Jan K. Teller

Presenilin-1 mutations in Alzheimer's disease

Mutations in the gene encoding the protein presenilin-1 are the most common cause of familial Alzheimers disease and they often produce a different disease course from sporadic Alzheimers and another familial form associated with mutations in the gene encoding β-amyloid precursor protein. Here we show that a peculiar form of β-amyloid that is devoid of the first ten amino acids accumulates in the brains of patients carrying presenilin-1 mutations, and is more abundant than in subjects affected by the other types of Alzheimers.

Heterogeneity of water-soluble amyloid β-peptide in Alzheimer's disease and Down's syndrome brains

Water‐soluble amyloid β‐peptides (sAβ), ending at residue 42, precede amyloid plaques in Downs syndrome (DS). Here we report that sAβ consists of the full‐length Aβ1–42 and peptides truncated and modified by cyclization of the N‐terminal glutamates, Aβ3(pE)–42 and Aβ11(pE)–42. The Aβ3(pE)–42 peptide is the most abundant form of sAβ in Alzheimers disease (AD) brains. In DS, sAβ3(pE)–42 concentration increases with age and the peptide becomes a dominant species in the presence of plaques. Both pyroglutamate‐modified peptides and the full‐length Aβ form a stable aggregate that is water soluble. The findings point to a crucial role of the aggregated and modified sAβ in the plaque formation and pathogenesis of AD.

Identification of Amino-Terminally and Phosphotyrosine-Modified Carboxy-Terminal Fragments of the Amyloid Precursor Protein in Alzheimer's Disease and Down's Syndrome Brain

The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered β-amyloid (Aβ) precursors as well as molecular species possibly amyloidogenic and neurotoxic by themselves in vitro or in animal models. The CTFs role in the pathogenesis of Alzheimers disease (AD) is however relatively unexplored in human brain. In this study, we analyzed brain extracted CTFs in subjects with AD, non-AD control, and Downs syndrome (DS) cases. Our data indicate that: (i) In fetal DS subjects CTFs levels are increased in comparison to age-matched control, suggesting that the enhanced CTFs formation is important for the early occurrence of plaques deposition in DS. No significant difference in CTFs level is present between AD and age-matched control cases. (ii) CTFs modified at their N-terminus are the direct precursors of similarly N-terminally modified Aβ peptides, which constitute the most abundant species in AD and DS plaques. This observation suggests that N-truncated Aβ peptides are formed directly at β-secretase level and not through a progressive proteolysis of full-length Aβ1-40/42. (iii) Among the differently cleaved CTFs, only the 22- and 12.5-kDa CTF polypeptides are tyrosine phosphorylated in both AD and control brain while the full-length APP and the CTFs migrating below the 12.5-kDa marker are not phosphorylated, suggesting that APP and CTFs may be involved in different pathways depending on their length and sequences. This study provides evidence that CTFs constitute in human brain a molecular species directly involved in AD pathogenesis and in the development of the AD-like pathology in DS subjects.

Amyloid-beta peptide Aβp3-42 affects early aggregation of full-length Aβ1-42

The major amyloid-beta (Abeta) peptides found in the brain of familial and late onset Alzheimers disease include the full-length Abeta1-42 and N-terminally truncated, pyroglutamylated peptides Abetap3-42 and Abetap11-42. The biophysical properties of Abeta1-42 have been extensively studied, yet little is known about the other modified peptides. We investigated the aggregation kinetics of brain-specific Abeta peptides to better understand their potential roles in plaque formation. Synthetic peptides were analyzed individually and in mixtures representing various ratios found in the brain. Spectrofluorometric analyses using Thioflavin-T showed that the aggregation of Abeta1-42 was faster compared to Abetap3-42; however, Abetap11-42 displayed similar kinetics. Surprisingly, mixtures of full-length Abeta1-42 and Abetap3-42 showed an initial delay in beta-sheet formation from both equimolar and non-equimolar samples. Electron microscopy of peptides individually and in mixtures further supported fluorescence data. These results indicate that Abeta-Abeta peptide interactions involving different forms may play a critical role in senile plaque formation and maintenance of the soluble Abeta pool in the brain.

reply: Alzheimer's disease: Molecular consequences of presenilin-1 mutation

Gandy et al. compare our results with their 1994 findings that the amino-terminally truncated amyloid Aβ11–42 was relatively abundant in two cases of familial Alzheimers disease involving two distinct mutations in β-APP. However, four important differences should be borne in mind: the authors compare Aβ11–42 with Aβ1–42 and ignore Aβ1–40, although both Aβ1–40 and Aβ1–42 are generated by β-secretase/BACE cleavage at residue Asp 1 (ref. 3); their data are not correlated with features related to disease severity, such as age at onset and duration; they did not examine brains with PS1 mutations (these were not known at that time); and their characterization was based on the use of size-exclusion chromatography and electrospray mass spectrometry to quantify formic-acid-extracted Aβ, whereas we used quantitative analysis of immunoprecipitated water-soluble Aβ on western blots, mass spectrometry to identify Aβ variants, and immunohistochemistry to reveal amino-truncated Aβ peptides in plaques.

Mechanisms of phenotypic heterogeneity in prion, Alzheimer and other conformational diseases

Department of Physiology, East Carolina University,Greenville, NC 27858, USA1. IntroductionOneof thechallengesfacedbyclinicians andpathol-ogistsis dealingwiththevariabilityoftheclinicalsignsandofthepathologicalchangesthatareassociatedwithdiseases. The truism that two patients with the samedisease are never identical poses no serious diagnosticproblems under most circumstances. However, therearediseasesthatpresentconsiderablevariabilityintheirclinical and pathological phenotype, which not onlymakes the diagnosis difficult but also raises the issue ofthe mechanisms that regulate it.While phenotypically Alzheimer disease, amy-otrophic lateral sclerosis and Huntington chorea havebeenconsideredfairlyhomogenousdiseases, priondis-eases include several clinically and pathologically dis-tinct conditions (Table 1) [33]. Until a few years ago,the sporadic form of prion diseases included only theCreutzfeldt-Jakobdisease(CJD)phenotype. Theinher-ited form included familial CJD, fatal familial insom-nia (FFI), and Gerstmann-Straussler-Scheinkerdisease¨(GSS). These three phenotypes are quite different andhave very unique features. In addition, a fourth sub-typeoffamilialpriondiseases associatedwithinsertionmutationshas eithera mixedphenotypewhichincludesfeatures of both CJD and GSS or a pathological phe-notype with no distinctive features. The form acquiredby infection consists of three phenotypes that are alsoquite distinct, namely the iatrogenic CJD, kuru, andthe new variant CJD reported almost exclusively in theUnited Kingdom.A major interest of our group has been the studyof the mechanisms that regulate the phenotypic het-erogeneity. The understanding of these mechanismsmay lead to a classification of prion diseases based onthe causes rather than the effects of this heterogene-ity. Such classification is likely to be more accurateand may result in a wider detection and more precisediagnosis of these diseases.2. Molecular, cell biology and pathology of theprion proteinThematurenormalorcellularprionprotein(PrP

Alzheimer Research Forum Live Discussion: Lost in Translation? Charting the Course in Preclinical Therapeutic Development1

Participants: Gabrielle Strobel (Alzheimer Research Forum), Patricia C. Heyn (University of Colorado Health Sciences Center), Jan Teller (Dystonia Medical Research Foundation), Howard Fillit, MD (Institute for the Study of Aging), Kelly R Koehn (Neuroxyn Pharmaceuticals), Jens Eckstein (principal at TVM, a transatlantic VC firm), Cynthia Joyce (Spinal Muscular Atrophy Foundation), Frank Longo (Department of Neurology, University of North Carolina-Chapel Hill), Eli Michaelis (University of Kansas), Jordan Tang (University of Oklahoma Health Science Center), Greg Brewer (Southern Illinois University School of Medicine), Edward Zamrini (University of Alabama Alzheimer’s Disease Research Center), June Kinoshita (Alzheimer Research Forum).