While Alzheimer's disease researchers continue to debate the underlying cause(s) of the disease, most agree that a diverse, multi-target approach to treatment will be necessary. To this end, the Alzheimer's Drug Discovery Foundation (ADDF) recently hosted the 11th International Conference on Alzheimer's Drug Discovery to highlight the array of exciting efforts from the ADDF's funded investigators.
The Alzheimer's Drug Discovery Foundation's 13th International Conference on Alzheimer's Drug Discovery was held on 10-11 September 2012 in Jersey City, NJ, USA. This meeting report provides an overview of Alzheimer's Drug Discovery Foundation-funded programs, ranging from novel biomarkers to accelerate clinical development to drug-discovery programs with a focus on targets related to neuroprotection, mitochondrial function, apolipoprotein E and vascular biology.
Most neurodegenerative diseases involve the accumulation of misfolded proteins in the nervous system. Impairment of protein degradation pathways such as autophagy is emerging as a consistent and transversal pathological phenomenon in neurodegenerative diseases, including Alzheimer's, Huntington's, and Parkinson's disease. Genetic inactivation of autophagy in mice has demonstrated a key role of the pathway in maintaining protein homeostasis in the brain, triggering massive neuronal loss and the accumulation of abnormal protein inclusions. However, the mechanism underlying neurodegeneration due to autophagy impairment remains elusive. A paper in Molecular Neurodegeneration from Abeliovich's group now suggests a role for phosphorylation of Tau and the activation of glycogen synthase kinase 3β (GSK3β) in driving neurodegeneration in autophagy-deficient neurons. We discuss the implications of this study for understanding the factors driving neurofibrillary tangle formation in Alzheimer's disease and tauopathies.
See research article http://www.molecularneurodegeneration.com/content/7/1/48
Autophagy is a major intracellular degeneration pathway involved in the elimination and recycling of damaged organelles and long-lived proteins by lysosomes. Many of the pathological factors, which trigger neurodegenerative diseases, can perturb the autophagy activity, which is associated with misfolded protein aggregates accumulation in these disorders. Alzheimer’s disease, the first neurodegenerative disorder between dementias, is characterized by two aggregating proteins, β-amyloid peptide (plaques) and τ-protein (tangles). In Alzheimer’s disease autophagosomes dynamically form along neurites within neuronal cells and in synapses but effective clearance of these structures needs retrograde transportation towards the neuronal soma where there is a major concentration of lysosomes. Maturation of autophago-lysosomes and their retrograde trafficking are perturbed in Alzheimer’s disease, which causes a massive concentration of autophagy elements along degenerating neurites. Transportation system is disturbed along defected microtubules in Alzheimer’s disease brains. τ-protein has been found to control the stability of microtubules, however, phosphorylation of τ-protein or an increase in the total level of τ-protein can cause dysfunction of neuronal cells microtubules. Current evidence has shown that autophagy is developing in Alzheimer’s disease brains because of ineffective degradation of autophagosomes, which hold amyloid precursor protein-rich organelles and secretases important for β-amyloid peptides generation from amyloid precursor. The combination of raised autophagy induction and abnormal clearance of β-amyloid peptide-generating autophagic vacuoles creates circumstances helpful for β-amyloid peptide aggregation and accumulation in Alzheimer’s disease. However, the key role of autophagy in Alzheimer’s disease development is still under consideration today. One point of view suggests that abnormal autophagy induction causes a concentration of autophagic vacuoles rich in amyloid precursor protein, β-amyloid peptide and the elements crucial for its formation, whereas other hypothesis points to marred autophagic clearance or even decrease in autophagic effectiveness playing a role in maturation of Alzheimer’s disease. In this review we present the recent evidence linking autophagy to Alzheimer’s disease and the role of autophagic regulation in the development of full-blown Alzheimer’s disease.
Alzheimer’s disease; Autophagy; Amyloid precursor protein; β-Amyloid peptide; τ-Protein; Neuronal death
Oxidative stress is a key pathologic factor in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. The failure of free-radical-scavenging antioxidants in clinical trials pinpoints an urgent need to identify and to block major sources of oxidative stress in neurodegenerative diseases. As a major superoxide-producing enzyme complex in activated phagocytes, phagocytic NADPH oxidase (PHOX) is essential for host defense. However, recent preclinical evidence has underscored a pivotal role of over-activated PHOX in chronic neuroinflammation and progressive neurodegeneration. Deficiency in PHOX subunits mitigates neuronal damage induced by diverse insults/stresses relevant to neurodegenerative diseases. More importantly, the suppression of PHOX activity correlates with less neuronal impairment in models of neurodegenerative diseases. The discovery of PHOX and non-phagocytic NADPH oxidases in astroglia and neurons further reinforces the critical role of NADPH oxidases in oxidative stress-mediated chronic neurodegeneration. Thus, proper modulation of NADPH oxidase activity might hold therapeutic potential for currently incurable neurodegenerative diseases.
Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia, affecting more than 5.4 million people in the USA. Although the cause of AD is not well understood, the cholinergic, amyloid and tau hypotheses were proposed to explain its development. Drug discovery for AD based on the cholinergic and amyloid theories have not been effective. In this article we summarize tau-based natural products as AD therapeutics from a variety of biological sources, including the anti-amyloid agent curcumin, isolated from turmeric, the microtubule stabilizer paclitaxel, from the Pacific Yew Taxus brevifolia, and the Streptomyces-derived Hsp90 inhibitor, geldanamycin. The overlooked approach of clearing tau aggregation will most likely be the next objective for AD drug discovery.
Neuronal inclusions comprised of the microtubule-associated protein tau are found in a number of neurodegenerative diseases, commonly known as tauopathies. In Alzheimer's disease, the most prevalent tauopathy, misfolded tau is probably a key pathological agent. The recent failure of Aβ-targeted therapeutics in Phase III clinical trials suggests that it is timely and prudent to consider alternative drug discovery strategies for Alzheimer's disease. Here we focus on those directed at reducing misfolded tau and compensating for the loss of normal tau function.
Purpose of review
To summarize key studies and recent thought on the role of neuroinflammation in chronic neurodegeneration, and whether it can be modulated by anesthesia and surgery.
A large and growing body of evidence shows that neuroinflammation participates in the development of neurodegeneration associated with Alzheimer’s disease. Modulation may be possible early in the pathogenesis, and less so when cognitive symptoms appear. A dysfunctional hypo-inflammatory response may permit accelerated damage due to other mechanisms in late disease. The peripheral inflammatory response elicited by surgery itself appears to provoke a muted neuroinflammatory response, which enhances ongoing neurodegeneration in some models. Anesthetics have both anti- and pro-inflammatory effects depending on the drug and concentration, but in general, appear to play a small role in neuroinflammation. Human studies at the intersection of chronic neurodegeneration, neuroinflammation, and surgery/anesthesia are rare.
The perioperative period has the potential to modulate the progression of chronic neurodegenerative diseases. The growing number of elderly having surgery, combined with the expanding life expectancy, indicates the potential for this interaction to have considerable public health implications, and call for further research, especially in humans.
neurodegeneration; surgery; perioperative neurotoxicity; cytokines; cognitive dysfunction; microglia
The discovery that mutations within the tau gene lead to frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) provided direct evidence that tau alterations can lead to neurodegenerative disease. While the presence of tau fibrils and tangles is a common feature of all tauopathies, including Alzheimer’s disease (AD), data are emerging from biochemical, cell-based and transgenic mouse studies which suggest that a pre-fibrillar form of pathological tau may play a key role in eliciting central nervous system (CNS) neurodegeneration and behavioral impairments. Herein we review recent findings that implicate diffusible tau pathology in the onset of neurodegeneration, and discuss the implications of these findings as they relate to tau tangles and possible therapeutic strategies for the treatment of AD and related tauopathies.
Fibrils; Neurodegeneration; Oligomers; Tangles; Tau; Transgenic
Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia among elderly patients. A biomarker for the disease could make diagnosis easier and more accurate, and accelerate drug discovery. In this study, NMR-based metabolomics analysis in conjunction with multivariate statistics was applied to examine changes in urinary metabolites in transgenic AD mice expressing mutant tau and β-amyloid precursor protein. These mice showed significant changes in urinary metabolites throughout the progress of the disease. Levels of 3-hydroxykynurenine, homogentisate and allantoin were significantly higher compared to control mice in 4 months (prior to onset of AD symptoms) and reverted to control values by 10 months of age (early/middle stage of AD), which highlights the relevance of oxidative stress to this neurodegenerative disorder even prior the onset of dementia. The level of these changed metabolites at very early period may provide an indication of disease risk at asymptomatic stage.
Alzheimer’s disease; metabolomics; NMR; oxidative stress; biomarker
Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascular-related sickness and death. Mexico City Metropolitan Area children exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, and innate and adaptive immune responses. Early dysregulated neuroinflammation, brain microvascular damage, production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit likely contribute to progressive neurodegenerative processes. The accumulation of misfolded proteins coincides with the anatomical distribution observed in the early stages of both Alzheimer's and Parkinson's diseases. We contend misfolding of hyperphosphorylated tau (HPπ), alpha-synuclein, and beta-amyloid could represent a compensatory early protective response to the sustained systemic and brain inflammation. However, we favor the view that the chronic systemic and brain dysregulated inflammation and the diffuse vascular damage contribute to the establishment of neurodegenerative processes with childhood clinical manifestations. Friend turns Foe early; therefore, implementation of neuroprotective measures to ameliorate or stop the inflammatory and neurodegenerative processes is warranted in exposed children. Epidemiological, cognitive, structural, and functional neuroimaging and mechanistic studies into the association between air pollution exposures and the development of neuroinflammation and neurodegeneration in children are of pressing importance for public health.
Numerous epidemiological studies demonstrate that genetic background modifies the onset and the progression of Alzheimer's disease and related neurodegenerative disorders. The efficacious influence of genetic background on the disease pathway of amyloid beta has been meticulously described in rodent models. Since the impact of genetic modifiers on the neurodegenerative and neuroinflammatory cascade induced by misfolded tau protein is yet to be elucidated, we have addressed the issue by using transgenic lines expressing the same human truncated tau protein in either spontaneously hypertensive rat (SHR) or Wistar-Kyoto (WKY) genetic background.
Brains of WKY and SHR transgenic rats in the terminal stage of phenotype and their age-matched non-transgenic littermates were examined by means of immunohistochemistry and unbiased stereology. Basic measures of tau-induced neurodegeneration (load of neurofibrillary tangles) and neuroinflammation (number of Iba1-positive microglia, their activated morphology, and numbers of microglia immunoreactive for MHCII and astrocytes immunoreactive for GFAP) were quantified with an optical fractionator in brain areas affected by neurofibrillary pathology (pons, medulla oblongata). The stereological data were evaluated using two-way ANOVA and Student's t-test.
Tau neurodegeneration (neurofibrillary tangles (NFTs), axonopathy) and neuroinflammation (microgliosis, astrocytosis) appeared in both WKY and SHR transgenic rats. Although identical levels of transgene expression in both lines were present, terminally-staged WKY transgenic rats displayed significantly lower final NFT loads than their SHR transgenic counterparts. Interestingly, microglial responses showed a striking difference between transgenic lines. Only 1.6% of microglia in SHR transgenic rats expressed MHCII in spite of having a robust phagocytic phenotype, whereas in WKY transgenic rats, 23.2% of microglia expressed MHCII despite displaying a considerably lower extent of transformation into phagocytic phenotype.
These results show that the immune response represents a pivotal and genetically variable modifying factor that is able to influence vulnerability to neurodegeneration. Therefore, targeted immunomodulation could represent a prospective therapeutic approach to Alzheimer's disease.
Formaldehyde can induce misfolding and aggregation of Tau protein and β amyloid protein, which are characteristic pathological features of Alzheimer’s disease (AD). An increase in endogenous formaldehyde concentration in the brain is closely related to dementia in aging people. Therefore, the discovery of effective drugs to counteract the adverse impact of formaldehyde on neuronal cells is beneficial for the development of appropriate treatments for age-associated cognitive decline.
In this study, we assessed the neuroprotective properties of TongLuoJiuNao (TLJN), a traditional Chinese medicine preparation, against formaldehyde stress in human neuroblastoma cells (SH-SY5Y cell line). The effect of TLJN and its main ingredients (geniposide and ginsenoside Rg1) on cell viability, apoptosis, intracellular antioxidant activity and the expression of apoptotic-related genes in the presence of formaldehyde were monitored.
Cell counting studies showed that in the presence of TLJN, the viability of formaldehyde-treated SH-SY5Y cells significantly recovered. Laser scanning confocal microscopy revealed that the morphology of formaldehyde-injured cells was rescued by TLJN and geniposide, an effective ingredient of TLJN. Moreover, the inhibitory effect of geniposide on formaldehyde-induced apoptosis was dose-dependent. The activity of intracellular antioxidants (superoxide dismutase and glutathione peroxidase) increased, as did mRNA and protein levels of the antiapoptotic gene Bcl-2 after the addition of geniposide. In contrast, the expression of the apoptotic-related gene - P53, apoptotic executer - caspase 3 and apoptotic initiator - caspase 9 were downregulated after geniposide treatment.
Our results indicate that geniposide can protect SH-SY5Y cells against formaldehyde stress through modulating the expression of Bcl-2, P53, caspase 3 and caspase 9, and by increasing the activity of intracellular superoxide dismutase and glutathione peroxidase.
Formaldehyde impairment; Geniposide; Neuroprotection
Lipid oxidative damage and Amyloid β (Aβ) misfolding contribute to Alzheimer’s disease (AD) pathology. Thus, the prevention of oxidative damage and Aβ misfolding are attractive targets for drug discovery. At present, no AD drugs approved by the Food and Drug Administration (FDA) prevent or halt disease progression. Hydralazine, a smooth muscle relaxant, is a potential drug candidate for AD drug therapy as it reduces Aβ production and prevents oxidative damage via its antioxidant hydrazide group. We evaluated the efficacy of hydralazine, and related hydrazides, in reducing 1) Aβ misfolding and 2) Aβ protein modification by the reactive lipid 4-hydroxy-2-nonenal (HNE) using transmission electron microscopy and Western blotting. While hydralazine did not prevent Aβ aggregation as measured using the protease protection assay, there were more oligomeric species observed by electron microscopy. Hydralazine prevented lipid modification of Aβ, and Aβ was used as proxies for classes of proteins which either misfold or are modified by HNE. All of the other hydrazides prevented lipid modification of Aβ, and also did not prevent Aβ aggregation. Surprisingly, a few of the compounds, carbazochrome and niclosamide, appeared to augment Aβ formation. Thus, hydrazides reduced lipid oxidative damage and hydralazine additionally reduced Aβ misfolding. While hydralazine would require specific chemical modifications for use as an AD therapeutic itself -(to improve blood brain barrier permeability, reduce vasoactive side effects, and optimization for amyloid inhibition)- this study suggests its potential merit for further AD drug development.
Amyloid-β; free radicals; oxidative stress; Alzheimer’s disease; hydrazide; hydralazine; 4-hydroxy-2-nonenal
Alzheimer’s disease (AD) is a neurodegenerative syndrom involving many different biological parameters, including the accumulation of copper metal ions in Aβ amyloid peptides due to a perturbation of copper circulation and homeostasis within the brain. Copper-containing amyloids activated by endogenous reductants are able to generate an oxidative stress that is involved in the toxicity of abnormal amyloids and contribute to the progressive loss of neurons in AD. Since only few drugs are currently available for the treatment of AD, we decided to design small molecules able to interact with copper and we evaluated these drug-candidates with non-transgenic mice, since AD is mainly an aging disease, not related to genetic disorders. We created a memory deficit mouse model by a single icv injection of Aβ1–42 peptide, in order to mimic the early stage of the disease and the key role of amyloid oligomers in AD. No memory deficit was observed in the control mice with the antisense Aβ42-1 peptide. Here we report the capacity of a new copper-specific chelating agent, a bis-8-aminoquinoline PA1637, to fully reverse the deficit of episodic memory after three weeks of treatment by oral route on non-transgenic amyloid-impaired mice. Clioquinol and memantine have been used as comparators to validate this fast and efficient mouse model.
The amyloid β (Aβ) and tau proteins, which misfold, aggregate, and accumulate in the Alzheimer's disease (AD) brain, are implicated as central factors in a complex neurodegenerative cascade. Studies of mutations that cause early onset AD and promote Aβ accumulation in the brain strongly support the notion that inhibiting Aβ aggregation will prevent AD. Similarly, genetic studies of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17 MAPT) showing that mutations in the MAPT gene encoding tau lead to abnormal tau accumulation and neurodegeneration. Such genetic studies clearly show that tau dysfunction and aggregation can be central to neurodegeneration, however, most likely in a secondary fashion in relation to AD. Additional pathologic, biochemical and modeling studies further support the concept that Aβ and tau are prime targets for disease modifying therapies in AD. Treatment strategies aimed at preventing the aggregation and accumulation of Aβ, tau, or both proteins should therefore be theoretically possible, assuming that treatment can be initiated before either irreversible damage is present or downstream, self-sustaining, pathological cascades have been initiated. Herein, we will review recent advances and also potential setbacks with respect to the myriad of therapeutic strategies that are designed to slow down, prevent, or clear the accumulation of either “pathological” Aβ or tau. We will also discuss the need for thoughtful prioritization with respect to clinical development of the pre-clinically validated modifiers of Aβ and tau pathology. The current number of candidate therapies targeting Aβ is becoming so large that a triage process is clearly needed to insure that resources are invested in a way such that the best candidates for disease modifying therapy are rapidly moved toward clinical trials. Finally, we will discuss the challenges for an appropriate “triage” after potential disease modifying therapies targeting tau and Aβ have entered clinical trials.
Alzheimer’s disease (AD) is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of intracellular neurofibrillary tangles and extracellular amyloid plaques that accumulate in vulnerable brain regions. AD etiology has been studied by many groups, but since the discovery of the APOE ε4 allele, no further genes have been mapped conclusively to the late-onset form of the disease. In this study, we examined genetic association with late-onset Alzheimer’s susceptibility in 738 Caucasian families with 4704 individuals and an independent case-control dataset with 296 unrelated cases and 566 unrelated controls exploring 11 candidate genes with 47 SNPs common to both samples. In addition to tests for main effects and haplotype analyses, the Multifactor Dimensionality Reduction Pedigree Disequilibrium Test (MDR-PDT) was used to search for single-locus effects as well as 2-locus and 3-locus gene-gene interactions associated with AD in the family data. We observed significant haplotype effects in ACE in both family and case-control samples using standard and cladistic haplotype models. ACE was also part of significant 2-locus and 3-locus MDR-PDT joint effects models with Alpha-2-Macroglobulin (A2M), which mediates the clearance of Aβ, and Leucine-Rich Repeat Transmembrane 3 (LRRTM3), a nested gene in Alpha-3 Catenin (CTNNA3) which binds Presenilin 1. This result did not replicate in the case-control sample, and may not be a true positive. These genes are related to amyloid beta clearance; thus this constellation of effects might constitute an axis of susceptibility for late-onset AD. The consistent ACE haplotype result between independent data sets of families and unrelated cases and controls is strong evidence in favor of ACE as a susceptibility locus for AD, and replicates results from several other studies in a very large sample.
Alzheimer’s disease; complex disease; epistasis; Multifactor Dimensionality Reduction; MDR-PDT
Dementia due to Alzheimer’s disease (AD) is estimated to reach epidemic proportions by the year 2030. Given the limited accuracy of current AD clinical diagnosis, biomarkers of AD pathologies are currently being sought. Reductions in cerebrospinal fluid levels of β-amyloid 42 (a marker of amyloid plaques) and elevations in tau species (markers of neurofibrillary tangles and/or neurodegeneration) are well-established as biomarkers useful for AD diagnosis and prognosis. However, novel markers for other features of AD pathophysiology (e.g., β-amyloid processing, neuroinflammation and neuronal stress/dysfunction) and for other non-AD dementias are required to improve the accuracy of AD disease diagnosis, prognosis, staging and therapeutic monitoring (theragnosis). This article discusses the potential of several promising novel cerebrospinal fluid analytes, highlights the next steps critical for advancement in the field, and provides a prediction on how the field may evolve in 5–10 years.
Alzheimer’s disease; amyloid; biomarker; cerebrospinal fluid; diagnostic accuracy; neurodegeneration; neurofibrillary tangles; neuroinflammation; prognosis; theragnosis
The clinical and scientific study of dementia in adults with Down syndrome led to the development of the amyloid hypothesis as a fundamental concept in Alzheimer's disease pathogenesis. The journey started with the discovery of the structure and metabolic processing of β-amyloid brain deposits associated with Alzheimer's dementia in adults with Down syndrome, and then the prediction and confirmation of the amyloid precursor protein gene on chromosome 21. The processes and genes responsible for tau hyperphosphorylation contributing to toxic brain deposits were additionally identified. With increasing sophistication in genetic experimental techniques, additional mechanisms associated with excessive amyloid deposits were postulated and tested in brains of people with Down syndrome and Alzheimer's disease and in those with early-onset Alzheimer's disease. This in turn led to the proposal and testing for particular genetic defects associated with familial early-onset Alzheimer's disease. Nearly 200 genetic causes of early-onset types of Alzheimer's disease have since been identified. Only a minority of these causes are on chromosome 21, although the aetiology of excess amyloid production remains fundamental to their pathogenesis. Knowledge of the pathogenic mechanisms of Alzheimer's disease in predisposed families and in people with Down syndrome is a step closer to prevention or cure of this devastating disease.
Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD, however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer's dementia. This review emphasizes on the dual key roles of complement system and complement regulators (CRegs) in disease pathology and progression. The particular focus of this review is on currently evolving strategies for design of complement inhibitors that might aid therapy by restoring the fine balance between activated components of complement system, thus improving the cognitive performance of patients. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.
Alzheimer’s disease; neurodegeneration; inflammation; β-amyloid peptide; complement; complement regulators; CD59; complement therapeutics.
A number of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and polyglutamine diseases, are characterized by the age-dependent formation of intracellular protein aggregates and neurodegeneration. Although there is some debate surrounding the role of these aggregates in neurotoxicity, the formation of aggregates is known to reflect the accumulation of misfolded and toxic proteins. The degradation of misfolded proteins occurs mainly via the ubiquitin–proteasome and autophagy pathways. In neuronal cells, polyglutamine protein inclusions are present predominantly in the nucleus, which is not accessible to autophagy. It remains unclear how the ubiquitin–proteasomal and autophagy pathways remove misfolded proteins in the different subcellular regions of neurons, where disease proteins become misfolded and aggregated in an age-dependent manner. Here we discuss the key findings to date about the roles of the ubiquitin–proteasome system and autophagy in polyglutamine diseases. Understanding how these two pathways function to clear mutant polyglutamine proteins will further the development of effective treatments for polyglutamine and other neurodegenerative diseases.
Ubiquitin; Proteasome; Autophagy; Polyglutamine; Huntingtin; Neurodegeneration
A hallmark of the Alzheimer disease (AD) brain is the presence of inclusions within neurons that are comprised of fibrils formed from the microtubule-stabilizing protein tau. The formation of misfolded multimeric tau species is believed to contribute to the progressive neuron loss and cognitive impairments of AD. Moreover, mutations in tau have been shown to cause a form of frontotemporal lobar degeneration in which tau neuronal inclusions observed in the brain are similar to those seen in AD. Here we review the more compelling strategies that are designed to reduce the contribution of misfolded tau to AD neuropathology, including those directed at correcting a possible loss of tau function resulting from sequestration of cellular tau and to minimizing possible gain-of-function toxicities caused by multimeric tau species. Finally, we discuss the challenges and potential benefits of tau-directed drug discovery programs.
Neurodegeneration in Alzheimer disease is likely caused by misfolded, multimeric tau. Therapeutic strategies have focused on overcoming tau loss-of-function and reducing levels of potentially toxic tau species.
Progressive cerebral deposition of the amyloid β-protein (Aβ) in brain regions serving memory and cognition is an invariant and defining feature of Alzheimer disease. A highly similar but less robust process accompanies brain aging in many nondemented humans, lower primates, and some other mammals. The discovery of Aβ as the subunit of the amyloid fibrils in meningocerebral blood vessels and parenchymal plaques has led to innumerable studies of its biochemistry and potential cytotoxic properties. Here we will review the discovery of Aβ, numerous aspects of its complex biochemistry, and current attempts to understand how a range of Aβ assemblies, including soluble oligomers and insoluble fibrils, may precipitate and promote neuronal and glial alterations that underlie the development of dementia. Although the role of Aβ as a key molecular factor in the etiology of Alzheimer disease remains controversial, clinical trials of amyloid-lowering agents, reviewed elsewhere in this book, are poised to resolve the question of its pathogenic primacy.
Amyloid β-proteins (Aβ) are biochemically heterogeneous, with different lengths, amino and carboxyl termini, and propensities for aggregation. A range of Aβ assemblies may promote neurodegeneration in Alzheimer disease.
Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.
The historical roots of Alzheimer’s disease provide a sound conceptual basis for linking the behavioral and neurological symptoms of the disease with the frequently associated pathology of amyloid plaques and neurofibrillary tangles. Out of these roots has grown the ‘amyloid cascade hypothesis’ – a vision of the etiology of Alzheimer’s that has spurred the discovery of many important insights into the neurobiology of the disease. Despite these successes, the wealth of new data now available to biomedical researchers urges a full review of the origins of Alzheimer’s and such a reconsideration is offered here. It begins with the most widely accepted risk factor for developing Alzheimer’s disease: age. Then, for an individual to progress from normal age-appropriate cognitive function to a condition where the full palette of clinical symptoms is expressed, three key steps are envisioned: 1) an initiating injury, 2) a chronic neuroinflammatory response and 3) a discontinuous cellular change-of-state involving most, if not all, of the cell types of the brain. The amyloid cascade is integrated into this sequence, but reconfigured as an amyloid deposition cycle. In this way, the pathology of amyloid plaques is envisioned as highly correlated with, but mechanistically distinct from, the three obligatory steps leading to Alzheimer’s disease. The implications of this new model are discussed with respect to our current diagnostic criteria and suggestions are put forward for expanding our future research efforts.