Lewy bodies. In spite the physiological
function is still unclear there is an ongoing discussion if
over-expression is already dangerous, or if toxicity is subjected
to oligomers, protofibrilles or mature aggregates. The fact
that the central hydrophobic part of AS is a constituent of
amyloid plaques in Alzheimer patients and the finding that
a majority of AD patients have Lewy bodies and Lewy neurites
in specific brain areas, raised our interest in the possible
contribution of AS to pathogenesis of AD. Beta-synuclein (βS)
a protein of the same gene family seems to be a naturally
occurring anti aggregatory factor preventing AS aggregation
in vitro and in vivo. The N-terminal amino
acid sequence 1 to 15 is responsible for this effect. Based
on this finding we synthesized a peptide library with different
sequence variations. Several of these peptides displayed distinct
neuroprotective activity in tissue culture models of neurodegeneration
induced by oxidative stress or Aβ1-42.
In spite these peptides have a short half-life, in vivo
significant reduction in brain plaque load and improvement
of behavioral deficits was demonstrated in an APP-tg mouse
model after intranasal treatment for 2 months. KEGV, the shortest
sequence was also active after intraperitoneal application.
Neuroprotective data in tissue cultures and results from transgenic
mice are some how in conflict because in vitro effects
can not be explained by the antiaggregatory potential, but
most likely by interaction of βS
derivates with anti-apoptotic PI3/Akt cell signaling or interference
with anti-oxidative pathways (JNK/JIB). The possibility that
such βS
derived peptidomimetics might act as neuroprotectants and
at the same time prevent protein missfolding suggests possible
therapeutic usefulness in different neurodegenerative disorders.
[Back to top]
Discovery of ADDL-Targeting Small Molecule
Drugs for Alzheimer’s Disease
Gary C. Look, Jasna Jerecic, Diana B. Cherbavaz, Todd R. Pray,
Jean-Claude R. Breach, Walter J. Crosier, Lev Igoudin, Catherine
M. Hironaka, Raymond M. Lowe, Michele McEntee, Lily Ruslim-Litrus,
Hsiu-Mei Wu, Sue Zhang, Susan M. Catalano, William F. Goure,
David Summa and Grant A. Krafft
Amyloid β-derived
diffusible ligands (ADDLs) comprise the neurotoxic subset
of soluble Aβ1-42
oligomers, now widely considered to be the molecular cause
of memory malfunction and neurodegeneration in Alzheimer’s
disease (AD). We have developed a screening cascade which
identifies small molecule modulators of ADDL-mediated neurotoxicity.
The primary screen involves a fluorescence resonance energy
transfer (FRET)-based assay which selects inhibitors of Aβ1-42
oligomer assembly. The identified hits were further characterized
by assessing their ability to inhibit the assembly and binding
of ADDLs to cultures of primary hippocampal neurons. This
approach has led to the identification of a number of small
molecules which inhibit ADDL assembly and their subsequent
binding to neurons. Here we describe our small molecule discovery
efforts to identify ADDL assembly blocker and ADDL binding
inhibitors, and to transform validated hits into pre-clinical
lead compounds.
[Back to top]
Nogo Receptor Interacts with Brain APP
and Aβ
to Reduce Pathologic Changes in Alzheimer’s Transgenic
Mice
James H. Park and Stephen M. Strittmatter
Pathophysiologic hypotheses for Alzheimer's disease
(AD) are centered on the role of the amyloid plaque Aβ
peptide and the mechanism of its derivation from the amyloid
precursor protein (APP). As part of the disease process, an
aberrant axonal sprouting response is known to occur near
Aβ
deposits. A Nogo to Nogo-66 receptor (NgR) pathway contributes
to determining the ability of adult CNS axons to extend after
traumatic injuries. Here, we consider the potential role of
NgR mechanisms in AD. Both Nogo and NgR are mislocalized in
AD brain samples. APP physically associates with the NgR.
Overexpression of NgR decreases Aβ
production in neuroblastoma culture, and targeted disruption
of NgR expression increases transgenic mouse brain Aβ
levels, plaque deposition, and dystrophic neurites. Infusion
of a soluble NgR fragment reduces Aβ
levels, amyloid plaque deposits, and dystrophic neurites in
a mouse transgenic AD model. Changes in NgR level produce
parallel changes in secreted APP and AB, implicating NgR as
a blocker of secretase processing of APP. The NgR provides
a novel site for modifying the course of AD and highlights
the role of axonal dysfunction in the disease.
[Back to top]
γ-Secretase
Modulators
Michael S. Wolfe
γ-Secretase
is responsible for the final cut of the amyloid β-peptide
(Aβ)
precursor (APP) to produce the Aβ
peptide implicated the pathogenesis of Alzheimer’s disease
(AD). Thus, this protease is a top target for the development
of AD therapeutics. γ-Secretase
is a complex of four different integral membrane proteins,
with the multi-pass presenilin being the catalytic component
of a novel intramembrane-cleaving aspartyl protease. γ-Secretase
cleaves other substrates besides APP, the most notorious being
the Notch receptor that is required for many cell differentiation
events. Because proteolysis of Notch by γ-secretase
is essential for Notch signaling, interference with this process
by γ-secretase
inhibitors can cause severe toxicities. Thus, the potential
of γ-secretase
as therapeutic target likely depends on the ability to selectively
inhibit Aβ
production without hindering Notch proteolysis. The discovery
of compounds capable of such allosteric modulation of the
protease activity has revived γ-secretase
as an attractive target. Structural modification of these
γ-secretase
modulators through medicinal chemistry should lead to
in vivo active agents suitable for clinical trials.
[Back to top]
A New Model for Academics Based Drug Discovery
Ross L. Stein
Drug discovery is a complex and costly endeavor, requiring
multidisciplinary know-how, interdisciplinary collaboration,
tenacity, and a bit of luck. For these reasons, the search
for new chemical agents to treat human disease has traditionally
been undertaken only within the walls of industry. While the
pharmaceutical industry is often successful where it focuses
its attention, it generally focuses only on those areas that
are allowed by corporate financial realities. Sadly, this
means that diseases effecting small populations of patients
may go untreated. As a society we should not be content with
this situation and must make a priority of the development
of new models that will allow and encourage drug discovery
in disease areas that are neglected by pharma. In this presentation,
I will describe one such model that has been established to
find treatments for neurodegenerative diseases.
[Back to top]
M1 Muscarinic Agonists Target Major Hallmarks
of Alzheimer's Disease – an Update
Abraham Fisher
The M1 muscarinic receptor (M1 mAChR), preserved
in Alzheimer's disease (AD), is a pivotal target that links
major hallmarks of AD, e.g. cholinergic deficiency, cognitive
dysfunctions, β-amyloid
(Aβ)
and tau pathologies. Some muscarinic agonists, while effective
in AD, had limited clinical value due to adverse effects and
lack of M1 selectivity. The M1 selective muscarinic agonists
AF102B [Cevimeline], AF150(S) and AF267B – i) elevated
αAPPs,
decreased Aβ
levels and tau hyperphosphorylation, and blocked Aβ-induced
neurotoxicity, in vitro, via M1 mAChR-modulation
of kinases (e.g. PKC, MAPK and GSK3β;
ii) restored cognitive deficits, cholinergic markers, and
decreased tau hyperphosphorylation in relevant models with
a wide safety margin. AF267B decreased brain Aβ
levels in hypercholesterolemic rabbits and decreased CSF Aβ42
in rabbits and removed vascular Aβ42
deposition from cortex in cholinotoxin-treated rabbits. In
3x transgenic-AD mice that recapitulate the major pathologies
and cognitive deficits of AD, chronic AF267B treatment rescued
cognitive deficits and decreased Aβ42
and tau pathologies in the cortex and hippocampus (not amygdala),
via M1 mAChR-activation of ADAM17/TACE and decreased
BACE1 steady state levels and inhibition of GSK3β,
extending findings from above. Conclusions: A comprehensive
therapy should target all AD hallmarks, regardless of the
culprit(s) responsible for the disease. In this context, AF267B
is the 1st reported low MW
CNS-penetrable mono-therapy that meets this challenge. Clinical
trials will determine if AF267B may become an important therapy
in AD.
[Back to top]
Cytotoxicity of Aβ1-42
RAGE23-54 and An Aβ-RAGE
Complex in PC-12 Cells
Shyamala Mruthinti, Nicholas Capito, Ajay Sood and Jerry J.
Buccafusco
The receptor for advanced glycation end products
(RAGE) binds amyloid peptides with high affinity. Soluble
RAGE-like peptides and Aβ-like
peptides occur in relatively high concentrations in the circulation
of individuals with Alzheimer’s disease. Protein complexes
with epitopes for both Aβ
and RAGE are also present. At physiological concentrations,
forms of Aβ
have different, but relatively low potencies as cytotoxicants
in neural cells in culture. The purpose of this study was
to determine whether a synthetic peptide complex composed
of Aβ1-42
and RAGE23--54 ,a conserved
N-terminal fragment of RAGE, exhibited increased cytotoxicity
in comparison with the constituent peptides. Western analysis
indicated that Aβ1-42
and RAGE23-54 remained primarily
in their original low molecular weight states (4-6 kDa) during
the maintenance of the individual peptides (37oC) in water
from 1 to 4 weeks. In contrast, over the same maintenance
periods the combined Aβ1-42
and RAGE2354 peptides shifted
to higher molecular weight complexes (up to 80-120 kDa). Protein
complexes of similar molecular weights with epitopes for Aβ
and RAGE antibodies were identified in human plasma. Incubation
of differentiated PC-12 cells with 10-100 μM
Aβ1-42
or with RAGE23-54 resulted
in concentration-dependent decreases in cell viability. The
cytotoxicity of each peptide was slightly enhanced by the
progressive maintenance of Aβ1-42
and RAGE23-54 in water over
3 weeks prior to the assay. Under the same conditions, the
Aβ1-42
RAGE23-54 complex became
significantly more cytotoxic. These results suggest that the
formation of soluble Aβ-RAGE
complexes in Alzheimer’s disease could represent a mechanism
for enhancing the neurotoxicity of amyloid peptides.
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