Alzheimer Disease: Schenk D

Schenk D. · Chief Scientific Officer, Elan Corporation, 800 Gateway Blvd., South San Francisco, CA 9480, USA. · Curr Alzheimer Res. · Pubmed #16842091 No free full text.

This publication has no abstract.

Carrillo MC, Blackwell A, Hampel H, Lindborg J, Sperling R, Schenk D, Sevigny JJ, Ferris S, Bennett DA, Craft S, Hsu T, Klunk W. · Alzheimer's Association, Chicago, IL, USA. · Alzheimers Dement. · Pubmed #19328456 No free full text.

Abstract: The purpose of the Alzheimer's Association Research Roundtable meeting was to discuss the potential of finding diagnostic tools to determine the earliest risk factors for Alzheimer's disease (AD). Currently, drugs approved for AD address symptoms which are generally manifest after the disease is already well-established, but there is a growing pipeline of drugs that may alter the underlying pathology and therefore slow or halt progression of the disease. As these drugs become available, it will become increasingly imperative that those at risk for AD be detected and possibly treated early, especially given recent indications that the disease process may start decades before the first clinical symptoms are recognized. Early detection must go hand-in-hand with qualified tools to determine the efficacy of drugs in people who may be asymptomatic or who have only very mild symptoms of the disease. Devising strategies and screening tools to identify and monitor those at risk in order to perform "prevention" trials is seen by many as a top public-health priority, made all the more urgent by an impending growth in the elderly population worldwide.

Schenk D. · Elan Pharmaceuticals, South San Francisco, CA, USA. · Alzheimers Dement. · Pubmed #18631987 No free full text.

Abstract: The need to develop meaningful therapeutics for Alzheimer's disease is beginning to reach the general awareness of the public. Matching this awareness is the accelerated pace of compounds entering clinical trials. In addition, the development of diagnostic tools, biomarkers, and imaging modalities of the past decade in AD have improved dramatically. Unfortunately, the use of these diagnostic and scientific tools in clinical trial practice has not yet aligned or optimized. Most agents still target clinical end points associated with mild to moderate AD rather than focus on modulation of the underlying pathologies. Although there are obvious practical reasons for this, meaningful progress in other areas of medicine such as cardiology and oncology have generally targeted and monitored improvement or abatement of pathology as the primary end point as a successful disease-modifying strategy. Perhaps it is time to consider a similar approach in treatment of Alzheimer's disease.

Games D, Buttini M, Kobayashi D, Schenk D, Seubert P. · Elan Pharmaceuticals, 800 Gateway Blvd., South San Francisco, CA 94080, USA. · J Alzheimers Dis. · Pubmed #16914852 No free full text.

Abstract: Progress in understanding and treating Alzheimer's disease (AD) has been tremendously bolstered by the era of transgenic models of AD. The identification of disease-causing mutations in proteins such as amyloid-beta precursor protein (betaAPP) and presenilin1 (PS1), together with the discovery of other high risk factors (e.g., Apolipoprotein E4), as well as pathogenic mutations in the tau protein has led to the creation of several transgenic mice, including those expressing bi- and tri-genic constructs. Each model has unique pathologies that provide insights into disease mechanisms and interactive features of neuropathologic cascades. More importantly, therapeutic hypotheses are now testable in a manner unheard of less than 15 years ago. The wealth of new approaches currently in clinical and preclinical evaluations can be directly attributed to the impact of these animals on our ability to model relevant aspects of the disease. As a result, we may see containment or even the elimination of AD in the near future as a direct consequence of these advances.

Thal LJ, Kantarci K, Reiman EM, Klunk WE, Weiner MW, Zetterberg H, Galasko D, Praticò D, Griffin S, Schenk D, Siemers E. · University of California San Diego, Department of Neurosciences, La Jolla, California, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16493230 links to  free full text

Abstract: Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer's Association's Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed.

Schenk D, Hagen M, Seubert P. · Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA. · Curr Opin Immunol. · Pubmed #15342006 No free full text.

Abstract: As neuroscientists, we are taught that the brain is immune privileged and thus unlikely to be affected by the peripheral immune system. Accordingly, initial results demonstrating the effectiveness of beta-amyloid (Abeta) immunotherapy in mouse models of Alzheimer's disease (AD) were viewed with considerable surprise and some skepticism. Many groups have since demonstrated efficacy with Abeta immunotherapy in models of AD, using Abeta-based immunogens and anti-Abeta antibodies. Clinical trials involving Abeta immunotherapy for AD are in progress and are providing a wealth of information around the amyloid hypothesis of AD. Abeta immunotherapy is also raising new opportunities and questions about the general role of the immune system in neurodegenerative diseases.

Selkoe DJ, Schenk D. · Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Annu Rev Pharmacol Toxicol. · Pubmed #12415125 No free full text.

Abstract: Degenerative diseases of the brain were long considered among the most obscure and intractable of human maladies. However, recent advances in understanding their mechanisms have brought us to the verge of potential disease-modifying agents. This progress is perhaps best exemplified by the case of Alzheimer's disease. The application of molecular pathology and genetics has led to the recognition that the four genes implicated to date in familial Alzheimer's disease all chronically elevate cerebral levels of the amyloid beta-protein (Abeta). Accordingly, small molecule inhibitors of the beta- and gamma-secretases, the proteases that generate Abeta from its precursor, are under active development, and some have shown in vivo efficacy in mouse models. An alternative approach, active or passive immunization against Abeta, has received extensive pre-clinical validation in mice, but an effective preparation free of significant side effects in humans is still awaited. Several other potential therapies are also reviewed here. If one or more of these varied approaches is ultimately proven to slow or prevent dementia, Alzheimer's disease will become a salient example of the successful application of reductionist biology to the most complex of organs, the human cerebral cortex.

Schenk D. · Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA. · Nat Rev Neurosci. · Pubmed #12360327 No free full text.

This publication has no abstract.

Schenk D, Games D, Seubert P. · Elan Pharmaceuticals, San Francisco, CA 94080, USA. · J Mol Neurosci. · Pubmed #11816797 No free full text.

Abstract: Research over the past ten years on Alzheimer's disease has pursued many opportunities. Notable amongst the various approaches are efforts related to the "amyloid hypothesis." This hypothesis posits that the beta amyloid peptide causes the extensive neuropathology and clinical decline associated with the disease. Extensive research in this area has shown that the beta amyloid peptide is produced by proteases termed "secretases" and it has been shown that blockade of secretase functions reduce the amount of beta amyloid peptide produced. An additional approach to reduce beta amyloid, through an increase in clearance mechanisms, is to immunize with the peptide itself and induce an antibody response. The specifically elicited antibodies then bind to and stimulate clearance of the peptide from the brain. These findings have stimulated several approaches to develop novel therapeutic strategies to treat Alzheimer's disease that either are about or have entered the clinic.

Sinha S, Anderson J, John V, McConlogue L, Basi G, Thorsett E, Schenk D. · Elan Pharmaceuticals, 800 Gateway Blvd., So. San Francisco, CA 94080, USA. · Ann N Y Acad Sci. · Pubmed #11193151 No free full text.

This publication has no abstract.

Schenk D, Carrillo MC, Trojanowski JQ. · Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA. · Alzheimers Dement. · Pubmed #19595899 No free full text.

Abstract: The Alzheimer's Association Research Roundtable, a consortium of Association senior scientists and leaders from pharmaceutical, biotech, and imaging companies, met to discuss strategies for developing novel therapeutics for the treatment of Alzheimer's disease (AD). The goal of the meeting was to address, primarily, strategies that do not hinge on directly modulating levels of beta-amyloid. The identification of beta-amyloid as the major constituent of senile plaques and the subsequent discovery that familial AD can be caused by mutations in either the beta-amyloid precursor protein or presenilins, proteases that cleaves beta-amyloid from its precursor, has spawned numerous therapeutic strategies for treating AD. These include passive and active vaccines for clearing beta-amyloid from the brain and the development of small molecule inhibitors of beta- and gamma-secretases that can attenuate the production of beta-amyloid. But the field recognizes that there is more to AD than beta-amyloid alone. What role do neurofibrillary tangles play in the disease, for example, and how are they influenced by beta-amyloid? What lies upstream of beta-amyloid production in the sporadic AD brain, and how do apolipoproteins and cholesterol influence disease progression? Are there environmental or behavioral factors that contribute to the initiation or progression of sporadic AD? Because of the complexity of AD, the field is continually looking to other therapeutic strategies that may complement or substitute for therapies that target beta-amyloid. This roundtable meeting was charged with discussing and evaluating some of those strategies.

Khachaturian ZS, Snyder PJ, Doody R, Aisen P, Comer M, Dwyer J, Frank RA, Holzapfel A, Khachaturian AS, Korczyn AD, Roses A, Simpkins JW, Schneider LS, Albert MS, Egge R, Deves A, Ferris S, Greenberg BD, Johnson C, Kukull WA, Poirier J, Schenk D, Thies W, Gauthier S, Gilman S, Bernick C, Cummings JL, Fillit H, Grundman M, Kaye J, Mucke L, Reisberg B, Sano M, Pickeral O, Petersen RC, Mohs RC, Carrillo M, Corey-Bloom JP, Foster NL, Jacobsen S, Lee V, Potter WZ, Sabbagh MN, Salmon D, Trojanowski JQ, Wexler N, Bain LJ. · Lou Ruvo Brain Institute, Las Vegas, NV 89106, USA. · Alzheimers Dement. · Pubmed #19328434 No free full text.

Abstract: This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

Spires-Jones TL, Mielke ML, Rozkalne A, Meyer-Luehmann M, de Calignon A, Bacskai BJ, Schenk D, Hyman BT. · MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Charlestown, MA, USA. · Neurobiol Dis. · Pubmed #19028582 No free full text.

Abstract: Senile plaque-associated changes in neuronal connectivity such as altered neurite trajectory, dystrophic swellings, and synapse and dendritic spine loss are thought to contribute to cognitive dysfunction in Alzheimer's disease and mouse models. Immunotherapy to remove amyloid beta is a promising therapy that causes recovery of neurite trajectory and dystrophic neurites over a period of days. The acute effects of immunotherapy on neurite morphology at a time point when soluble amyloid has been cleared but dense plaques are not yet affected are unknown. To examine whether removal of soluble amyloid beta (Abeta) has a therapeutic effect on dendritic spines, we explored spine dynamics within 1 h of applying a neutralizing anti Abeta antibody. This acute treatment caused a small but significant increase in dendritic spine formation in PDAPP brain far from plaques, without affecting spine plasticity near plaques or average dendritic spine density. These data support the hypothesis that removing toxic soluble forms of amyloid-beta rapidly increases structural plasticity possibly allowing functional recovery of neural circuits.

Zhao B, Yu M, Neitzel M, Marugg J, Jagodzinski J, Lee M, Hu K, Schenk D, Yednock T, Basi G. · Elan Pharmaceuticals Inc., 700 Gateway Boulevard, South San Francisco, CA 94080, USA. · J Biol Chem. · Pubmed #18032377 links to  free full text

Abstract: Production of amyloid beta peptides (Abeta), followed by their deposition in the brain as amyloid plaques, contributes to the hallmark pathology of Alzheimer disease. The enzymes responsible for production of Abeta, BACE1 and gamma-secretase, are therapeutic targets for treatment of Alzheimer disease. Two presenilin (PS) homologues, referred to as PS1 and PS2, comprise the catalytic core of gamma-secretase. In comparing presenilin selectivity of several classes of gamma-secretase inhibitors, we observed that sulfonamides in general tend to be more selective for inhibition of PS1-comprising gamma-secretase, as exemplified by ELN318463 and BMS299897. We employed a combination of chimeric constructs and point mutants to identify structural determinants for PS1-selective inhibition by ELN318463. Our studies identified amino acid residues Leu(172), Thr(281), and Leu(282) in PS1 as necessary for PS1-selective inhibition by ELN318463. These residues also contributed in part to the PS1-selective inhibition by BMS299897. Alanine scanning mutagenesis of areas flanking Leu(172), Thr(281), and Leu(282) identified additional amino acids that affect inhibitor potency of not only these sulfonamides but also nonsulfonamide inhibitors, without affecting Abeta production and presenilin endoproteolysis. Interestingly, many of these same residues have been identified previously to be important for gamma-secretase function. These findings implicate TM3 and a second region near the carboxyl terminus of PS1 aminoterminal fragment in mediating the activity of gamma-secretase inhibitors. Our observations demonstrate that PS-selective inhibitors of gamma-secretase are feasible, and such inhibitors may allow differential inhibition of Abeta peptide production and Notch signaling.

Ren Z, Schenk D, Basi GS, Shapiro IP. · Elan Pharmaceuticals, Inc., South San Francisco, California 94080, USA. · J Biol Chem. · Pubmed #17890228 links to  free full text

Abstract: Amyloid beta-protein (Abeta), the major component of cerebral plaques associated with Alzheimer disease, is derived from amyloid beta-protein precursor (APP) through sequential proteolytic cleavage involving beta- and gamma-secretase. The intramembrane cleavage of APP by gamma-secretase occurs at two major sites, gamma and epsilon, although the temporal and/or mechanistic relationships between these cleavages remain unknown. In our attempt to address this issue, we uncovered an important regulatory role for the APP luminal juxtamembrane domain. We demonstrated in cell-based assays that domain replacements in this region can greatly reduce secreted Abeta resulting from gamma-cleavage without affecting the epsilon-cleavage product. This Abeta reduction is likely due to impaired proteolysis at the gamma-cleavage site. Further analyses with site-directed mutagenesis identified two juxtamembrane residues, Lys-28 and Ser-26 (Abeta numbering), as the critical determinants for efficient intramembrane proteolysis at the gamma-site. Consistent with the growing evidence that epsilon-cleavage of APP precedes gamma-processing, longer Abeta species derived from the gamma-cleavage-deficient substrates were detected intracellularly. These results indicate that the luminal juxtamembrane region of APP is an important regulatory domain that modulates gamma-secretase-dependent intramembrane proteolysis, particularly in differentiating gamma- and epsilon-cleavages.

Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, Vlachouli C, Wilkinson D, Bayer A, Games D, Seubert P, Schenk D, Holmes C. · Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK. · J Neuropathol Exp Neurol. · Pubmed #17086100 No free full text.

Abstract: Neuropathologic examination of 3 patients with Alzheimer disease in the Elan Pharmaceuticals trial using antibodies specific for different Abeta species showed in one case, 4 months after the immunization, evidence of a stage of active plaque clearance with "moth-eaten" plaques and abundant Abeta phagocytosis by microglia. At 1 to 2 years after immunization, 2 cases showed extensive areas cleared of plaques (69% and 86% of the temporal cortex was plaque-free). Cortex cleared of plaques in all 3 cases had a characteristic constellation of features, including a very low plaque burden, sparse residual dense plaque cores, and phagocytosed Abeta within microglia. There was resolution of tau-containing dystrophic neurites, although other features of tau pathology (tangles and neuropil threads) remained and cerebral amyloid angiopathy persisted. Although most antibodies generated by Abeta42 immunization in humans bind the intact N-terminus, immunohistochemistry with specific antibodies showed clearance of all major species of Abeta (Abeta40, Abeta42, and N-terminus truncated Abeta). Abeta immunotherapy can clear all Abeta species from the cortex. However, if it is to be used for treatment of established Alzheimer disease, then the residual tau pathology and cerebral amyloid angiopathy require further study.

Buckwalter MS, Coleman BS, Buttini M, Barbour R, Schenk D, Games D, Seubert P, Wyss-Coray T. · Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA. · J Neurosci. · Pubmed #17079673 links to  free full text

Abstract: Immunotherapy targeting the amyloid beta (Abeta) peptide is a novel therapy under investigation for the treatment of Alzheimer's disease (AD). A clinical trial using Abeta(1-42) (AN1792) as the immunogen was halted as a result of development of meningoencephalitis in a small number of patients. The cytokine TGF-beta1 is a key modulator of immune responses that is increased in the brain in AD. We show here that local overexpression of TGF-beta1 in the brain increases both meningeal and parenchymal T lymphocyte number. Furthermore, TGF-beta1 overexpression in a mouse model for AD [amyloid precursor protein (APP) mice] leads to development of additional T cell infiltrates when mice were immunized at a young but not old age with AN1792. Notably, only mice overproducing both Abeta (APP mice) and TGF-beta1 experienced a rise in T lymphocyte number after immunization. One-third of infiltrating T cells were CD4 positive. We did not observe significant differences in B lymphocyte numbers in any of the genotypes or treatment groups. These results demonstrate that TGF-beta1 overproduction in the brain can promote T cell infiltration, in particular after Abeta(1-42) immunization. Likewise, levels of TGF-beta1 or other immune factors in brains of AD patients may influence the response to Abeta(1-42) immunization.

Buttini M, Masliah E, Barbour R, Grajeda H, Motter R, Johnson-Wood K, Khan K, Seubert P, Freedman S, Schenk D, Games D. · Elan Pharmaceuticals, South San Francisco, California 94080, USA. · J Neurosci. · Pubmed #16207868 links to  free full text

Abstract: Alzheimer's disease neuropathology is characterized by key features that include the deposition of the amyloid beta peptide (Abeta) into plaques, the formation of neurofibrillary tangles, and the loss of neurons and synapses in specific brain regions. The loss of synapses, and particularly the associated presynaptic vesicle protein synaptophysin in the hippocampus and association cortices, has been widely reported to be one of the most robust correlates of Alzheimer's disease-associated cognitive decline. The beta-amyloid hypothesis supports the idea that Abeta is the cause of these pathologies. However, the hypothesis is still controversial, in part because the direct role of Abeta in synaptic degeneration awaits confirmation. In this study, we show that Abeta reduction by active or passive Abeta immunization protects against the progressive loss of synaptophysin in the hippocampal molecular layer and frontal neocortex of a transgenic mouse model of Alzheimer's disease. These results, substantiated by quantitative electron microscopic analysis of synaptic densities, strongly support a direct causative role of Abeta in the synaptic degeneration seen in Alzheimer's disease and strengthen the potential of Abeta immunotherapy as a treatment approach for this disease.

Lee M, Bard F, Johnson-Wood K, Lee C, Hu K, Griffith SG, Black RS, Schenk D, Seubert P. · Elan Pharmaceuticals, Inc., So. San Francisco, CA 94080, USA. · Ann Neurol. · Pubmed #16130106 No free full text.

Abstract: Serum samples from Alzheimer's disease (AD) patients immunized with Abeta42 (AN1792) were analyzed to determine the induced antibody properties including precise amyloid-beta peptide (Abeta) epitopes and amyloid plaque-binding characteristics. The predominant response in these patients is independent of whether or not meningoencephalitis developed and is against the free amino terminus of Abeta. The immunostaining of amyloid plaques in brain tissue by patient sera is adsorbable by a linear Abeta1-8 peptide, demonstrating that the antibodies are directed predominantly to this epitope and not dependent on Abeta conformations or aggregates specific to plaques. Furthermore, the antibodies are not capable of binding amyloid precursor protein and would be predicted to be competent in facilitating clearance of amyloid plaques in AD brains.

Malinin NL, Wright S, Seubert P, Schenk D, Griswold-Prenner I. · Elan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, USA. · Proc Natl Acad Sci U S A. · Pubmed #15710903 links to  free full text

Abstract: Based on a variety of genetic, biochemical, and neuropathological evidence, amyloid-beta peptide (Abeta) has been suggested to be causal in Alzheimer's disease (AD). Abeta has been shown to mediate neurodegenerative and inflammatory changes associated with amyloid plaques, as well as exert direct neurotoxicity through oligomeric forms of Abeta. The mechanism of Abeta toxicity, however, remains largely unknown. In this work, we show that an early event after exposure of postmitotic neurons to Abeta is tyrosine phosphorylation of FISH adapter protein. FISH binds to and potentially regulates certain ADAM family members. We present evidence that FISH and ADAM12 mediate the neurotoxic effect of Abeta. Expression of an ADAM12 protease-deficient mutant (ADAM12DeltaMP) blocks Abeta-induced neuronal death, and expression of an N-terminal fragment of FISH reduces Abeta toxicity. The C-terminal fragment of FISH containing the ADAMs binding region is found to be sufficient for induction of neuronal death, which is prevented by coexpression of the ADAM12DeltaMP. Abeta treatment, as well as expression of the C-terminal toxic FISH fragment, induces accumulation of ADAM12 N-terminal cleavage product in conditioned medium, demonstrating activation of the ADAM metalloprotease/sheddase activity. ADAM12 protein is reduced in AD brains, pointing to a possible increase in ADAM12 proteolytic activity. These data suggest that Abeta toxicity is mediated by FISH and ADAM12 and may provide insights into therapeutic strategies for AD treatment.

Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C, Seubert P, Games D, Kirby L, Schenk D. · Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, USA. · Neurology. · Pubmed #15642916 No free full text.

Abstract: The authors report a patient with Alzheimer disease (AD) without encephalitis who was immunized with AN-1792 (an adjuvanted formulation of Abeta-42). There were no amyloid plaques in the frontal cortex and abundant Abeta-immunoreactive macrophages, but tangles and amyloid angiopathy were present. The white matter appeared normal and minimal lymphocytic infiltration in the leptomeninges was observed. This case illustrates the effects of an Abeta-based immunization on AD pathogenesis in the absence of overt meningoencephalitis and leukoencephalopathy.

Bussière T, Bard F, Barbour R, Grajeda H, Guido T, Khan K, Schenk D, Games D, Seubert P, Buttini M. · Elan Pharmaceuticals, South San Francisco, California, USA. · Am J Pathol. · Pubmed #15331422 links to  free full text

Abstract: Transgenic mice mimicking certain features of Alzheimer's disease (AD)-pathology, namely amyloid plaques and neurofibrillary tangles, have been developed in an effort to better understand the mechanism leading to the formation of these characteristic cerebral lesions. More recently, these animal models have been widely used to investigate emergent therapies aimed at the reduction of the cerebral amyloid load. Several studies have shown that immunotherapy targeting the amyloid peptide (Abeta) is efficacious at clearing the amyloid plaques or preventing their formation, and at reducing the memory/behavior impairment observed in these animals. In AD, different types of plaques likely have different pathogenic significance, and further characterization of plaque pathology in the PDAPP transgenic mice would enhance the evaluation of potential therapeutics. In the present study, a morphological classification of amyloid plaques present in the brains of PDAPP mice was established by using Thioflavin-S staining. Neuritic dystrophy associated with amyloid plaques was also investigated. Finally, the efficacy of passive immunization with anti-Abeta antibodies on the clearance of Thio-S positive amyloid plaques was studied. Our results show that distinct morphological types of plaques are differentially cleared depending upon the isotype of the antibody.

Krezowski J, Knudson D, Ebeling C, Pitstick R, Giri RK, Schenk D, Westaway D, Younkin L, Younkin SG, Ashe KH, Carlson GA. · McLaughlin Research Institute, 1520 23rd Street South, Great Falls, MT 59405, USA. · Hum Mol Genet. · Pubmed #15254013 links to  free full text

Abstract: Phenotypes produced by expression of human amyloid precursor protein (APP) transgenes vary depending on the genetic background of the mouse. FVB/N mice overexpressing human APP695 develop a central nervous system disorder and die prematurely, precluding development of Abeta peptide amyloid plaques. 129S6 mice are resistant to the lethal effects of APP overexpression, allowing sufficient levels of Abeta expression for the development of amyloid plaques and age-dependent memory deficits. To identify the genes that determine susceptibility or resistance to APP we analyzed crosses involving FVB/NCr and 129S6.Tg2576 mice that overexpress 'Swedish' mutant (K670N, M671L) APP695. APP transgene-positive FVB129S6F1 (F1) mice are resistant to the lethal effects of APP overexpression, so FVBxF1 backcross and F2 intercross offspring were produced. Analysis of age of death as a quantitative trait revealed significant linkage to loci on proximal chromosome 14 and on chromosome 9; 129S6 alleles protect against the lethal effects of APP. Within the chromosome 14 interval are segments homologous to regions on human chromosome 10 that have been linked to late onset Alzheimer's disease or to levels of Abeta peptide in plasma. However, analysis of plasma Abeta peptide concentrations at 6 weeks in backcross offspring produced no significant linkage. Similarly, elevation of human Abeta peptide concentrations by expression of mutant presenilin transgenes did not increase the proportion of mice dying prematurely, suggesting that early death reflects effects of APP or fragments other than Abeta.

Reilly JF, Games D, Rydel RE, Freedman S, Schenk D, Young WG, Morrison JH, Bloom FE. · Neurome, Inc., La Jolla, CA 92037, USA. · Proc Natl Acad Sci U S A. · Pubmed #12697936 links to  free full text

Abstract: Various transgenic mouse models of Alzheimer's disease (AD) have been developed that overexpress mutant forms of amyloid precursor protein in an effort to elucidate more fully the potential role of beta-amyloid (A beta) in the etiopathogenesis of the disease. The present study represents the first complete 3D reconstruction of A beta in the hippocampus and entorhinal cortex of PDAPP transgenic mice. A beta deposits were detected by immunostaining and thioflavin fluorescence, and quantified by using high-throughput digital image acquisition and analysis. Quantitative analysis of amyloid load in hippocampal subfields showed a dramatic increase between 12 and 15 months of age, with little or no earlier detectable deposition. Three-dimensional reconstruction in the oldest brains visualized previously unrecognized sheets of A beta coursing through the hippocampus and cerebral cortex. In contrast with previous hypotheses, compact plaques form before significant deposition of diffuse A beta, suggesting that different mechanisms are involved in the deposition of diffuse amyloid and the aggregation into plaques. The dentate gyrus was the hippocampal subfield with the greatest amyloid burden. Sublaminar distribution of A beta in the dentate gyrus correlated most closely with the termination of afferent projections from the lateral entorhinal cortex, mirroring the selective vulnerability of this circuit in human AD. This detailed temporal and spatial analysis of A beta and compact amyloid deposition suggests that specific corticocortical circuits express selective, but late, vulnerability to the pathognomonic markers of amyloid deposition, and can provide a basis for detecting prior vulnerability factors.

Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, Khan K, Kholodenko D, Lee C, Lee M, Motter R, Nguyen M, Reed A, Schenk D, Tang P, Vasquez N, Seubert P, Yednock T. · Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA. · Proc Natl Acad Sci U S A. · Pubmed #12566568 links to  free full text

Abstract: Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing beta-amyloid peptide (Abeta) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the Abeta peptide. Similar protection could be achieved by passive administration of some but not all monoclonal antibodies against Abeta. In the current studies we sought to define the optimal antibody response for reducing neuropathology. Immune sera with reactivity against different Abeta epitopes and monoclonal antibodies with different isotypes were examined for efficacy both ex vivo and in vivo. The studies showed that: (i) of the purified or elicited antibodies tested, only antibodies against the N-terminal regions of Abeta were able to invoke plaque clearance; (ii) plaque binding correlated with a clearance response and neuronal protection, whereas the ability of antibodies to capture soluble Abeta was not necessarily correlated with efficacy; (iii) the isotype of the antibody dramatically influenced the degree of plaque clearance and neuronal protection; (iv) high affinity of the antibody for Fc receptors on microglial cells seemed more important than high affinity for Abeta itself; and (v) complement activation was not required for plaque clearance. These results indicate that antibody Fc-mediated plaque clearance is a highly efficient and effective process for protection against neuropathology in an animal model of Alzheimer's disease.