Immunotherapy of Alzheimers disease

Immunotherapy For Alzheimer

Nitsch1 and Christoph Hock1 Early in April 1906, Auguste Deter's brain was obtained by autopsy after four and a half years of progressive dementia that ultimately led to her death. Her doctor, Alois Alzheimer, who had cared for her, examined and photographed her since the initial admission in November 1901, stained microscopic sections of her brain by using his colleague's Franz Nissl newly established protocols. Besides profound neuron loss and fibrillar tangles, he found multiple...

Detecting Early Stage Alzheimers Disease in MCI and PreMCI The value of informants

Morris1 and Martha Storandt2 In the century since Alzheimer's seminal presentation of the original patient with Alzheimer's disease (AD Alzheimer et al. 1987), emphasis now is being given to the recognition of early-stage AD in comparison to nondemented aging. As a consequence, there is intense interest in mild cognitive impairment (MCI). The concept of MCI was introduced to characterize older individuals with cognitive deficits that, although abnormal for age, fell short of overt...

Magic bullets shotguns or cocktails to treat or prevent Alzheimers disease

For the most part, the single target approach to drug discovery has failed to identify magic bullets that significantly impact the clinical manifestations of CNS diseases (Roth et al. 2004). Even when a magic bullet that is purportedly selective for a single target proves efficacious in a certain disease setting, in time, a more complete understanding of its pharmacology often shows that efficacy can be attributable to 1) interaction with several molecular targets or 2) a more complex...

Was there a rediscovery

In terms of the history of science, Alzheimer's case presents an unusual problem, as it is a discovery in the process of expansion. Admittedly, there are large numbers of concepts or theories that are at first undervalued and whose full significance only becomes evident rather belatedly. But, Alzheimer's disease is not a theory or an idea. It is a disease that, since Alois Alzheimer's report in 1906, has never stopped affecting humans and which, of course, affected them before this time. How...

Ap is a secreted protein

Both Mark and Todd were fully supported by the NIH-sponsored Medical Scientist Training Program (MSTP) directed by Les Webster. To permit two of his coveted MSTP students to train simultaneously in my laboratory, which was largely unproven, was an act of enormous faith. I do not know why Les decided to back us, but I will always be grateful because his support enabled all of us to work to the limit of our ability. Within a few years, we learned that the APP was normally cleaved within the Ap...

The cholinergic deficit in Alzheimers disease

In the period immediately prior to publication of the first reports of cholinergic markers in the brains of patients with Alzheimer's disease, there was very little hard science going on in this field. This was before the recognition that Alzheimer's disease was the most common cause of dementia in the elderly, and it was generally thought to be a rather rare, pre-senile dementia. Having spent some time trying to do neurochemical analyses on the brains of schizophrenics, I became disillusioned...

Reanalysis of the first described cases of Alzheimers disease

The diagnosis of Auguste D. has since been confirmed by a re-examination of Alzheimer's original histological slides (Graeber et al. 1998 Graeber and Mehraein 1999). These analyses verified the loss of neurons in various areas of the cortex, the accompanying gliosis, as well as the presence of large numbers of typical neurofibrillary tangles and amyloid plaques in her cerebral cortex, precisely as had been described and depicted by Alzheimer. Moreover, the studies proved the absence of any...

Intracellular abnormal protein aggregates are ubiquitinated

Thanks to collaboration with Dr Shigeki Kuzuhara, presently Professor of Neurology at Mie University Hospital, a great number of brain tissue sections from consecutive autopsies were available in Tokyo Metropolitan Geriatric Hospital. Using these tissue sections, I examined whether DF2 might stain abnormal organelles other than NFT. To my surprise, DF2 strongly immunolabeled Lewy bodies, the major component of which was not known then. Staining was so strong that one could effortlessly...

Discovery of the tangle

On 3 November 1906 Alois Alzheimer, head of the Anatomical Laboratory of the Royal Psychiatric Clinic at the University of Munich, described a novel form of dementia at the 37th meeting of the Society of Southwest German Psychiatrists in T bingen. He published these findings in the short paper of 1907 and the more extensive article of 1911 (Alzheimer 1907,1911). In 1912, Alzheimer became Professor of Psychiatry at the University of Breslau (now Wroclaw). He died in 1915, aged 51. The paper...

Anatomical changes underlying dementia in Alzheimers disease

The severity of the clinical problem of Alzheimer's disease (AD) is astounding the Alzheimer's Association estimates that 1 in 10 Americans is affected by someone with AD in their family. Despite decades of research and advances in the cell biology and genetics of AD, current medications provide only subtle symptomatic benefits. Studies of the natural history of the illness present an even more worrisome image the pathologic changes of AD begin years prior to the emergence of overt clinical...

Acetylcholine in AD Expectations meet reality

The neuropharmacological consequences of finding evidence for deficient acetylcholine neurotransmission in AD have been complex. The initial optimism for a quick cure from choline or lecithin precursor administration, inspired by the success of levodopa in Parkinson's disease, quickly faded when put to the test. Nonetheless, the cholinergic hypothesis of memory dysfunction in AD was valid, and eventually it led to the introduction of AChEI drugs to increase acetylcholine transmission....

The genetic Alzheimerfrontotemporal dementia spectrum

Neurodegenerative brain diseases, including dementias, are common diseases among elderly people, and their population frequency is increasing rapidly because people are living longer due to high quality health care systems. Predictions indicate that in 2030 at least one in four people in Western European countries will be 65 years or older. In this age group, people are at high risk for neurodegenerative dementias such as Alzheimer's disease (AD), with risk increasing with age to as high as 20...

Alzheimers Disease at midCentury 19271977 and a little more

In 1959, when Saul Korey and I began to think about planning a study of Alzheimer's disease (AD), the situation seemed quite simple and straightforward. It was widely accepted that AD was exclusively a rare pre-senile disorder, that it was entirely different from senile dementia, that it had a simple dominant genetic inheritance, and that there had been little or no work related to the problem for several decades. All of these ideas soon showed themselves to be at least partially wrong....

Staging of cortical neurofibrillary inclusions of the Alzheimers type

Alzheimer's disease (AD) is the most widespread degenerative illness of the human central nervous system. It is progressive and is not subject to remission. Central to the pathological process that underlies this disorder is the formation of proteinaceous inclusions in selectively vulnerable neuronal types (Goedert 1993 Goedert et al. 1997 Jellinger 1998 Dickson 1999 Trojanowski and Lee 2000). The pathological inclusions consist, for the most part, of abnormal tau protein and appear as...

Aggregated and hyperphosphorylated tau proteins a powerful marker of neurofibrillary degeneration

Tau proteins are the basic component of neurofibrillary degeneration (NFD), as observed using histological (Brion et al. 1985c) and biochemical means. Using Western blots, we were able to detect and quantify abnormal tau species in AD brains, as they are aggregated, hyperphosphorylated and abnormally phosphorylated (Delacourte and Defossez 1986), in good agreement with the pioneer work of Brion et al. (1985c) and Grundke-Iqbal et al. (1986b). In addition, we were able to develop the concept of...

The spatiotemporal biochemical pathway oftau pathology in aging and sporadic AD

Tau pathology spreading in cortical areas is invariable and hierarchical A prospective and multidisciplinary study of more than 200 cases, including 70 non-demented patients, was undertaken. We gathered clinical and neuropathological data and, in parallel, studied the presence of NFD at the biochemical level, using the triplet of abnormal tau proteins as a marker. In Alzheimer brains, we observed that tau pathology always extended along 10 stages, corresponding to 10 brain areas that are...

Tau proteins are abnormally phosphorylated

The identification of tau as the core component of PHF was soon followedby the finding that the tau proteins in PHF were abnormally phosphorylated (Grundke-Iqbal et al. 1986b Ihara et al. 1986). The consequences of tau hyperphosphorylation in AD were further shown by studies demonstrating a much-reduced induction of MT assembly in AD brain (Iqbal et al. 1986). We also later observed a reduction of the immunoreactivity for stable microtubules in neurons containing PHF (Hempen and Brion 1996). By...

Genetics molecular biology and animal modeling of Alzheimers disease

Fraser1, D. Westaway1, J. McLaurin1, E. Rogaeva1, G. Schmitt-Ulms, A. Tandon1, H.T.J Mount1, J. Robertson1, and C. Bergeron1 Our group at the Center for Research in Neurodegenerative Disease, at the University of Toronto, first became interested in several aspects of the biology of Alzheimer's disease (AD) during the early 1980s. The relative homogeneity of the clinical and neuropathological features of (AD) had led to the prevailing assumption that AD was likely...

Mileposts in Discovering Biological Phenotypes

In the post WWII era, the factors that account for the accelerated pace of progress in Alzheimer's research were advances in biochemistry, neuroscience and methods to study the a) detailed structural and functional features of single neurons, b) mechanisms of intra- and intercellular communication, c) protein chemistry-synthesis, degradation aggregation, turnover and folding, d) genomics-proteomics, and e) mechanisms of regeneration and apoptosis. In 1961, the first NIH grant on Alzheimer's...

Pathways to the discovery of the neuronal origin and proteolytic biogenesis of Ap amyloid of Alzheimers disease

Colin L Masters1 and Konrad Beyreuther1 Our contributions in the 1980s (Kang et al. 1987 Martins et al. 1986 Masters et al. 1985a,b) to the purification and N-terminal sequencing of the amyloid plaque cores (APC) of Alzheimer's disease (AD) and the discovery of its biogenesis from a neuronal precursor (the amyloid protein precursor - APP) by proteolytic cleavages (the P- and y- secretases) need to be seen against the background of many years of prior research activity from a diverse range of...

The Frankfurt Institution of the Mentally Ill and Epileptics

After his studies, Alzheimer spent five months as a personal physician to a wealthy mentally ill lady. This assignment stimulated his interest in psychiatry. And thus, in 1888, he applied for a position at the Municipal Institution for the Mentally Ill and Epileptics in Frankfurt (am Main), Germany. Despite not being one of the hubs of neuroscience research at the time, Frankfurt's psychiatric institution was an innovative work place. Its founder, Heinrich Hoffmann - today better remembered for...

Prospects for the Future

- Only thirty years ago Alzheimer's disease was regarded as a hopelessly untreatable condition. Except for a handful of investigators, the area attracted little interest and virtually no support for research. - Twenty five years ago, the essential clinical infrastructures for longitudinal studies of well-characterized patients did not exist. - Twenty years ago, ideas about cure and prevention were unconceivable such things as diagnostic criteria, standardized assessment instruments, cadres of...

Was there a discovery

Alzheimer, of course, is not the father of the concept of dementia, or even of dementia in the elderly. Some have been aware of this concept for at least 2,500 years (Hoyer 1987 Berchtold and Cotman 1998), and if it were to be accredited to somebody, that person would be the French psychiatrist Jean-Etienne-Dominique Esquirol (1772-1840), who worked with Philippe Pinel - the man who on September 1793 freed the mentally disabled of the Bicetre in Paris by removing their chains - and coined the...

The seventh age of man Solving senility

Less than three years prior to his death at age 52, William Shakespeare remained hard at work, co-authoring The Two Noble Kinsmen with John Fletcher. Although he lived relatively long for his time, the Bard escaped the ravages of late-life dementia that he described briefly but poignantly in Jacques' soliloquy in As You Like It. The loss of memory and intellect that often accompanies great age must have been experienced throughout human history. Thus, the specific disorder that Alzheimer...

Concerning a unique disease of the cerebral cortex

A. reports a case which he observed in the Mental Asylum in Frankfurt a.M. and whose central nervous system was given to him for study by the director Mr. Sioli. Clinically, this case presented an unusual picture that did not fit any known disease, while anatomically it demonstrated a finding that was distinct from other known disease processes. A 51 year old woman showed as her first obvious symptom j ealousy concerning her husband. Soon a very rapidly progressive impairment of memory became...

Alzheimers early years and medical studies

Aloysius (Alois) Alzheimer (Fig. 1) wasborn on June 14,1864, to the royal notary Eduard Alzheimer and his second wife, Therese, in the small Bavarian town of Marktbreit.2 Early on in school, he showed a vivid interest in the natural sciences. His school leaving certificate remarked on his academic achievements This student shows outstanding knowledge of the Natural Sciences, which he has studied with particular predilection throughout his time at high school. In the autumn of 1883, after having...

The Potamkin prize for research in Picks Alzheimers and related diseases

According to the American Academy of Neurology, the Potamkin Prize is regarded by many as the Nobel Prize of dementia research. It has become the bellwether for progress in international research into Alzheimer's and related diseases. The Potamkin familyworked with leading neurologists to create this 100 000 annual award sponsored by the American Academy Neurology. The first Potamkin prize was established in 1988 at a time when very little was known about what happened in the brain during the...

Apolipoprotein E and Alzheimers disease A brief retrospective

The past 14 years from 1992 to 2006 provide an interesting perspective for the application of genetic methods to Alzheimer's disease (AD) research. In the science of genetics, these years saw the beginning of linkage analyses for the identification of inherited disease mutations as well as susceptibility genes for complex diseases. This was followed in 1999-2001 with maps of single nucleotide polymorphisms (SNPs) across the now-sequenced genome, ushering in the latest era of whole genome...

Imaging the pathology of Alzheimers disease Building on a centuryOld blueprint

Mathis2 Alois Alzheimer carefully described the clinical and histological findings of an unusual case of pre-senile dementia in his benchmark presentation in T bingen, Germany, in 1906. He meticulously documented the presence of tangled bundle s of fibrils and miliary foci of a peculiar substance. With this description of neurofibrillary tangles and amyloid-beta (A ) plaques, the basis for the characteristic neuropathology that still defines Alzheimer's disease...

Alzheimers case report

A full transcription of Alzheimer's questions and Auguste D.'s answers appears in previous publications as well as in a biography of Alzheimer (Maurer and Maurer 1998), and will not be printed here in their entirety. Alzheimer's notes in the file begin on November 26,1901. He asked very simple questions and wrote down the dialogues systematically. His questioning continues on four handwritten pages, dated through November 30,1901 (Fig. 9). Fig. 8. Portrait of Auguste D. aged 51 Fig. 8. Portrait...

First mouse model of CAA proper

It was late at night when Matthias Staufenbiel, Markus Tolnay and I were brainstorming at the Institute of Pathology in Basel about future strategies to generate new mouse models of AD and CAA. We decided on a mouse model for Hereditary Cerebral Hemorrhage with Amyloidosis Dutch-Type HCHWA-D , again using the neuron-specific Thy-1 promoter cassette. Although this project was realized within months, our disappointment was great when we saw no amyloid at 6,12 and 18 months of age, and the project...

The Amyloid Hypothesis history and alternatives

Amyloid Plaques

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

Auguste Neurofibrils

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

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

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 familial Alzheimers disease

Swedish Mutation

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

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 Tauopathies

Tau Phosphorylation Kinase

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 neurotransmitter modulators psychotropic

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 observations contributed to the understanding of

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

Alzheimer Disease Stages

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

Alzheimer Disease Biological Pathways

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

Eeg Pathway

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 hemorrhage Dutch type The role of amyloid in

Christian Haass

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

Tau Protein Domains

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

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

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

Hippocampal Atrophy

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

Anorectal Malformation Pathophysiology

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...

Tau and microtubules

Tau Microtubule Binding Transport

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

Creutzfeldt Hans Gerhard

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

Alois Alzheimer

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

Eikelenboom Piet

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...