The Amyloid Hypothesis history and alternatives
In this centenary review, I outline two emerging hypotheses for us to consider if anti-amyloid approaches fail to have significant clinical impact. The amyloid hypothesis of Alzheimer's disease, which was first explicitly proposed on the basis of genetic data by my colleagues and me in 1991 and 1992 Hardy and Allsop 1991 Hardy and Higgins 1992 and, contemporaneously, by Selkoe 1991 and was implicit in the earlier work of Glenner and Murphy 1989 and Masters and Beyreuther 1987 , has become the...
Collaboration with Hiroshi Mori in establishing DF2
In October 1984, after two years of constant exhaustion as the person in charge of the neurology outpatient clinic, I moved to the Tokyo Metropolitan Institute of Gerontology director Dr. Kazutomo Imahori as the head of the Second Laboratory, Department of Physiology. I was almost free from clinical practice and was devoted to lab work every day, in efforts to identify the components of PHF. Dennis and I frequently discussed our progress by letter and over the phone. He wrote that he had read a...
A place of knowledge liberty and friendship
What lessons can we take away from these 20 years of dedication to Alzheimer's disease and collaboration with its heroes I see at least three. The first has to do with the spirit of cultivating knowledge. As both specialists and non-specialists in Alzheimer's disease have always been involved in studying the disease, research has been able to benefit massively from the outside contributions. This fact can be plainly seen by anyone reading the themes and speakers' names at Fondation Ipsen's...
The proteolytic function of Presenilin
Genetic deficiency of Presenilin in C. elegans Levitan and Greenwald 1995 , as was later confirmed in mice Shen et al. 1997 Wong et al. 1997 and fly Struhl and Greenwald 1999 Ye et al. 1999 , causes essentially Notch signalling deficiencies. Notch is an important regulator of cell differentiation and is involved in embryogenesis, neurite outgrowth, and T cell differentiation, but also in cancer. The mechanism by which Presenilin regulates Notch signalling was unravelled in 1999, by showing that...
How did the eponym Alzheimers disease come into being
In the autumn of 1903, Alois Alzheimer left Frankfurt. Following a short stay in Heidelberg, he moved to Munich to continue his scientific and medical activities at the Royal Psychiatric Clinic under director Emil Kraepelin. After Auguste D. died on April 8, 1906, Alzheimer asked that the record and the brain be sent to Munich. He immediately did a report on the admission formulas used in Munich at this time and wrote a full-page epicrisis. After this he made an entry to the autopsy book of the...
Year Recipient name recipient institution
1988 Robert D. Terry, MD University of California, San Diego, CA 1989 Dennis Selkoe, MD Harvard Medical School, Boston, MA George G. Glenner MD University of California, San Diego, CA 1990 Colin Masters, MD University of Melbourne, Australia Konrad Beyreuther, PhD University of Heidelberg, Germany 1991 Stanley Prusiner, MD University of California, San Francisco, CA 1992 Donald L. Price, MD Johns Hopkins University School ofMedicine, Baltimore, MD Robert Katzman, MD University of California,...
Historical Background
In the late 1980s, when it was first recognized that the Ap peptide is a proteolytic cleavage product of the large amyloid precursor protein Kang et al. 1987 , the protease activities that cleave the peptide from the precursor, termed p- and y-secretases, became highly interesting. Initially, it was unclear whether numerous proteases were involved and it was unknown whether p- and y-secretases were constitutively active or only became activated in the brains of Alzheimer's disease AD patients....
Alzheimers final years
Alzheimer was a passionate scientist. He worked very long hours andrarely took time off for a holiday. In Munich, he worked without a salary for years and even paid a large part of the cost incurred by his research from his private funds. In 1909, his commitment was honored and he was appointed as extraordinarius assistant professor at the University of Munich. His scientific merits are reflected by his appointment as editor of a newly established psychiatric journal in 1910, at a time when the...
The Discovery of Amyloid
Dr. George G. Glenner died too young in 1995 due to complications of cardiac amy-loidosis. If he had survived, perhaps he and I would be writing this story together. Instead it will only be my personal recollections of the work we did in 1982-85 that led us to the discovery of the Alzheimer's disease beta protein, Glenner and Wong 1984a now also known as A-beta and beta-A amyloid. My introduction to George Glenner was in 1982, when I interviewed for a job in his new laboratory at the University...
Segregation of a missense mutation in the amyloid protein precursor gene with
In 1991, little was known about the pathogenesis of Alzheimer's disease AD . Earlier studies had demonstrated that plaques contain amyloid p Ap and that neurofibril-lary tangles were composed of paired-helical filaments of hyperphosphorylated tau Glenner and Wong 1984a Masters et al. 1985a Grundke-Iqbal et al. 1986a . However, a major impediment to a more detailed understanding of AD was the absence of cellular or animal models of disease. Mutations in APP cause AD and stroke resulting from...
Targeting ySecretase for Alzheimers Disease
Y-Secretase is responsible for the final proteolysis that produces the amyloid p-peptide Ap from its precursor, amyloid precursor protein APP , and has been considered a potential therapeutic target for Alzheimer's disease AD since the early 1990s, even before anything was known about its character or identity. This protease activity, which takes place within the transmembrane domain of APP, generates heterogeneity at the C-terminus of Ap peptides, forming longer, minor variants, especially the...
Early History Pre WWII Era
The current approach of combining clinical and biological studies of dementia started to take shape at the beginning of the 20th century in parallel with advances in histology chemistry of tissue stains , light microscopy and neuroanatomy Beach 1987 Bick et al. 1987 . The early pioneers of the field were able to make some groundbreaking observations about dementia because of access to a wealth of new technologies for studying the brain and the emergence of vibrant academic environments that...
The relationship between tauopathy and amyloidosis in aging and sporadic AD
It is not surprising that tau pathology is well correlated to cognitive impairment, since it shows the neurodegeneration process and its extent. However, we do not know the factors that generate tauopathy and its extension in brain areas. ApPP dysfunction is the best candidate, as revealed by genetic studies. Therefore, we quantified all ApPP metabolic products to locate a possible relationship with the different stages of tau pathology. ApPP holoproteins, ApPP-CTFs and Ap species were analyzed...
Tau focused drug discovery for Alzheimers disease and related Neurodegenerative
Virginia M.-Y. Lee1 and John Q. Trojanowski1 Alzheimer's disease AD , like most neurodegenerative disorders, results from the aggregation of misfolded proteins that deposit as fibrillar amyloid lesions in the central nervous system CNS , where they are thought to be toxic and compromise brain function reviewed in Forman et al. 2004 Skovronsky et al. 2006 . For example, neurofibrillary tangles NFTs and senile plaques SPs were first recognized by Alois Alzheimer at the beginning of the 20th...
Future directions
Now, as there is evidence that the strategy of a-secretase activation may work, the question arises how such an activation may be achieved in humans with beneficial effects for the prevention or treatment of AD. One approach is to stimulate the non-amyloidogenic pathway by activation of G protein-coupled receptors that are localized in brain areas affected by AD. Recently, it has been reported that a newly developed Ml agonist reducedboth the P-and tau-pathologyin hippocampus and cortex and...
Symptomatic agents eg acetylcholinesterase inhibitor NMDA antagonist other
Fig. 2. New Way to manage Alzheimer's disease Those pre-symptomatic subjects who have altered test results as above but also have a clearly positive Ap brain scan will be categorized as harboring active AD-type disease that requires even more vigorous treatment. This treatment may include a p- or Y-secretase modulator plus a form of anti-Ap immunotherapy. At this writing, one can still speculate that an active vaccine employing a small N-terminal Ap peptide might turn out to be both safe and...
Of stains and brains a brief account of how microscopic and clinical
Charles Duyckaerts1 and Jean-Jacques Hauw1 At the eve of the 20th century, when Max Bielschowsky, using chemicals common in photography, described the silver technique to which his name is now attached, he believed that he had discovered a reliable way of staining the so-called neurofibrils Bielschowsky 1902, 1903 . Neurofibrils, described by Remak in 1838, make up a visible network of thin intracellular structures visible in the cell body and the processes mainly the axon of neurons. It is no...
Stages I and II
The first cortical neurons to become involved are usually specific projection cells of the transentorhinal region, which is located in the rhinal sulcus found in anteromedial portions of the temporal lobe Fig. 1, stage I . From there, the pathology reaches the superficial cellular layer layer pre-a or layer II and then the deep layer pri-a of the entorhinal region Fig. 1, stage II Braak and Braak 1992 . Additionally, the first sector and or second sector of the hippocampal formation become...
Fondation Ipsen and Alzheimers disease a 20year relationship
Shortly after its founding in 1983, Fondation Ipsen's destiny became intertwined with that of alzheimerology and although its activities extend to fields as diverse as endocrinology, oncology, neuroscience and cardiovascular pathologies, the foundation is most often associated with its focus on Alzheimer's disease. Chance, rather than strategy, was the main engineer at work. As the foundation published the first issue of Alzheimer Actualit s Alzheimer News in June 1986, and later organized its...
Molecular and cellular pathways towards and away from Alzheimers disease
Research in my laboratory is aimed at understanding the factors that determine whether neurons thrive or degenerate during aging http www.grc.nia.nih.gov branches lns index.html . Our approach is to elucidate molecular and cellular mechanisms that regulate neuronal plasticity and survival, in the contexts of brain development and aging, and to determine if and how these mechanisms are altered in neurodegenerative disorders. We are particularly interested in signaling and metabolic pathways that...
Synaptic activity amyloidp and Alzheimers disease
John R. Cirrito1'2'4 and David M. Holtzman1'3'4'5 An unsolved mystery for most neurodegenerative disorders, including Alzheimer's disease AD , is why the underlying pathology that occurs is region-specific. In other words, why are some brain regions vulnerable and others not Several interesting findings and events have come together over the last six years that have led us to hypothesize that one of the reasons that the amyloid-p Ap peptide deposits in aregion-specific fashion in AD is related...
Mutation of the Alzheimers disease amyloid gene in hereditary cerebral
The first cerebral amyloid molecule identified was extracted in 1983 from cerebral blood vessels obtained at autopsy from Icelandic patients who died from massive brain hemorrhages due to the deposition of cystatin C fibrils in the vessel walls Cohen et al. 1983 , a condition referred to as hereditary cerebral hemorrhage with amyloidosis HCHWA . The importance of this study extended beyond the identification of a molecule linked to a cerebral amyloid disease it described a novel and simple...
Tauopathies and neurodegeneration
By the early 1990s, the presence of tau had also been revealed by immunological studies in the deposits of progressive supranuclear palsy PSP , corticobasal degeneration CBD and Pick's disease PiD Pollock et al. 1986 Lee et al. 2001 . Unlike AD, these diseases lack significant Ap pathology. Hyperphosphorylation of tau is a feature common to all these diseases. The phos-phorylated sites are similar, with only minor differences between diseases. However, differences in the tau isoform composition...
Properties of tau protein Cellular traffic system
An early feature of AD is the loss of synapses in the hippocampus and entorhinal region, which corresponds to a loss of memory Flood and Coleman 1990 Terry et al. 1991 . It may be initiated by factors such as inflammatory cytokines, oxidative stress, loss of growth factors, or the toxic Ap peptide Raff et al. 2002 Selkoe 2002 . Synapse loss precedes the abnormal protein aggregation in senile plaques, neurofibrillary tangles, and others. One clue for this vulnerability comes from the elongated...
Tau and Alzheimer paired helical filaments
The molecular structure of PHFs is still unknown but determining it represents one of the major goals in the field, since this would greatly aid in the development of methods and drugs to prevent pathological aggregation. From a structural point of view, there was a long gap between Alzheimer's discovery of neurofibrillary tangles Alzheimer 1907a and the identification of PHFs as their basic elements, made possible by the advances in electron microscopy Kidd 1963 Terry 1963 . Another two...
antiaggr mutant
Fig. 7. Cell model of tau aggregation, based on the inducible expression of tau protein repeat domain in N2a cells. The red fluorescence left column shows the presence of tau repeat domain after switching on its gene expression. The green fluorescence right column illustrates aggregation aggr. with cross-p structure, visualized by the dye thioflavin-S. Note the pronounced aggregation with the pro-aggregation mutant AK280 middle row , but much lower or no aggregation in the case of the wild-type...
From Insoluble to Soluble and from Pathogen to Protector
The new era of Alzheimer's disease AD research, catalyzed by the studies of Tomlin-son, Blessed and Roth in the UK and Katzman in the US, can be broadly characterized into two major epochs. The first era involved studying the insoluble protein components of fibrils of the canonical lesions of AD, the senile plaques and neurofibrillary tangles NFT . While classifying the pathology as causative in disease pathogenesis was noseological, the die was cast and, for the first epoch, research centered...
Hippocampal imaging in the early diagnosis of AD 1988 to 2006
Groucho Marx said, Time flies like an arrow. Fruit flies like a banana such are my experiences in writing this summary. In 1977, as a tuition-poor Columbia University student, intrigued about the anatomical basis for dementia, I needed to develop a doctoral dissertation project. Computed Tomography CT , introduced in 1972, was in its first generation in New York City. A fellow student told me, that at NYU, Steven Ferris was using CT scans to screen dementia patients for clinical trials. I was...
ApoE4 A case of evolutionary underperformance
The original arguments that we put forward to support the concept that apoE4 acts on synaptic integrity and plasticity through alterations of brain lipid physiology were, and are still, based on several key biochemical observations 1 ApoE4, with its polymorphisms at amino acid sites 112 and 158, represents the ancestral form of the apoE gene Finch and Stanford 2004 . Homo sapiens only recently acquired the apoE3 and apoE2 allelic variants. All the other mammals and primates examined so far...
Springer
Department of Cellular Neurology Hertie Institute for Clinical Brain Research University of T bingen 72076 T bingen Germany e-mail mathias.jucker uni-tuebingen.de Christian Haass Adolf-Butenandt-Institute Department of Biochemistry Laboratory for Alzheimer's and Parkinson's Disease Research Ludwig-Maximilians-University 80336 Munich Germany Division of Psychiatry Research University of Zurich 8008 Zurich Switzerland Cover illustration by Ingram Pinn ISSN 0945-6066 ISBN-10 3-540-37651-8 Springer...
Tau and microtubules
The scientific history of tau protein is closely linked to the discovery of microtubule self-assembly in the early 1970s. Previously, tubulin was known as a major colchicine-binding protein in the brain BorisyandTaylor 1967 ,butthe conditions for assembling this protein into microtubules remained elusive until they were found by Weisenberg 1972 and others. This finding paved the way for identifying the central roles of microtubules for cell division, cell shape, and intracellular transport. An...
Discovery of tau as the major protein subunit of PHF
We generated both monoclonal Wang et al. 1984 and polyclonal Grundke-Iqbal et al. 1984, 1985a,b antibodies against PHF purified from AD brains Iqbal et al. 1984 . These antibodies labeled neurofibrillary tangles and plaque neurites in AD brain sections and six protein bands in the 50-kDa-70-kDa area, a typical tau pattern on Western blots of isolated PHF. By immunoabsorption of the polyclonal antibodies to PHF and antisera to microtubules that labeled tangles on tissue sections, with tubulin,...
Alois Alzheimers Life
Alois Alzheimer was born on June 14,1864, in Marktbreit, a small town in lower Fran-conia on the Main river in Bavaria, southern Germany. His father was a Royal Bavarian 1 Department of Psychiatry Psychosomatic and Psychotherapy, Johann Wolfgang Goethe- University, Heinrich Hoffmann Str. 10, 60528 Frankfurt, Germany From Concepts of Alzheimer Diseasae, Biological, Clinical and Cultural Perspectives Eds. Peter J. Whithehouse, Konrad Maurer, Jesse Ballenger 2000 The John Hopkins University Press...
Reaction to our paper and independent confirmations
Our study was published in Science in October 1999, and we were able to present it at very short notice during the same week at the Neuroscience meeting in Miami. The significance of the study was immediately and widely recognized both by the scientific Alzheimer's community and by the news media. Because of the extensive validation that we had provided, there was essentially no discussion regarding whether we had identified the enzyme or not the data were conclusive. Subsequently four other...
Auguste D and her File
Until 1989 the whereabouts of Alzheimer's birthplace were largely unknown. That year, on the occasion of a symposium to celebrate Alzheimer's 125th birthday, the house, located in Marktbreit was discovered by Dr. and Mrs. Mony de Leon from New York on a side trip from the W rzburg Imaging in Psychiatry conference organized by Dr. Maurer, verified as correct by Dr. Konrad Maurer, subsequently fitted by the Maurer couple with a memorial plaque, and after purchase by Eli Lilly, converted into a...
How did the eponym Alzheimers Disease came into being
The year 2006 marks the centenary of Alois Alzheimer's remarkable presentation on A Characteristic Disease of the Cerebral Cortex. Alzheimer read this paper during an afternoon session of the 37th Assembly of Southwest German Psychiatrists in T bingen. Eighty-eight physicians and researchers were present including Binswanger, Curschmann, D derlein, Levi, Merzbacher, Nissl and Romberg. Besides Alzheimer Binswanger and Levi were to become well know eponymists. Carl Gustav Jung from the Burgh lzli...
Auguste D the first patient diagnosed with Alzheimers disease
On the November 26, 1901, Alzheimer examined Auguste D. for the first time. The entry into her case file revealed that, eight months earlier, Auguste D. had developed increasing signs of a change in her personality Maurer et al. 1997, 2000, 2003 . Her memory failed her. More and more, she neglected her household chores and began hiding objects. When preparing food, she made mistakes and spoiled the dishes. She became agitated and aimlessly paced around her apartment. Frequently, she was lost in...
Alzheimer joins Kraepelin
In 1903, after 14 years in Frankfurt, Alzheimer left the Frankfurt institution. Emil Kraepelin Fig. 4 , one of the most influential psychiatrists of his time, had offered him a position as scientific assistant at his clinic in Heidelberg. Alzheimer's close friend, Franz Nissl, who had previously also moved to Heidelberg, persuaded Alzheimer to join them. Alzheimer's stay in Heidelberg, however, was to be short. Only six months after he had taken up his new position, in the autumn of 1903,...
List of Contributors
Departments of Neurology and Neuroscience, University of Minnesota Medical School, 420 Delaware St., And Geriatric Research, Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417, USA Departments of Medicine, Medical Biophysics, Laboratory Medicine and Pathobiology, Tanz Neuroscience Bldg, University of Toronto, Toronto, Ontario M5S 3H2, Canada Centre for Molecular Biology, The University of Heidelberg, Neuenheimer Feld 282, 6900 Heidelberg, Germany...
One hundred years of Alzheimer research
Few medical or scientific addresses have so unmistakeably made history as the presentation delivered by Alois Alzheimer on November 4,1906 in T bingen. The one-hundred year anniversary of that event has been marked on several occasions in 2006, most notably at the very site of the original lecture, namely the Institute of Psychiatry of the University of T bingen in Germany on November 2-5,2006. The celebratory event, Alzheimer 100 Years and Beyond organized on the initiation of the Alzheimer...
Cholinergic Deficit
The cholinergic deficit in Alzheimer's disease Acetylcholine in AD Expectations meet reality Pathways to the discovery of the neuronal origin and proteolytic biogenesis of Ap amyloid of Alzheimer's disease Colin L Masters, Konrad Beyreuther 143 The Amyloid Hypothesis history and alternatives Segregation of a missense mutation in the amyloid p-protein precursor gene with familial Alzheimer's disease From the amyloid p protein A4 to isolation of the first Alzheimer's disease gene amyloid p A4...