| Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer Research
Volume 3, Number 1, February 2006
Contents
Neurogenesis Catalyst Conference
Guest Editors: Howard M. Fillit & Gunnar
Gouras
Editorial - A Milestone for Current Alzheimer
Research Pp. 1
Debomoy K. Lahiri
Introduction - Neurogenesis as a Therapeutic Strategy
for Cognitive Aging and Alzheimer’s Disease Pp.
3
Gunnar Gouras and Howard Fillit
[Abstract]
Small Molecule Approaches for Promoting Neurogenesis
Pp. 5-10
Frank M. Longo, Tao Yang, Youmei Xie and Stephen M. Massa
[Abstract]
Preclinical Analyses of the Therapeutic Potential
of Allopregnanolone to Promote Neurogenesis In Vitro
and In Vivo in Transgenic Mouse Model of Alzheimer’s
Disease Pp. 11-17
Roberta Diaz Brinton and Jun Ming Wang
[Abstract]
Dissecting the Diverse Actions of Pro- and Mature
Neurotrophins Pp. 19-24
Barbara L. Hempstead
[Abstract]
Neurodegeneration and Neurogenesis: Focus on Alzheimer’s
Disease Pp. 25-28
David A. Greenberg and Kunlin Jin
[Abstract]
VEGF, a Mediator of the Effect of Experience on
Hippocampal Neurogenesis Pp. 29-33
Matthew J. During and Lei Cao
[Abstract]
Effects of Paliroden (SR57667B) and Xaliproden
on Adult Brain Neurogenesis Pp. 35-36
C. Labie, B. Canolle, S. Chatelin, C. Lafon and J. Fournier
[Abstract]
Implications for CNS Repair of Redox Modulation
of Cell Survival, Division and Differentiation Pp.
37-47
Mark Noble
[Abstract]
Environment, Physical Activity, and Neurogenesis:
Implications for Prevention and Treatment of Alzhemier’s
Disease Pp. 49-54
Teresita L. Briones
[Abstract]
Discovery of Neurogenic, Alzheimer’s Disease
Therapeutics Pp. 55-62
Judith Kelleher-Andersson
[Abstract]
sAPPα
Enhances the Transdifferentiation of Adult Bone Marrow Progenitor
Cells to Neuronal Phenotypes Pp. 63-70
Chun-Wei David Chen, Rene M. Boiteau, Wen-Fu Thomas Lai,
Steven W. Barger and Anne M. Cataldo
[Abstract]
Debate Section Papers
Has the Amyloid Cascade Hypothesis for Alzheimer’s
Disease been Proved? Pp. 71-73
John Hardy
[Abstract]
Amyloid Beta: The Alternate Hypothesis Pp. 75-80
Hyoung-gon Lee, Xiongwei Zhu, Akihiko Nunomura, George
Perry and Mark A. Smith
[Abstract]
A Partial Failure of Membrane Protein Turnover May
Cause Alzheimer’s Disease: A New Hypothesis
Pp. 81-91
Kumar Sambamurti, Anitha Suram, Chitra Venugopal, Annamalai
Prakasam, Yan Zhou, Debomoy K. Lahiri and Nigel H. Greig
[Abstract]
Acknowledgement
List Pp. 91
Abstracts
[Back to top]
Editorial - A Milestone for Current Alzheimer
Research
Current Alzheimer Research enters the third year
of suc-cessful publication with a great sense of satisfaction
and accomplishment. All five issues of its second volume were
completed and published on time, as promised. The second volume
featured a total of 65 articles, a 100% jump from its previous
volume. These articles, which are comprised of primary research
and review work, were written by experts in the field of Alzheimer’s
disease (AD) and duly peer-reviewed prior to publication.
In total, this work was a contribution by researchers from
19 countries: Australia, Canada, Chile, China, Cuba, Denmark,
France, Germany, Hungary, Israel, Japan, Netherlands, Poland,
Portugal, Spain, Switzerland, Taiwan, UK and the USA. The
journal, hence, remains a truly international one - covering
diverse aspects of research related to AD. The success of
the journal has been recognized by its acceptance for listing
in Pub-Med/MEDLINE databases. This constitutes a milestone
event for Current Alzheimer Research. In addition
to the print format, it is accessible via online
(http://www.bentham.org/car/).
Abstracts of the articles are freely available on the journal's
website. Furthermore, the journal has expanded its Editorial
Advisory Board (EAB) by including several renowned experts
in the arena of neuro-science and AD.
The key and important aspect of this journal concerns reporting
a combination of mechanistic and translational studies that
encompass a wide range of AD research, such as amyloid biology,
apolipoprotein E, apoptosis, brain imag-ing, immunotherapy,
genetics, statins and tauopathy. The journal has also reported
studies from clinical drug trials. Interestingly, during the
last single year, alone, the AD research field has burst with
activity - as evident from the listing of approximately 4,000
papers on MEDLINE. Thus, the necessity of timely dissemination
of this knowledge can never be greater. Current Alzheimer
Research can expertly cover a fraction of primary research;
however, the journal’s ‘review’ articles
provide a comprehensive overview of selected high interest
topics and remain an invaluable re-source for the AD field.
In the third volume, with 5 different issues, Current
Alzheimer Research plans to present a wide range of topics,
as critical review articles or original research reports,
which will address the molecular basis of the disease, potential
drug targets, and therapeutic strategies for AD. The journal
will present research from a combination of appropriate cellular,
genetic, and in vivo models. In the 3rd
volume, we also plan to publish special issues written by
experts on different hot topics, such as apoptotic mechanisms
in AD, as well as on the current understanding of AD therapeutics
- based on the upcoming ‘9th International
Geneva/Springfield Symposium on Advances in Alzheimer Therapy’.
Our major goals in the 3rd volume are to continue
to re-port cutting edge research on AD from biochemical, epidemiological
and neuroscience studies, and to provide an in-sightful summary
of important advances in AD research with an emphasis on potential
drug development strategies. The 3rd volume (issue
1) begins with a special issue entitled, “Neurogenesis
as a Therapeutic Strategy for Cognitive Aging and Alzheimer’s
Disease”, and is ably edited by Gunnar Gouras and Howard
Fillit. This issue contains 11 articles, which address one
of the most interesting and relevant topics in the field of
neurodegenerative disorders, neurogenesis, especially its
role in the pathogenesis of AD and its potential utility as
a valid target for the therapy of AD.
In addition, this issue presents an interesting "Debate
section" with three papers that both argue and present
major novel hypotheses to explain the fundamental pathobio-chemical
events occurring in AD: i) the amyloid cascade hypothesis;
ii) an alternative to the amyloid beta hypothesis; and iii)
a faulty protein-turnover model. Further models, ideas and
hypotheses will, additionally, be discussed in future issues
to stimulate research and build the road to cure this scourge.
On behalf of the Editorial Board and the Bentham Science
Publishers, I deeply appreciate the enormous support received
from the readers, authors, reviewers, sponsors and the neuroscience
community. I truly believe that the journal will continue
to make great progress with all of your invaluable support
and patronage. I welcome your comments, advice, and suggestions
to further improve this journal, and also solicit review papers,
and original reports in the numerous diverse areas of AD research.
It has been an exciting journey of knowledge to unlock the
mysteries of Alzheimer’s disease and I thank you all
for both your company and contributions.
Debomoy K. Lahiri
Editor-in-Chief
Departments of Psychiatry and of Medical and
Molecular Genetics,
Institute of Psychiatric Research,
Indiana University School of Medicine,
Indianapolis, Indiana-46202,
USA
[Back to top]
Introduction - Neurogenesis as a Therapeutic Strategy
for Cognitive Aging and Alzheimer’s Disease
Gunnar Gouras and Howard Fillit
Stem cells, particularly human embryonic stem cells, have
received considerable attention in the general public as a
potential therapy for debilitating and incurable diseases,
including Alzheimer’s disease. However, neuroscientists
and other Alzheimer’s researchers have been skeptical
of the feasibility of replacing neurons within the complex
cy-toarchitecture of the adult human brain, especially in
regions involved in cognitive and memory function. Neurogenesis
relates to a process of replenishing neurons through endogenous
mechanisms in the brain. Recent work indicates that neurogenesis
plays a role in normal brain functions, such as memory formation
and response to injury. As a result, enhancing neurogenesis
may represent a feasible and important new target for drug
development in the aging brain and in Alzheimer’s disease.
The Institute for the Study of Aging (ISOA) sponsored catalyst
conference on “Neurogenesis as a therapeutic strategy
for cognitive aging and Alzheimer’s disease” brought
together leading investigators at The Rockefeller University
in New York on September 16, 2005. The conference high-lighted
the diversity in approaches when considering stem cells or
promoting neurogenesis as therapeutic strategies for Alzheimer’s
disease. In fact, none of the scientific presentation considered
the direct use of human embryonic stem cells as a therapy
to replace brain areas damaged by the ravages of Alzheimer’s
disease. Approaches ranged from pharmacological small molecules
to environmental enrichment to promote neurogenesis of dentate
granule cells in the hippocampus, to the use of marrow-derived
adult progenitor cells to introduce cholinergic neurons into
the central nervous system.
The goals of the conference were to review knowledge of neurogenesis,
especially with regards to the pathogenesis of Alzheimer’s
disease, to develop a consensus on whether neurogenesis is
a valid target for therapy of Alzheimer’s disease, and
to stimulate discussion on the most compelling therapeutic
strategies to pursue with regards to neurogenesis as a treatment
for age-related cognitive decline and Alzheimer’s disease.
Neurogenesis was long suspected to occur in the adult human
brain, but following a series of landmark studies over the
past decade, neurogenesis moved to the forefront as a potential
therapeutic strategy for diseases of the central nervous system
[1-3]. Since the hippocampus plays a central role in laying
down new memories and is severely affected in Alzheimer’s
disease, the potential that newly generated-neurons in the
dentate granule layer of the hippocampus might protect against
the loss of memory has been increasingly considered. As yet,
it remains unclear whether alterations in neurogenesis of
dentate granule cells occur in the disease. That environmental
enrichment promoted neurogenesis [4] provided another plausible
link with Alzheimer’s disease, since increasing evidence
indicates that environmental enrichment protects against Alzheimer’s
pathogenesis [5].
The following articles written by speakers at the conference
provide an overview of approaches being considered. A theme
stressed by the participants was that in thinking about neurogenesis
as a drug target, different small molecule and peptide drugs
could be considered to promote the various individual stages
of neurogenesis, including proliferation, survival, migration
and/or maturation of neural progenitor cells. The conference
also highlighted that the field of neurogenesis as a therapy
for age-related cognitive decline and Alzheimer’s disease,
while exciting, is still at an early stage.
REFERENCES
[1] Gould E, Gross CG. Neurogenesis in adult mammals: some
progress and problems. J Neurosci 22(3): 619-623 (2002).
[2] Kempermann G, Wiskott L, Gage FH. Functional significance
of adult neurogenesis. Curr Opin Neurobiol 14(2): 186-191
(2004).
[3] Emsley JG, Mitchell BD, Kempermann G, Macklis JD. Adult
neuro-genesis and repair of the adult CNS with neural progenitors,
precur-sors, and stem cells. Prog Neurobiol 75(5): 321-341
(2005).
[4] Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons
in adult mice living in an enriched environment. Nature 386(6624):
493-495 (1997).
[5] Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics
Z, Lee VM et al. Environmental enrichment reduces
Abeta levels and amyloid deposition in transgenic mice. Cell
120(5): 701-713 (2005).
[Back to top]
Small Molecule Approaches for Promoting Neurogenesis
Frank M. Longo, Tao Yang, Youmei Xie and Stephen M. Massa
The discovery of small molecules capable of promoting neurogenesis
will contribute to the elucidation of the physiological roles
of neurogenesis and to novel therapeutic approaches. Small
molecule development can be targeted to the promotion of precursor
proliferation, survival, migration or maturation and might
be applied to augmenting physiological neurogenesis already
present in the dentate gyrus or subventricular zone/olfactory
bulb or to normally non-neurogenic regions relevant to neuropathological
states. Current small molecule discovery can be assessed from
the perspective of the following categories: compounds modulating
physiological signaling pathways regulating neurogenesis including
the sonic hedgehog, bone morphogenic protein Wnt/,-catenin,
Notch and chemokine systems; growth factor mimetics; protein
tyrosine phosphatase inhibitors; existing drugs including
antidepressants, lithium, valproate, sidenafil and statins;
hormones, steroids and peptides; and neurotransmitter receptor
agonists and antagonists. Unbiased, high throughput screening
will likely lead to the discovery of additional active compounds
and the recognition of novel mechanisms regulating neurogenesis.
A major therapeutic challenge will consist of the identification
of molecular targets and mechanisms relatively specific for
precursor cells of interest.
[Back to top]
Preclinical Analyses of the Therapeutic Potential
of Allopregnanolone to Promote Neurogenesis In Vitro
and In Vivo in Transgenic Mouse Model of Alzheimer’s
Disease
Roberta Diaz Brinton and Jun Ming Wang
Herein, we present data to support a preclinical proof of
concept for the therapeutic potential of allopregnanolone
to promote neurogenesis. Our recent work has demonstrated
that the neuroactive progesterone metabolite, allopregnanolone
(3α-hydroxy-5α-pregnan-20-one),
(APα)
induced, in a dose dependent manner, a significant increase
in proliferation of neuroprogenitor cells (NPCs) derived from
the rat hippocampus and human neural stem cells (hNSM) derived
from the cerebral cortex [1]. Proliferative efficacy was determined
by incorporation of BrdU and 3H-thymidine, FACS
analysis of MuLV-GFP-labeled mitotic NPCs and quantification
of total cell number. Allopregnanolone–induced proliferation
was isomer and steroid specific, in that the stereoisomer
3β-hydroxy-5β-pregnan-20-one
and related steroids did not increase 3H-thymidine
uptake. Immunofluorescent analyses for the NPC markers, nestin
and Tuj1, indicated that newly formed cells were of neuronal
lineage. Furthermore, microarray analysis of cell cycle genes
and real time RT-PCR and western blot validation revealed
that allopregnanolone increased the expression of genes which
promote mitosis and inhibited the expression of genes that
repress cell proliferation. Allopregnanolone-induced proliferation
was antagonized by the voltage gated L-type calcium channel
blocker nifedipine consistent with the finding that allopreg-nanolone
induces a rapid increase in intracellular calcium in hippocampal
neurons via a GABA type A receptor activated L-type calcium
channel. Preliminary in vivo data indicate that APα
for 24 hrs significantly increased neurogenesis in dentate
gyrus, as determined by unbiased stereological analysis of
BrdU positive cells, of 3-month-old male triple transgenic
Alzheimer’s disease mice. The in vitro and
in vivo neurogenic properties of APα
coupled with a low molecular weight, easy penetration of the
blood brain barrier and lack of toxicity, are key elements
required for developing APα
as a neurogenic / regenerative therapeutic for restoration
of neurons in victims of Alzheimer’s disease.
[Back to top]
Dissecting the Diverse Actions of Pro- and Mature
Neurotrophins
Barbara L. Hempstead
The neurotrophins mediate diverse actions in the developing
peripheral and central nervous systems. They are initially
synthesized as precursor forms, or proneurotrophins, that
are cleaved to release C-terminal mature forms that bind to
Trk receptor tyrosine kinases to enhance synaptic plasticity
and neuronal survival. Recent studies suggest that proneurotrophins
are not inactive precursors, but signaling proteins that can
activate the p75 receptor to mediate diverse responses. Proneurotrophins
can activate a heteromeric receptor complex of p75 and sortilin
to initiate cell death, or bind to p75 in hippocampal neurons
to enhance long term depression. Thus, neurotrophin actions
are regulated by the form of the neurotrophin (pro- or mature)
secreted by cells, by extracellular proteolytic cleavage of
proneurotrophins to generate mature forms, and by the expression
of neurotrophin receptors Trk, or p75 and sortilin, that are
selectively activated by mature or proneurotrophins, respectively.
Here, recent studies are reviewed that reveal that pro- and
mature neurotrophins have distinct and sometimes opposing
actions in regulating cell death and survival in development
and in pathophysiologic states, in regulating neurotrophin
secretion, and in modulating synaptic plasticity.
[Back to top]
Neurodegeneration and Neurogenesis: Focus on Alzheimer’s
Disease
David A. Greenberg and Kunlin Jin
Neurogenesis, or the production of new neurons from neuronal
precursor cells, is a normal phenomenon in the adult brain,
and is accentuated by brain injury. Forms of injury associated
with increased neurogenesis include both acute (e.g., stroke)
and chronic neurodegenerations. Studies on human postmortem
material and transgenic mice over-expressing amyloid precursor
protein mutations found in familial Alzheimer’s disease
(AD) suggest that AD is associated with enhanced neurogenesis.
However, the mechanism responsible for this effect is unknown,
as is what influence it may have on the clinical course of
murine or human AD. If AD leads to the production of fully
functional, mature neurons that can restore brain function,
strategies aimed at further increasing endogenous neurogenesis
may have therapeutic value.
[Back to top]
VEGF, a Mediator of the Effect of Experience on Hippocampal
Neurogenesis
Matthew J. During and Lei Cao
Rodents housed in an enriched environment, exercise by running
or perform learning and memory tasks show an increase in hippocampal
neurogenesis. We show that both environmental enrichment,
as well as performance in the Morris water maze, a hippocampaldependent
learning task, leads to an increase in local VEGF expression
in rats. We genetically recreated this situation by somatic
cell gene transfer using recombinant adeno-associated virus
(AAV) vectors. Genetically increasing hippocampal VEGF in
adult rats resulted in a ~2 fold increase in neurogenesis
associated with improved cognition. In contrast, gene transfer
of placental growth factor (PGF) which signals through Flt1,
but not KDR receptors had negative effects on neurogenesis
and inhibited learning, although it similarly increased endothelial
cell proliferation. Expression of a dominant negative, mKDR,
inhibited basal neurogenesis and impaired learning. Co-expression
of mKDR antagonized VEGF-enhanced neurogenesis and learning
without inhibiting endothelial cell proliferation. Furthermore,
inhibition of VEGF expression by RNA interference completely
blocked the environmental induc-tion of neurogenesis. These
data support a model whereby VEGF acting via KDR is a mediator
of the effect of the environment on neurogenesis and cognition
[1].
[Back to top]
Effects of Paliroden (SR57667B) and Xaliproden on
Adult Brain Neurogenesis
C. Labie, B. Canolle, S. Chatelin, C. Lafon and J. Fournier
Adult neurogenesis is a process allowing the replacement
in adult brain of damaged or dying neurons by new neurons
derived from neural stem cells. These peculiar stem cells,
which mainly reside in the ventricle wall of adult brain,
can differentiate into neurons and macroglial cells and migrate
in all parts of the brain parenchyma to undergo cell replacement.
Except in regions where it is constitutively active (i.e hippocampus
and olfactory bulb), neurogenesis is activated only after
brain damage but can partially compen-sate for the neuronal
loss (for recent reviews see, Lie et al., 2004. Annu.
Rev. Pharmacol. Toxicol, and J.G Emsley et al., 2005,
Prog. Neurobiol.). Accordingly, amplification of adult neurogenesis
represents a great potential for brain repair following acute
brain insults as well as for chronic slow neurodegenerative
pathologies.
[Back to top]
Implications for CNS Repair of Redox Modulation of
Cell Survival, Division and Differentiation
Mark Noble
Studies on oligodendrocytes, the myelin-forming cells of
the central nervous system, and on the progenitor cells from
which they are derived, have provided several novel insights
into the role of intracellular redox state in cell function.
A central unifying theme of this research is that redox state
modulation lies at the heart of understanding cell-intrinsic
aspects of precursor cell function, responsiveness of precursor
cells to cell-extrinsic signals and even the means by which
cell-extrinsic signaling molecules alter cellular function.
This review discusses our studies on the role in redox state
as a critical modulator of cellular function, and considers
the implications of these findings for optimizing tissue repair.
[Back to top]
Environment, Physical Activity, and Neurogenesis:
Implications for Prevention and Treatment of Alzhemier’s
Disease
Teresita L. Briones
Age is the biggest risk factor for the development of neurodegenerative
diseases. Consequently, as the population ages it becomes
more critical to find ways to avoid the debilitating cost
of neurodegenerative diseases such as Alzheimer’s. Some
of the non-invasive strategies that can potentially slow down
the mental decline associated with aging are exercise and
use of multi-sensory environmental stimulation. The beneficial
effects of both exercise and multi-sensory environmental stimulation
have been well-documented, thus it is possible that these
strategies can either provide neuroprotection or increase
resistance to the development of age-related cognitive problems.
[Back to top]
Discovery of Neurogenic, Alzheimer’s Disease
Therapeutics
Judith Kelleher-Andersson
Many researchers have questioned whether new potential therapies
aimed at reversing Alzheimer’s disease (AD) are indeed
scientifically feasible. A number of approved therapies already
exist for Alzheimer’s disease, yet these drugs only
slow the disease progression for a period of time and treat
the symptoms of this devastating disease. New therapies intended
to reverse the disease would necessarily need to replace dead,
dying and dysfunctional neurons in affected regions of the
brain. This complex drug discovery problem is further complicated
by the knowledge that AD is mainly an aging disorder and that
aging, though not considered a disease, causes biological
changes that may also need to be overcome [1]. The requirement
for new, functional neurons under neurodegenerative diseases,
as seen in AD and stroke suggests that an inhibitor of neuronal
death, like Memantine, is insufficient to reverse the cognitive
and physical loss. New neurons, or neurogenesis, may be required
for real improvement or reversal of the cognitive deficit.
Adult neurogenesis, first described by Altman in the early
1960s [2, 3], has more recently been observed as a response
to in-jury or disease. Of interest was the finding that new
neurons appear to migrate to disease/injury-affected areas
in the brain not normally neurogenic in the adult. This pathological-stimulation
of neurogenesis does not appear sufficient to stave off the
disease and subsequent behavioral decline. Therefore, the
desire to amplify and improve upon the neurogenesis-response
to neurodegenerative disease appears warranted, if not yet
feasible. The key to doing so lies in identi-fying what signals
are required to promote neurogenesis and neuron survival,
either in injury and disease or under envi-ronmental stimuli.
This could provide clues for how to pharmacologically induce
neurogenesis under neurodegenerative conditions. Currently,
progress in identifying therapeutics that appear to promote
ameliorative neurogenesis for AD is lagging behind the pharmacological
induction of neurogenesis as a therapy for depression.
[Back to top]
sAPPα
Enhances the Transdifferentiation of Adult Bone Marrow Progenitor
Cells to Neuronal Phenotypes
Chun-Wei David Chen, Rene M. Boiteau, Wen-Fu Thomas Lai,
Steven W. Barger and Anne M. Cataldo
The remediation of neurodegeneration and cognitive decline
in Alzheimer’s Disease (AD) remains a challenge to basic
scientists and clinicians. It has been suggested that adult
bone marrow stem cells can transdifferentiate into different
neuronal phenotypes. Here we demonstrate that the α-secretase-cleaved
fragment of the amyloid precursor protein (sAPPα),
a potent neurotrophic factor, potentiates the nerve growth
factor (NGF)/retinoic acid (RA) induced transdifferentiation
of bone marrow-derived adult progenitor cells (MAPCs) into
neural progenitor cells and, more spe-cifically, enhances
their terminal differentiation into a cholinergic-like neuronal
phenotype. The addition of sAPPα
to NGF/RA-stimulated MAPCs resulted in their conversion to
neuronal-like cells as evidenced by the extension of neurites
and the appearance of immature synaptic complexes. MAPCs differentiated
in the presence of sAPPα
and NGF/RA ex-hibited a 40% to as much as 75% increase in
neuronal proteins including NeuN, β-tubulin
III, NFM, and synaptophysin, compared to MAPCs differentiated
by NGF/RA alone. This process was accompanied by an increase
in the levels of choline acetyltransferase, a marker of cholinergic
neurons, compared to those of GABAergic and dopaminergic neuronal
subtypes. MAPCs immunpositive for sAPPα
were identified within the septohippocampal system of transgenic
PS/APP mice injected intravenously with sAPPα-transfected
MAPCs and found in close proximity to the cerebral vasculature.
Given that in AD cholinergic neurons are severely vulnerable
to neurodegeneration and that the levels of sAPPα
are significantly reduced, these findings suggest the combined
use of sAPPα
and MAPCs offers a new and potentially powerful therapeutic
strategy for AD treatment.
[Back to top]
Has the Amyloid Cascade Hypothesis for Alzheimer’s
Disease been Proved?
John Hardy
After much initial debate for and against the role of amyloid
in Alzheimer’s disease (AD), mutations on the amyloid
precursor protein (APP) and processing pathways that increase
levels of the amyloid b peptide of 42 residues (Aβ42)
have established that faulty function or processing of these
proteins are responsible for AD pathogenesis. Given the neurotoxicity
of aggregates of Ab42, the central role of this peptide in
AD pathogenesis is self evident. In this article, I summarize
the major pieces of evidence adduced to support the amyloid
cascade hypothesis and point out their limitations
[Back to top]
Amyloid Beta: The Alternate Hypothesis
Hyoung-gon Lee, Xiongwei Zhu, Akihiko Nunomura, George
Perry and Mark A. Smith
Alzheimer disease (AD) is a devastating condition and patients,
caregivers, clinicians, and scientists are eager to decipher
the underlying disease mechanism and, thereafter, target this
therapeutically. Most investigators studying the underlying
cause of AD have focused on amyloid-β
(Aβ)
such that the Amyloid Cascade Hypothesis is the predominant
mechanism thought to be responsible for the disease. However,
a number of caveats have led us to seriously question the
validity of this hypothesis. First, in addition to increases
in Aβ,
genetic mutations in AD lead to increased vulnerability to
oxidative/apoptotic insults indicating that the mutated protein
disturbs redox balance. Whether mutations result in Aβ
deposition that then causes oxidative stress or whether mutations
cause oxidative stress that results in Aβ
deposition is unclear. Indeed, while in vitro experiments
show that Aβ
can directly cause oxidative stress to cells in culture, it
is apparent from other studies that the reverse is also true,
namely that oxidative stress leads to increases in Aβ.
Notably, in vivo studies in both sporadic and genetic forms
of the disease show that oxidative stress temporally precedes
increases in Aβ
and that increases in Aβ
are associated with a decrease in oxidative stress. Based
on these findings, we herein propose an Alternate Amyloid
Hypothesis in which pathogenic factors for disease lead
to increased oxidative stress that then leads to increases
in Aβ.
Further, we propose that Aβ
serves as a redox sensor and that oxidatively-induced Aβ
serves to attenuate oxidative stress.
Obviously, whether Aβ
is the culprit, as argued by the Amyloid Cascade Hypothesis,
or a much maligned protector, as argued by the Alternate
Amyloid Hypothesis, is clearly important to decipher
to advance our understanding and design efficacious therapeutics
for this disease.
[Back to top]
A Partial Failure of Membrane Protein Turnover May
Cause Alzheimer’s Disease: A New Hypothesis
Kumar Sambamurti, Anitha Suram, Chitra Venugopal, Annamalai
Prakasam, Yan Zhou, Debomoy K. Lahiri and Nigel H. Greig
The amyloid hypothesis has dominated the thinking in our
attempts to understand, diagnose and develop drugs for Alzheimer’s
disease (AD). This article presents a new hypothesis that
takes into account the numerous familial AD (FAD) mutations
in the amyloid precursor protein (APP) and its processing
pathways, but suggests a new perspective beyond toxicity of
forms of the amyloid β-peptide
(Aβ).
Clearly, amyloid deposits are an invariable feature of AD.
Moreover, although APP is normally processed to secreted and
membrane-bound fragments, sAPPβ
and CTFβ,
by BACE, and the latter is subsequently processed by γ-secretase
to Aβ
and CTFγ,
this pathway mostly yields Aβ
of 40 residues, and increases in the levels of the amyloidogenic
42-residue Aβ
(Aβ42)
are seen in the majority of the muta-tions linked to the disease.
The resulting theory is that the disease is caused by amyloid
toxicity, which impairs memory and triggers deposition of
the microtubule associated protein, Tau, as neurofibrillary
tangles. Nevertheless, a few exceptional FAD mutations and
the presence of large amounts of amyloid deposits in a group
of cognitively normal elderly patients suggest that the disease
process is more complex. Indeed, it has been hard to demonstrate
the toxicity of Aβ42
and the actual target has been shifted to small oligomers
of the peptide, named Aβ
derived diffusible ligands (ADDLs). Our hypothesis is that
the disease is more complex and caused by a failure of APP
metabolism or clearance, which simultaneously affects several
other membrane proteins. Thus, a traffic jam is created by
failure of important pathways such as γ-secretase
processing of residual intramembrane domains released from
the metabolism of multiple membrane proteins, which ultimately
leads to a multiple system failure. In this theory, toxicity
of Aβ42
will only contribute partially, if at all, to neurodegeneration
in AD. More significantly, this theory would predict that
focussing on specific reagents such as γ-secretase
inhibitors that hamper metabolism of APP, may initially show
some beneficial effects on cognitive perform-ance by elimination
of acutely toxic ADDLs, but over the longer term may exacerbate
the disease process by reducing membrane protein turnover
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