Current Alzheimer Research - Volume 3, Issue 5, 2006

Current Alzheimer Research presents the fifth issue of its third volume and this special issue is meant to mark the centennial of Alois Alzheimer 's original de-scription of the disease that would come to bear his name. How best can one commemorate this seminal discovery' Since the field has become quite diverse and large, it is difficult to accommodate all the fasci-nating areas of Alzheimer's disease (AD), nor could we invite contributions from all the respective field's lead-ing scientists within a limited space of the special issue. Instead of adopting the historical approach, we have invited selected leaders in the field to share their work with the readers of the journal in order to capture a glimpse of current research on AD. We review the pro-gress of a sample of cutting-age work in various as-pects of the disorder in terms of mechanism and thera-peutic implication. The articles in this special issue cover a wide range of cellular, molecular and animal-based research, ranging from the roles of amyloid, tau protein, genetics and oxidative stress to brain imaging on neurobiology and pathogenesis of AD using innova-tive experimental models. AD is the most common form of dementia in the US and most of the world, with rates increasing exponen-tially from age 65. A significant increase in life expec-tancy during the last century has resulted in a large number of people living to old age, and this will cause a quadrupling of AD cases by the middle of the cen-tury. Therefore, a systematic study of the disease is of paramount importance to understand the neurobiology, genetics and environmental risk factors of AD; these studies will lead to development of effective drug tar-gets and therapeutic approaches. The present issue reports fourteen articles discuss-ing the most exciting and relevant topics in the field of AD. The first article is a timely review by Kawas and Corrada (page 411-419) on the ‘90+ Study’ to address some of the unanswered questions about AD and de-mentia in the oldest-old. Since the initial description one hundred years ago by Alzheimer, the disorder is still being mainly characterized by the occurrence of two brain lesions: amyloid plaques and neurofibrillary tangles (NFTs). From that time, onwards, a significant advance has been made in characterization of these lesions and their role in AD pathogenesis, employing different cellular and animal models. For example, amyloid plaques have been shown mostly to comprise amyloid β-peptide (Aβ), whereas NFTs are composed of hyperphosphoryalted tau proteins. However, the pre-cise relationship between Aβ and tau, the two proteins that accumulate within the brain lesions, is just begin-ning to be understood. Two papers discuss about the production of Aβ , and its proteolytic degradation. Golde et al. present (page 421-430) different aspects of the ‘Aβ Cascade Hypothesis’ of AD, and argue for an array of therapeutic interventions that could target Aβ metabolism. In addition to Aβ production, Leissring emphasizes (page 431-435) the role of Aβ clearance (proteolytic degradation) by Aβ-degrading proteases in AD. The relationship between Aβ and tau proteins is the subject matter of another set of two papers. Blur-ton-Jones and LaFerla discuss (page 437-448) how Aβ accumulation facilitates tau pathology, whereas Mi and Johnson describe (page 449-463) the role of tau phos-phorylation in AD pathogenesis. In addition to neuro-pathological markers, genetic and environmental factors are elucidated. Ryman and Lamb analyze (page 465-473) the implications of genetic modifiers for mouse and human AD research, and responsiveness to environmental or treatment interventions. A detailed molecular analysis by Lahiri et al. (page 475-484) of an important gene, beta secretase (BACE1), reveals poten-tial drug targets within the BACE1 regulatory region. Cruts and colleagues narrate (page 485-491) the dis-covery of novel genetic mutations in frontotempral dementia, and such work represents how far genetic research has progressed in the field of neurodegenera-tion and AD over the years. But genes are not the only culprits as steps can go awry down at the protein level during the disease process. Urbane and colleagues update (page 493-504) on proper protein folding and assembly and their role in AD, which represent an important area of current research. Apart from the characteristic β-amyloid and tau proteins, Tesseur and Wyss-Coray highlight (page 505-513) the role of trophic factors and dysregulation of TGF-β signaling in neurodegeneration. Cell signaling to mitochondria and oxidative stress constitute two other important articles......

Alzheimer's disease (AD) is the most common type of dementia in the US and much of the world with rates increasing exponentially from age 65. Increases in life expectancy in the last century have resulted in a large number of people living to old ages and will result in a quadrupling of AD cases by the middle of the century. Preventing or delaying the onset of AD could have a huge impact in the number of cases expected to develop. The oldest-old are the fastest growing segment of the population and are estimated to account for 12% of the population over 65. Establishing accurate estimates of dementia and AD rates in this group is crucial for public health planning. Prevalence and incidence estimates above age 85 are imprecise and inconsistent because of the lack of very old individuals in most studies. Moreover, risk and protective factors in our oldest citizens have been studied little, and clinical-pathological correlations appear to be poor. We introduce The 90+ Study, established to address some of the unanswered questions about AD and dementia in the oldest-old. Our preliminary results show that close to half of demented oldest-old do not have known cerebral pathology to account for their cognitive deficits. Furthermore, the APOE-e4 allele appears to be a risk factor for AD only in the women in our study. In addition to the challenge of preventing and treating AD, the oldest-old will require major investigative energy to better understand the concomitants of longevity, the causes of dementia, and the factors that promote successful aging in oldest citizens.

Advances in the understanding of Alzheimer's disease (AD) pathogenesis provide strong support for a modified version of the amyloid cascade hypothesis, which is now often referred to as the amyloid β protein (Aβ) cascade hypothesis. The basic tenant of this modified hypothesis is that Aβ aggregates trigger a complex pathological cascade leading to neurodegeneration. Thus, as opposed to the original amyloid hypothesis, whose basic tenant was that amyloid deposits cause AD, the Aβ hypothesis is more inclusive in that it takes into account the possibility that several different Aβ assemblies might contribute to AD pathogenesis and not merely the detectable amyloid deposits within the brain. Significantly, the Aβ hypothesis has provided the rationale for a plethora of therapeutic interventions that target Aβ production, aggregation or clearance. Indeed, AD research is entering an exciting phase in which strategies derived from basic research will be tested in humans. Despite this progress, many aspects of AD pathogenesis, particularly those downstream of Aβ accumulation are not well understood. Herein, we explore several observations that serve to illustrate the more enigmatic aspects of the Aβ hypothesis, and discuss why further basic research may be critical in order to develop therapies designed to halt neurodegeneration and reverse cognitive decline in patients already suffering from AD dementia.

Proteases have long played a central role in the molecular pathogenesis of Alzheimer’s disease (AD), yet proteases that degrade the amyloid β-protein (Aβ) itself were largely ignored until only quite recently. Today, we know that Aβ-degrading proteases are critical regulators of brain Aβ levels in vivo, with evidence accumulating that their dysfunction may play a role in the etiology of AD. This review explores the historical factors that obscured this important aspect of amyloidogenesis, and discusses the many fresh insights it offers into the causes of and potential treatments for AD.

Since the initial description one hundred years ago by Dr. Alois Alzheimer, the disorder that bears his name has been characterized by the occurrence of two brain lesions: amyloid plaques and neurofibrillary tangles (NFTs). Yet the precise relationship between beta-amyloid (Aβ) and tau, the two proteins that accumulate within these lesions, has proven elusive. Today, a growing body of work supports the notion that Aβ may directly or indirectly interact with tau to accelerate NFT formation. Here we review recent evidence that Aβ can adversely affect distinct molecular and cellular pathways, thereby facilitating tau phosphorylation, aggregation, mis-localization, and accumulation. Studies are presented that support four putative mechanisms by which Aβ may facilitate the development of tau pathology. A great deal of work suggests that Aβ may drive tau pathology by activating specific kinases, providing a straightforward mechanism by which Aβ may enhance tau hyperphosphorylation and NFT formation. In the AD brain, Aβ also triggers a massive inflammatory response and pro-inflammatory cytokines can in turn indirectly modulate tau phosphorylation. Mounting evidence also suggests that Aβ may inhibit tau degradation via the proteasome. Lastly, Aβ and tau may indirectly interact at the level of axonal transport and evidence is presented for two possible scenarios by which axonal transport deficits may play a role. We propose that the four putative mechanisms described in this review likely mediate the interactions between Aβ and tau, thereby leading to the development of AD neurodegeneration.

The microtubule-associated protein tau, which is abundantly expressed in neurons, is deposited in cells in an abnormally phosphorylated state as fibrillar lesions in numerous neurodegenerative diseases, with the most notable being Alzheimer's disease. Tau plays a crucial role in the neuron as it binds and stabilizes microtubules, and can regulate axonal transport; functions that are regulated by site-specific phosphorylation events. In pathological conditions such as Alzheimer's disease and other tauopathies, tau is abnormally phosphorylated, and that this contributes to its dysfunction. Given the increasing evidence that a disruption in the normal phosphorylation state of tau followed by conformational changes plays a key role in the pathogenic events that occur in Alzheimer's disease and other tauopathies; it is critical to elucidate the regulation of tau phosphorylation. This review focuses on recent literature pertaining to the regulation of tau phosphorylation and function, and the role that a dysregulation of tau phosphorylation may play in the neuronal dysfunction in Alzheimer's disease.

As a group, strains of laboratory mice carrying Alzheimer's disease (AD)-related transgenes are currently the most widely studied animal models of AD. Many AD mouse models carrying the same or similar transgene constructs demonstrate strikingly different phenotypic responses to transgene expression, mimicking the apparent genetic complexity of AD pathogenesis seen in the human population. Genetic differences between the numerous mouse model strains used for AD research can significantly affect correct interpretation and cross-comparison of experimental findings, making genetic background an important consideration for all work in mouse models of AD. Furthermore, because of the potential for discovering novel genetic modifiers of AD pathogenesis, the effects of genetic background on AD phenotypes in the mouse can prove a worthwhile subject of study in their own right. This review discusses the implications of genetic modifiers for mouse and human AD research, and summarizes recent findings identifying significant roles for genetic background in modifying important phenotypes in AD mouse models, including premature death, amyloid deposition, tau hyperphosphorylation, and responsiveness to environmental or treatment interventions.

Major hallmarks of Alzheimer's disease (AD) include brain deposition of the amyloid-β peptide (Aβ), which is proteolytically cleaved from a large Aβ precursor protein (APP) by β and β- secretases. A transmembrane aspartyl protease, β-APP cleaving enzyme (BACE1), has been recognized as the β-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5'-untranslated region (UTR) contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the “ATG” start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD.

Two genetically distinct types of frontotemporal dementia (FTD) are linked to chromosome 17q21. FTD with parkinsonism (FTDP-17) results from mutations in the gene encoding microtubule associated protein tau (MAPT) and is associated with tau deposition in the patient's brain. An increasing number of FTD families are linked to 17q21 in the absence of a demonstrable MAPT mutation. Brains of these patients do not show tau deposits, but tau-negative intra- and perinuclear inclusions of unknown composition that are immunoreactive to ubiquitin (FTDU-17). These ubiquitin inclusions are located in the cytoplasm or nucleus of predominantly neuronal cells of affected brain regions. By extensive segregation analyses in conclusively linked FTDU-17 families, the candidate region was reduced to a 6.2 Mb segment containing MAPT; however, genomic sequencing of MAPT in FTDU-17 patients excluded disease-causing mutations. Further, the linked region was characterized by the presence of multiple low-copy repeat regions associated with genomic instability. However, we excluded genomic rearrangements as the cause of FTDU-17. Subsequent sequencing of positional candidate genes identified loss-of-function mutations in the gene encoding progranulin (PGRN), a growth factor involved in multiple physiological processes such as cellular proliferation and survival and tissue repair, and pathological processes including tumorigenesis. In a Belgian FTD patient series, the prevalence of PGRN mutations was 3.5 times higher than that of MAPT mutations underscoring a major role for PGRN in FTD pathogenesis. Together, mutation data provided convincing evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. The PGRN protein is not deposited in the ubiquitin-positive inclusions, the nature of which remains unknown. Due to the functions of PGRN in neuronal survival and the clinicopathological overlaps between FTD and other dementias it is likely that reduced PGRN expression is associated with the progression of other neurodegenerative brain diseases including Alzheimer's disease. These findings open promising novel targets for therapeutic intervention against neurodegeneration.

Pathological folding and aggregation of the amyloid β-protein (Aβ) are widely perceived as central to understanding Alzheimer's disease (AD) at the molecular level. Experimental approaches to study Aβ self-assembly are limited, because most relevant aggregates are quasi-stable and inhomogeneous. In contrast, simulations can provide significant insights into the problem, including specific sites in the molecule that would be attractive for drug targeting and details of the assembly pathways leading to the production of toxic assemblies. Here we review computer simulation approaches to understanding the structural biology of Aβ. We discuss the ways in which these simulations help guide experimental work, and in turn, how experimental results guide the development of theoretical and simulation approaches that may be of general utility in understanding pathologic protein folding and assembly.

Neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD) afflict growing numbers of people but treatments are not available or ineffective. These diseases are characterized by the loss of specific neuronal populations, the accumulation of protein aggregates inside and sometimes outside neurons, and an activation of immune pathways in the brain. The causes of sporadic forms of AD or PD are not known but it has been postulated that reduced trophic support to neurons together with age dependent increases in cellular stress lead to chronic injury and ultimately the demise of neurons. TGF-βs are neuroprotective factors and organizers of injury responses and as such might have a role in neurodegenerative disease. We review here the evidence mostly from genetically manipulated mice that links the TGF-β signaling pathway to neuronal phenotypes and neurodegeneration. Although many of these mutant models did not produce overt CNS phenotypes or adult brain were not studied due to embryonic lethality, there is growing support for a role of TGF-β signaling in neuronal maintenance, function, and degeneration. Future studies will have to determine whether dysregulation of TGF-β signaling in neurodegenerative diseases is significant and whether this signaling pathway may even be a target for treatment.

Mitochondrial dysfunction has been implicated in causing metabolic abnormalities in Alzheimer's disease (AD). The searches for mitochondrial DNA variants associated with AD susceptibility have generated conflicting results. The age-related accumulation of somatic mitochondrial DNA deletion has been suggested to play a pathogenic role in the development of AD. Recent studies have demonstrated that amyloid-beta peptide (Aβ) progressively accumulates in mitochndrial matrix, as demonstrated in both transgenic mice over-expressing mutant amyloid precursor protein (APP) and autopsy brain from AD patients. Aβ-mediated mitochondrial stress was evidenced by impaired oxygen consumption and decreased respiratory chain complexes III and IV activities in brains from AD patients and AD-type transgenic mouse model. Furthermore, our studies indicated that interaction of intramitochondrial Aβ with a mitochondrial enzyme, amyloid binding alcohol dehydrogenase (ABAD), inhibits its enzyme activity, enhances generation of reactive oxygen species (ROS), impairs energy metabolism, and exaggerates Aβ-induced spatial learning/memory deficits and neuropathological changes in transgenic AD-type mouse model. Interception of ABAD-Aβ interaction may be a potential therapeutic strategy for Alzheimer's disease.

Down syndrome (DS) provides a model for studying important aspects of Alzheimer disease (AD). Chromosome 21 contains several genes that have been implicated in neurodegenerative mechanisms. These include Cu/Zn superoxide dismutase (SOD-1), Ets-2 transcription factors, Down Syndrome Critical Region 1 (DSCR1) stress-inducible factor, and the amyloid precursor protein (APP). The accumulation of Aβ plaques is progressive across the lifespan in DS. Overexpression of APP in the obligate region for DS is associated with abundant Aβ plaques and tangles consistent with Braak stage V-VI. Intraneuronal Aβ in DS appears to trigger a pathological cascade leading to oxidative stress and a neurodegeneration typical of AD. There are suggestions that an increase in subcellular processing of APP and factors related to membrane APP cleavage favor the secretion of Aβ with age in DS. A misbalance between SOD-1 and glutathione perioxidase activity in DS has been linked to free radical generation. Ets-2 and DSCR1 overexpression in DS has been linked to cell degeneration. Age-related accumulation of somatic DNA mutations in both DS and AD contribute to oxidative stress that exacerbates the imbalance in gene expression. This leads to enhanced Aβ deposition and further neuronal vulnerability. The consequence of these factors and their temporal relationships is likely to be the subject of future research. Since the pathological processes leading to AD are seen across the lifespan in DS, an opportunity is afforded for early pharmacological intervention in the disorder.

Historical progress in medicine can be charted along the lines of technical innovations that have visualized the invisible. One hundred years ago, Alois Alzheimer exploited newly developed histological stains to visualize his eponymonous disease in dead tissue under the microscope. Now, as we are entering the second century of Alzheimer's disease research, technical innovation has endowed us with a range of in vivo imaging techniques that promise to visualize Alzheimer' disease in living people. The earliest stage of Alzheimer's disease is characterized by cell-sickness, not cell-death, and can occur before the deposition of amyloid plaques or neurofibrillary tangles. In principle, 'functional' imaging techniques might be able to detect this early stage of the disease, a stage that was invisible to Alzheimer himself. Here, we will first define the neurobiological meaning of 'function' and then review the different approaches that measure brain dysfunction in Alzheimer' disease.

The therapeutic use of enzyme inhibitors in treatment of neurodegenerative diseases has its origin in the anti Parkinson action of the selective monoamine oxidase (MAO) B inhibitor, l-deprenyl (selegiline ), a failed anti depressant in 1975. This led to further development of MAO- A and B, catechol-O-methyltansferase and cholinestrerase inhibitors as anti Parkinson and Alzheimer drugs. One of the main reasons for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB) is degeneration of cholinergic cortical neurones and synaptic plasticity. This led to a correlation that similar to Parkinson's Disease (PD), cholinesterase inhibitors (ChEI) may also have therapeutic activity in AD. Significant percentage of AD and DLB subjects also nigrostriatal dopaminergic, locus ceruleous noradrenergic and raphe nucleus serotoninergic neurones. The present ChEI anti AD drugs have limited symptomatic activity and devoid of neuroprotective property that is needed for disease modifying action. It is becoming clear that there are no magic bullets for neurodegenerative disorders and shut gun approach is needed either as polypharmacology or drugs with multiple activity at different target sites in the CNS. The complex pathology of AD as well as cascade of events that leads to the neurodegenerative process has led us to develop several multifunctional neuroprotective drugs with several CNS targets with possible disease modifying activity. Employing the pharamcophore of our antiparkinson drug rasagiline (Azilect, Agilect, N-propagrgyl-1R-aminoindan) we have developed a novel multifunctional neuroprotective drug, ladostigil [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterasebutyrylesterase (Ch-BuE) and brain selective monoamine-oxidase (MAO) AB inhibitory activities possessing the neuroprotective- neurescue propargyl moiety, as potential treatment of AD and DLB and PD with dementias. Since brain MAO and iron increase in AD, PD and ageing, that could lead to iron dependent oxidative stress neurodegeneration, we have developed another series of multifunctional drugs (M30 HLA-20 series) which are brain permeable iron chelators- brain selective MAO inhibitors and possess the propargyl neuroprotective moiety. These series of drugs have the ability of regulating and processing APP (amyloid precursor protein) and reducing Aβ peptide, since APP is a metaloprotein, with an iron responsive element 5”UTR similar to transferring and ferritin.