CONFERENCE COVERAGE SERIES
Center for Neurogenerative Disease Research Retreat 2001
Philadelphia, Pennsylvania
07 November 2001
CNDR 2nd Annual Retreat: Welcome and Introduction
The Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania School of Medicine organized the 2nd Annual CNDR Retreat as a one day symposium entitled "Emerging Alzheimer's Disease Therapies: Focusing on the Future," which was held on November 7, 2001, at the University of Pennsylvania in Philadelphia, Pennsylvania. John Q. Trojanowski and Virginia M.-Y. Lee, codirectors of CNDR, formulated a scientific agenda that considered a number of novel therapeutic approaches for the treatment of Alzheimer's disease (AD). Briefly, the approaches are those that target prevention or elimination of brain amyloid deposits resulting from accumulations of Aβ fibrils. Although fibrillar Aβ deposits in the extracellular space, known as senile plaques (SPs), and intraneuronal aggregates of tau fibrils, known as neurofibrillary tangles (NFTs), are the hallmark amyloid lesions of the AD brain, most patients with familial or sporadic forms of AD also exhibit a third type of amyloid lesion, known as a Lewy body, which is formed by intraneuronal accumulations of α-synuclein fibrils (1-3). Thus, AD is a brain amlyloidosis wherein at least three different building block proteins or peptides undergo pathological fibrillization to form deposits of amyloid within and outside neurons. Nonetheless, because most progress in the last decade of AD research has been made towards identifying therapeutic targets to prevent or eliminate amyloid deposits formed by Aβ fibrils, the symposium concentrated on emerging therapies for AD that are directed at these targets. This brief report summarizes highlights from the presentations at this symposium and it is notable that the presentations reflect the remarkable progress in understanding AD in the last decade since all of the potential therapeutic interventions described at the symposium resulted from insights into basic mechanisms of AD that have emerged only within the past 10 years, and they remain to be tested for their therapeutic efficacy (4-5). After Trojanowski opened the symposium by providing a brief overview of the major strategies for preventing or eliminating Aβ deposits upon which each presentation was based, the following 25-minute talks were given by 11 different speakers from industry and academia.—John Trojanowski
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CNDR 2nd Annual Retreat: Amyloid-binding Ligands as AD Therapies
Virginia M.-Y. Lee, University of Pennsylvania School of Medicine, summarized studies conducted by investigators in CNDR in collaboration with the Kung lAβ at Penn that seek to identify new therapies for AD, and the therapeutic targets of studies they propose are the extracellular SPs formed by fibrillar Aβ. Dr. Lee noted that although Aβ vaccines and inhibitors of amyloidogenic secretases are potential AD therapies, multifaceted strategies may be needed to effectively interrupt Aβ amyloidosis and prevent/arrest AD. Thus, she and her colleagues have specifically targeted the inhibition of Aβ fibrillization as a potential therapy for AD. Certain amyloid-binding molecules, such as Congo red (CR) and chrysamine G (CG), can indeed arrest the formation of Aβ fibrils; however CR and CG are unsuitable for AD therapy because they do not cross the blood-brain barrier (BBB). Therefore, working with the Kung lAβ at Pennsylvania, Dr. Lee and colleagues in CNDR have generated novel CG derivatives and other small molecules that specifically recognize fibrillar Aβ in vitro, arrest the formation of Aβ fibrils, and cross the BBB of transgenic mice that model AD amyloidosis. As proof of their ability to cross the BBB and of their high specificity for Aβ fibrils in vivo, Dr. Lee and coworkers showed that following intravenous injection in transgenic mice these compounds specifically label AD-like brain deposits of fibrillar Aβ. Building on these preliminary data, they propose to test the hypothesis that small amyloid-binding compounds that inhibit Aβ fibrillization in vitro and cross the BBB are potential AD therapeutic agents. To accomplish this, Dr. Lee described a multidisciplinary research program, including the design and synthesis of novel amyloid-binding compounds, biophysical, biochemical, molecular biological and ultrastructural studies using cell culture and animal models of AD-like Aβ amyloidosis to develop such novel amyloid-binding compounds and evaluate their potential as therapeutic agents for the treatment of AD. While these studies are still at the preclinical stage in model systems, amyloid disrupting compounds hold promise not only for targeting Aβ amyloidosis, but also other types of brain amyloid including those due to accumulations of tau and α-synuclein fibrils.—John Trojanowski
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CNDR 2nd Annual Retreat: Gonadal Hormones Control β-Amyloid in Vivo
Dr. Samuel Gandy of Thomas Jefferson Medical School began his presentation by stating that since 1990, 14 of 15 epidemiological studies reported that hormone replacement therapy (HRT) reduced the relative risk of AD in postmenopausal women by about 50 percent. Dr. Gandy and coworkers hypothesized that HRT might modulate AD risk through hormonal control of Aβ metabolism, and they have tested this hypothesis by examining the effect of ovariectomy on Aβ levels in the brains of experimental animals and in the circulation of elderly men with prostate cancer treated with antigonadal therapy. Notably, compared to controls, brain levels of Aβ40 and 42 were increased 150 percent in guinea pigs subjected to ovariectomy, but brain levels of Aβ returned nearly to control values when the ovariectomized guinea pigs were treated orally with one or five mg/kg/day 17β-estradiol. Dr. Gandy and colleagues then extended these studies to a model of the human clinical situation by examining six men who were undergoing therapeutic androgen suppression therapy for treatment of prostate cancer, and they reported that plasma levels of β-amyloid doubled in association with declining levels of circulating testosterone and estrogen. Further, the elevated plasma Aβ levels persisted for at least the first six months of therapy. Thus, these data suggest that gonadal hormones play a key role in controlling Aβ levels in vivo in experimental animals and in humans, and, despite the lack of efficacy in treating advanced AD with HRT in recent clinical trials using estrogens, it is possible that earlier HRT intervention in individuals with mild cognitive impairment, a prodromal phase of AD, or even in early AD, may be effective in slowing disease progression.—John Trojanowski
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CNDR 2nd Annual Retreat: Metal Complexing Agents as Therapies for AD
According to Ashley Bush of Harvard Medical School, Aβ is rapidly precipitated by Zn2+ at low physiological concentrations, and Cu2+ and Fe3+ also induce Aβ aggregation. Zn/Cu-selective chelators markedly enhance the solubilization of Aβ deposits from postmortem AD brains, and Dr. Bush and his colleagues have purified Aβ from human brain showing that it is metallated with Zn and Cu. Hence, Aβ should be regarded as a metalloprotein. Zinc, copper, and iron are markedly elevated in the AD brain, and are especially highly concentrated in Aβ deposits in humans and in APP transgenic mice. When it binds Cu2+ or Fe3+, Aβ reduces the metal ions and produces H2O2 by electron transfer to O2. This is important because of growing evidence for oxidation injury in AD, and Aβ cytotoxicity could be mediated by Cu2+:Aβ interactions that generate H2O2 which can be blocked by chelators. For these reasons, Dr. Bush and colleagues have pursued metal-Aβ interactions as a target for therapeutics, and they recently reported that Aβ1-42 possesses an attomolar affinity Cu2+ binding site that is among the strongest known, and similar to the affinity of Cu2+ for the antioxidant enzyme superoxide dismutase 1. They also found that the Cu2+-mediated H2O2 production by Aβ is suppressed by cobinding of Zn2+, and indeed, despite precipitating Aβ into amyloid, Zn2+ rescues Aβ neurotoxicity in cell culture. These and other studies have led them to conclude that AD amyloid plaques may represent the redox-silencing and entombment of Aβ by zinc. Hence, the plaques may not be the pathogenic culprit in AD, and evidence suggests that the toxic forms of Aβ may be the soluble or diffuse Aβ collections in the brain. On the basis of growing information about Zn2+ and Cu2+ interactions with Aβ mediating the biochemistry of Aβ, Dr. Bush and colleagues recently embarked on a trial of copper-chelators to attempt to inhibit Aβ accumulation in APP2576 transgenic mice. Treatment with clioquinol (CQ), a retired antibiotic and bioavailable Cu/Zn chelator, induced a 49% decrease in brain Aβ deposition in a blinded study of APP2576 transgenic mice treated orally for nine weeks. There was no evidence of neurotoxicity or increased non-amyloid pathology. The drug may work by a combined action that facilitates disaggregation of the Aβ collections, while also inhibiting H2O2 production. Importantly, CQ treatment did not induce a loss in metal levels systemically, probably because it is a relatively weak chelator and the metals are redistributed rather than excreted. Thus, CQ treatment appears to be a potent inhibitor of Aβ accumulation. CQ may be the first credible drug candidate based on the amyloid hypothesis of AD, and Dr. Bush reported that a phase II double-blind clinical trial on the effects of CQ in AD patients is currently in progress.—John Trojanowski
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CNDR 2nd Annual Retreat: Modification of Soluble Aβ Derivatives
Due to the illness of Blas Frangione, New York University School of Medicine, E. M. Sigurdsson, gave this presentation on another alternative for immunotherapy of AD. Dr. Sigurdsson reviewed recent studies of transgenic mice with AD-like brain amyloidosis that were immunized with aggregated human Aβ1-42 showing the mice have a reduced cerebral Aβ amyloid burden. However, Dr. Sigurdsson noted that the use of Aβ1-42 in humans may have drawbacks because it crosses the blood-brain barrier, forms toxic fibrils, and could seed Aβ fibril formation in the brain, even if it were present in very small quantities. Indeed, these investigators suggest that these safety issues are of particular concern in the elderly because older individuals do not always mount an adequate immune response to vaccines. Thus, Drs. Frangione, Sigurdsson and colleagues developed an Aβ homologue, Aβ1-30NH2 with polylysine on its N-terminus (K6Aβ1-30) that is highly soluble, non-amyloidogenic and nontoxic in human neuronal cell culture. Recently, they reported that immunization with K6Aβ1-30 in 11-12 months old Tg2576 APP mice for seven months reduced the brain Aβ amyloid burden by >80%, while brain levels of soluble Aβ1-42 were reduced by 57%. Ramified microglia expressing interleukin-1β associated with the Aβ plaques were absent in the immunized mice consistent with reduced inflammation. While additional studies of this method of immunotherapy are in progress in these transgenic mice, based on their data, these investigators suggest that immunization with soluble Aβ derivatives represents a potentially safer therapeutic approach to reduce Aβ amyloid burden in AD patients.—John Trojanowski
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CNDR 2nd Annual Retreat: Systemic Immunotherapy for Alzheimer's Disease
Ivan Lieberburg of Elan Corporation summarized evidence over the past 15 years supporting the role of amyloid as causal in the onset and/or progression of AD. Aβ, a 42 amino acid long peptide derived the amyloid precursor protein (APP), is released from APP following β and βc-secretase cleavage, and both are aspartyl proteases that are targets for AD drug discovery, as discussed in subsequent presentations. Using the first transgenic mouse model of AD-like Aβ amyloidosis that was reported in 1995, Elan scientists discovered that immunization of young PDAPP mice with human Aβ peptides prevented the immunized mice from developing AD-like Aβ amyloid neuropathology at six months of age and beyond throughout their life span, while similar immunization of one-year-old mice with substantial Aβ amyloid neuropathology stabilized, prevented further Aβ deposition, or even reversed this pathology with advancing age for six months. These results have been repeated and extended by several other groups, and Elan scientist have gone on to show that passive immunization with some, but not all anti-Aβ antibodies yield similar therapeutic effects in these mice. Current thinking by Elan scientists is that the anti-Aβ antibodies cross the blood-brain barrier into brain, bind to Aβ fibrils in amyloid deposits and promote clearance of these plaques by brain microglia. Other groups have also shown that Aβ immunized mice with evidence of Aβ amyloid clearance learn more effectively than non-immunized transgenic mice. Elan scientists have conducted extensive toxicological testing of this immunotherapy in several mammalian species, and they have not detected evidence of toxicity, but studies in human AD and control subjects have not demonstrated any correlation between the presence or absence of anti-Aβ antibodies or levels thereof with the disease state. However, Elan scientists have completed two phase 1 clinical trials of this immunotherapy in the USA and the UK, and they now have initiated a multisite phase 2 study in 375 mild to moderate AD patients.—John Trojanowski
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CNDR 2nd Annual Retreat: β-Secretase Inhibitor Therapy for AD
Dr. Citron began his presentation by emphasizing that the cerebral deposition of Aβ is an early and critical feature of AD, and that Aβ is released from APP by the sequential action of two proteases, β-secretase and γ-secretase. Thus, Dr. Citron noted that these proteases are prime targets for therapeutic intervention, and for this reason he and his colleagues recently cloned a novel aspartic protease, BACE1, with all the known properties of the β-secretase that in part is responsible for the release of Aβ from APP. Dr. Citron then briefly summarized how he and his colleagues conducted studies that led to the initial identification of BACE1 and he also described some of its properties. He then went on to review the crystal structure of BACE1 and data from his studies of BACE1 knockout mice that he and his colleagues recently generated. This presentation concluded with a discussion of the pros and cons of BACE1 inhibition as a therapeutic strategy compared to other amyloid therapies. While lively, this discussion was largely theoretical since, compared to the other therapies that currently target Aβ amyloid deposits, there is little published preclinical data from studies in model systems upon which to base solid predictions on there relative merits of the different approaches to the therapy of AD.—John Trojanowski
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Papers
- Imaizumi K, Miyoshi K, Katayama T, Yoneda T, Taniguchi M, Kudo T, Tohyama M. The unfolded protein response and Alzheimer's disease. Biochim Biophys Acta. 2001 May 31;1536(2-3):85-96. PubMed.
- Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, Morihara T, Yoneda T, Gomi F, Mori Y, Nakano Y, Takeda J, Tsuda T, Itoyama Y, Murayama O, Takashima A, St George-Hyslop P, Takeda M, Tohyama M. Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat Cell Biol. 1999 Dec;1(8):479-85. PubMed.
CNDR 2nd Annual Retreat: γ-Secretase: Implications for AD Therapy
Yue-Ming Li, Merck and Company, began his presentation by reviewing the known biology of γ-secretase, a membrane-bound protease that cleaves within the transmembrane region of APP to generate the C-termini of the two predominant forms of Aβ known as Aβ40 and Aβ42, which are major constituents of SPs in AD brains. Further, Dr. Li pointed out that presenilin 1 (PS1) and presenilin 2 (PS2) are polytopic membrane spanning proteins that harbor mutations which give rise to early onset familial AD, and he then reviewed recent biochemical studies which provide compelling evidence that presenilins are novel aspartyl proteases that mediate γ-secretase activity when engaged in the putative γ-secretase macromolecular complex. PS1 and PS2 activities can be discriminated from one another on the basis of their susceptibility to inhibition by a potent γ-secretase inhibitor. Thus, Dr. Li concluded that presenilin/γ-secretase is a potential target for AD therapy and plays an important role in regulated intramembrane proteolysis. However, as with the efforts described above to develop β-secretase inhibitor therapy for AD, there is little published preclinical data on γ-secretase inhibitors upon which to base solid predictions on the merits of this approach to the therapy of AD.—John Trojanowski
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CNDR 2nd Annual Retreat: Summary and Conclusions
Current Status of Emerging Therapies for Alzheimer's Disease-Sangram Sisodia, University of Chicago
Dr. Sangram Sisodia provided a summary and critique of the foregoing scientific presentations wherein he outlined the strengths and weaknesses of each of the approaches discussed at the symposium. A number of these points, as well as others made by the some of the >300 symposium participants are incorporated in the summaries above.
What Are the Next Steps? The Challenges of Transforming Laboratory Advances into Treatments for Patients-Christopher Clark, and Jason Karlawish, University of Pennsylvania
Finally, in a closing session to the symposium designed for attendance by scientists and clinicians as well as for the caregivers and families of AD patients, Drs. Chris Clark and Jason Karlawish concluded the symposium by summarizing the key elements involved in the conduct of human clinical trials of new AD therapies. They noted a number of unfinished tasks for the design of such trials including issues such as informed consent for trials involving subjects who may not be able to give consent themselves, but instead require surrogates for this, the importance of the "dyad" of patient and caregiver in judging the merits and efficacy of new drugs for AD, the need for better outcome measures for testing new drugs including better imaging strategies and reliable AD biomarkers that can be used in conjunction with clinical outcome measures to assess the response of the disease process to therapeutic interventions, and the types of patient populations most suitable for evaluating new AD therapies in a timely and informative manner.
However, it is notable that, in addition to the efforts of industry to carry out clinical trials of proprietary drugs for AD, the National Institute on Aging of the National Institutes of Health has established an infrastructure of AD Centers around the USA for this and a funding mechanism through the AD Clinical Studies program to conduct clinical trials of other potential therapies for AD (6). This presentation stimulated robust discussion and dialogue among all the participants on the prospects of translating laboratory advances in AD research into effective therapies for AD patients. Acknowledgements The codirectors of CNDR who organized this symposium kindly acknowledge a grant from Nastech Pharmaceutical Co., Inc., to support this meeting and the publications of the proceedings of the meeting in a future issue of the journal Neurobiology of Aging, as well as generous support for the meeting from Janssen Pharmaceutica. Other support came from the Memory Disorder Clinic, the Institute on Aging and the AD Center Core at Penn as well as from all of the members of CNDR, but especially Ms. Gayle Viale, who provided key design, logistical and administrative support. In addition, the National Institute on Aging of the National Institutes of Health, and the Oxford Foundation made the symposium possible. Dr. V.M.-Y. Lee is the recipient of the John H. Ware 3rd Chair for Alzheimer's Disease Research. Additional information on AD and related neurodegenerative diseases can be obtained at ,the CNDR website . Finally, all of the speakers are thanked for their insightful presentations and discussions at the meeting, and none of the research leading to the identification of better therapies for AD has been made possible by the families of our AD patients who made our research possible.—John Trojanowski
See also:
Duda J, Lee VM-Y, Trojanowski JQ. Pathogenesis of dementia: Updating the role of synuclein pathology in sporadic and hereditary Alzheimer's disease. Neuroscientific Basis of Dementia. Tanaka C, Ihara Y and McGeer PL(Eds.), Birkhaeuser Verlag, Basel, Switzerland, pp. 131-136, 2001.
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Further Reading
Papers
- Trojanowski JQ, Lee VM. "Fatal attractions" of proteins. A comprehensive hypothetical mechanism underlying Alzheimer's disease and other neurodegenerative disorders. Ann N Y Acad Sci. 2000;924:62-7. PubMed.
- Galvin JE, Lee VM, Trojanowski JQ. Synucleinopathies: clinical and pathological implications. Arch Neurol. 2001 Feb;58(2):186-90. PubMed.
- Irizarry MC, Hyman BT. Alzheimer disease therapeutics. J Neuropathol Exp Neurol. 2001 Oct;60(10):923-8. PubMed.
- Mayeux R, Sano M. Treatment of Alzheimer's disease. N Engl J Med. 1999 Nov 25;341(22):1670-9. PubMed.
- Trojanowski JQ. Alzheimer's disease centers and the dementias of aging program of the national institute on aging: a brief overview. J Alzheimers Dis. 2001 Apr;3(2):249-251. PubMed.
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