Journal of Alzheimer's Disease - Volume 64, issue s1

Authors: Butterfield, D. Allan

Article Type: Review Article

Abstract: Oxidative stress, an overproduction of free radicals or a diminution of free radical scavenging ability relative to those of cognitively aged-matched controls, is widely recognized as a critical component of the pathogenesis and progression of Alzheimer’s disease (AD). This recognition arose in significant part from the work in the author’s laboratory, complemented by research from others’ laboratories. The Butterfield laboratory discovered the oxidative stress associated with oligomeric amyloid-β peptide manifested primarily as elevated oxidative modification of proteins and peroxidation of lipids. Such oxidative damage caused neuronal death, which undoubtedly underlies the progressive loss of cognition in AD. Identification of specific …oxidatively modified brain proteins in subjects with AD or amnestic mild cognitive impairment was achieved by the methods of redox proteomics, pioneered in the author’s laboratory. The importance and significance of the research emanating from the Butterfield laboratory rest on the paradigm shift of thinking regarding the roles of oxidative stress and resulting damage to key proteins and biochemical pathways in the pathogenesis and progression of AD. Predictions of future research directions also are presented. Given the enormous financial and personal burden placed upon citizens (and governments) of the US from AD, and the surety that the number of AD patients will greatly increase over the next 20–30 years, greater understanding of the molecular basis of pathogenesis and progression of AD is essential. Our laboratory is privileged to have contributed to better understanding of AD and provided rationales to identify effective therapeutic targets for this devastating dementing disorder. Show more

Keywords: Alzheimer’s disease, lipid peroxidation, neuronal death, oxidative stress, pathogenesis, predictions, progression, protein oxidation, redox proteomics

DOI: 10.3233/JAD-179912

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S469-S479, 2018

Authors: Lauretti, Elisabetta | Praticò, Domenico

Article Type: Review Article

Abstract: Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss. Despite intensive research, the molecular mechanism(s) leading to tau hyperphosphorylation are still unknown and there is no cure for these diseases. Development of an effective strategy that successfully prevents …tau excessive phosphorylation and/or tau aggregation may offer a real therapeutic opportunity for these less investigated neurodegenerative conditions. Beside tau, chronic brain inflammation is a common feature of all tauopathies and 5-lipoxygenase, an inflammatory enzyme, is upregulated in brain regions affected by tau pathology. Recently, in vitro studies and preclinical investigations with animal models of tauopathy have implicated 5-lipoxygenase in the regulation of tau phosphorylation through activation of the cyclin-dependent kinase 5 pathway, supporting the novel hypothesis that this protein is a promising therapeutic target for the treatment of tauopathies. In this article, we will discuss the contribution of the 5-lipoxygenase signaling pathway in the development of tau neuropathology, and the promising potential that drugs targeting this enzyme activation hold as a novel disease-modifying therapeutic approach for tauopathies. Show more

Keywords: 5-lipoxygenase, phosphorylation, tau protein, tauopathies

DOI: 10.3233/JAD-179931

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S481-S489, 2018

Authors: Thordardottir, Steinunn | Graff, Caroline

Article Type: Review Article

Abstract: This is a brief summary of the findings from the Swedish study on familial Alzheimer’s disease (FAD). Similar to other FAD studies, it includes prospective assessments of cognitive function, tissue sampling, and technical analyses such as MRI and PET. This 24-year-old study involves 69 individuals with a 50% risk of inheriting a disease-causing mutation in presenilin 1 (PSEN1 H163Y or I143T), or amyloid precursor protein (the Swedish APP or the arctic APP mutation) who have made a total of 169 visits. Our results show the extraordinary power in this study design to unravel the earliest changes in …preclinical AD. The Swedish FAD study will continue and future research will focus on disentangling the order of pathological change using longitudinal data as well as modeling the changes in patient derived cell systems. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, genetics, neuroimaging, neuropsychology

DOI: 10.3233/JAD-179922

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S491-S496, 2018

Authors: Teixeira, Catia M. | Pallas-Bazarra, Noemí | Bolós, Marta | Terreros-Roncal, Julia | Ávila, Jesús | Llorens-Martín, María

Article Type: Review Article

Abstract: Neurogenesis occurs in a limited number of brain regions during adulthood. Of these, the hippocampus has attracted great interest due to its involvement in memory processing. Moreover, both the hippocampus and the main area that innervates this structure, namely the entorhinal cortex, show remarkable atrophy in patients with Alzheimer’s disease (AD). Adult hippocampal neurogenesis is a process that continuously gives rise to newborn granule neurons in the dentate gyrus. These cells coexist with developmentally generated granule neurons in this structure, and both cooperative and competition phenomena regulate the communication between these two types of cells. Importantly, it has been revealed …that GSK-3β and tau proteins, which are two of the main players driving AD pathology, are cornerstones of adult hippocampal neurogenesis regulation. We have shown that alterations either promoting or impeding the actions of these two proteins have detrimental effects on the structural plasticity of granule neurons. Of note, these impairments occur both under basal conditions and in response to detrimental and neuroprotective stimuli. Thus, in order to achieve the full effectiveness of future therapies for AD, we propose that attention be turned toward identifying the pathological and physiological actions of the proteins involved in the pathogenesis of this condition. Show more

Keywords: Adult hippocampal neurogenesis, Alzheimer’s disease, granule neuron, GSK-3β, morphology, neuroprotection, tau

DOI: 10.3233/JAD-179918

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S497-S505, 2018

Authors: Alonso, Alejandra D. | Cohen, Leah S.

Article Type: Review Article

Abstract: The microtubule associated protein tau in a hyperphosphorylated form was identified as the building block of the filamentous aggregates found in the neurons of Alzheimer’s disease (AD) patients. In the abnormal state, hyperphosphorylated tau from AD brains (AD P-tau) was unable to promote microtubule assembly and more importantly, it could inhibit the normal activity of tau and other MAPs. AD P-tau was able to disrupt preformed microtubules and, by binding to normal tau, turn the latter into an AD P-tau like molecule. AD P-tau toxic behavior was prevalent in the soluble form and it was lost upon dephosphorylation. Mutations on …tau associated with disease, e.g., R406W in frontotemporal dementia with Parkinsonism linked to chromosome 17, altered its conformation to make it a better substrate for kinases. Using phospho-mimetics, it was found that the minimum phospho-sites necessary to acquire such a toxic behavior of tau were at 199, 212, 231 and 262, and tau pseudophosphorylated at those sites in combination with R406W was named Pathological Human Tau (PH-Tau). PH-Tau expressed in cells had similar behavior to AD P-tau: disruption of the microtubule system, change in the normal subcellular localization, and gain of toxic function for cells. In animal models expressing PH-Tau, it was found that two putative mechanisms of neurodegeneration exist depending on the concentration of the toxic protein, both involving cognitive decline, due to synaptic dysfunction at lower concentration and neuronal death at higher. Studies investigating the mechanism of tau pathology and its transmission from neuron to neuron are currently ongoing. Show more

Keywords: Hyperphosphorylation, microtubules, neurodegeneration, tau, tau mouse model

DOI: 10.3233/JAD-179906

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S507-S516, 2018

Authors: Nisbet, Rebecca M. | Götz, Jürgen

Article Type: Review Article

Abstract: Accumulation of the peptide amyloid-β (Aβ) and the protein tau in Alzheimer’s disease (AD) brains is a gradual process that involves the post-translational modification and assembly of monomeric forms into larger structures that eventually form fibrillar inclusions. This process is thought to both drive and initiate AD. However, why the axonally enriched tau in the course of AD accumulates in the somatodendritic domain is not fully understood. We discuss new data that provide a possible explanation that involves de novo protein synthesis, induced by Aβ and mediated through the kinase Fyn. We further discuss how in a pathological state, …tau, being a scaffolding protein, impairs nuclear and mitochondrial functions and reduces action potential generation at the axon initial segment. Pathological tau can further be packaged into exosomes, released by one neuron and taken up by another, contributing to its pathogenicity. We also present our new work that suggests ultrasound as a new treatment modality to clear pathological Aβ and tau. We put this work into perspective, discussing current vaccination strategies and improved brain delivery methods involving antibody engineering and viral approaches. We propose that rather than reducing post-translational modifications of tau, its levels and de novo synthesis need to be reduced. We anticipate a surge in combinatorial strategies, simultaneously targeting multiple pathologies, and an improved drug delivery to the brain facilitated by emerging technologies such as ultrasound. Show more

Keywords: Alzheimer’s disease, amyloid, axon initial segment, focused ultrasound, fyn kinase, microtubule-associated protein tau, non-invasive, phosphorylation, spreading, vaccination

DOI: 10.3233/JAD-179907

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S517-S527, 2018

Authors: Hernández, Félix | Llorens-Martín, María | Bolós, Marta | Pérez, Mar | Cuadros, Raquel | Pallas-Bazarra, Noemí | Zabala, Juan C. | Avila, Jesús

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is characterized by the presence of two aberrant structures: namely senile plaques, composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, composed of tau protein. In this regard, Aβ and tau protein have been widely studied in research efforts aiming to find a therapy for AD. Aβ and tau pathologies do not always overlap. The precursor of Aβ is expressed in peripheral tissues and in the central nervous system (CNS), whereas tau is mainly a neuronal protein. Since AD is a disease of the CNS, it has been proposed that Aβ may initiate the disease process, with tau …being the executor. In this review, we will focus on future studies of tau pathology, although we will comment on new beginnings for AD, as other molecules other than Aβ and tau may be involved in the onset of dementia. Show more

Keywords: Extracellular tau, MAPs, tau functions, tauopathies

DOI: 10.3233/JAD-179916

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S529-S534, 2018

Authors: Novak, Petr | Cehlar, Ondrej | Skrabana, Rostislav | Novak, Michal

Article Type: Review Article

Abstract: Tau protein plays a major role in the pathogenesis of Alzheimer’s disease. Despite many decades of intensive research, the cause of the conformational switch that leads to the remodeling of the highly flexible conformational ensemble of intrinsically disordered protein tau into insoluble filaments is still elusive. We show here that truncation of tau may play a causative role in this conformational change, as evidenced by results obtained from in vitro experiments and from transgenic animal models. This conformational change is a common denominator of pathological tau protein assemblies, and a salient drug target. The long-running research of truncated tau …has led to the generation of the first active tau vaccine that has entered clinical trials. Show more

Keywords: Aggregation, Alzheimer’s disease, conformational ensemble, immunotherapy, tau protein, truncation

DOI: 10.3233/JAD-179942

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S535-S546, 2018

Authors: Bhat, Ratan V. | Andersson, Ulf | Andersson, Shalini | Knerr, Laurent | Bauer, Udo | Sundgren-Andersson, Anna K.

Article Type: Review Article

Abstract: Spanning over three decades of extensive drug discovery research, the efforts to develop a potent and selective GSK3 inhibitor as a therapeutic for the treatment of type 2 diabetes, Alzheimer’s disease (AD), bipolar disorders and cancer have been futile. Since its initial discovery in 1980 and subsequent decades of research, one cannot underscore the importance of the target and the promise of a game changing disease modifier. Several pharmaceutical companies, biotech companies, and academic institutions raged in a quest to unravel the biology and discover potent and selective GSK3 inhibitors, some of which went through clinical trials. However, the …conundrum of what happened to the fate of the AstraZeneca’s GSK3 inhibitors and the undertaking to find a therapeutic that could control glycogen metabolism and aberrant tau hyperphosphorylation in the brain, and rescue synaptic dysfunction has largely been untold. AstraZeneca was in the forefront of GSK3 drug discovery research with six GSK3 drug candidates, one of which progressed up to Phase II clinical trials in the quest to untangle the tau hypothesis for AD. Analysis of key toxicity issues, serendipitous findings and efficacy, and biomarker considerations in relation to safety margins have limited the potential of small molecule therapeutics as a way forward. To guide future innovation of this important target, we reveal the roller coaster journey comprising of two decades of preclinical and clinical GSK3 drug discovery at AstraZeneca; the understanding of which could lead to improved GSK3 therapies for disease. These learnings in combination with advances in achieving kinase selectivity, different modes of action as well as the recent discovery of novel conjugated peptide technology targeting specific tissues have potentially provided a venue for scientific innovation and a new beginning for GSK3 drug discovery. Show more

Keywords: Alzheimer’s disease, drug targeting, tau

DOI: 10.3233/JAD-179934

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S547-S554, 2018

Authors: Sigurdsson, Einar M.

Article Type: Review Article

Abstract: Tau immunotherapies have now advanced from proof-of-concept studies to Phase II clinical trials. This review briefly outlines developments in the field and discusses how these therapies may work, which involves multiple variables that are connected in complex ways. These various factors are likely to define therapeutic success in humans and have not been thoroughly investigated, at least based on published reports.

Keywords: Alzheimer’s disease, antibodies, clinical trials, immunotherapies, mechanisms, tau, tauopathy

DOI: 10.3233/JAD-179937

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S555-S565, 2018

Authors: Cline, Erika N. | Bicca, Maíra Assunção | Viola, Kirsten L. | Klein, William L.

Article Type: Review Article

Abstract: The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer’s disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998). The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor. Over 4,000 articles concerning AβOs have been published since then, including more than 400 reviews. AβOs have been shown to accumulate in …an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. As reviewed by Hayden and Teplow in 2013, the AβO hypothesis “has all but supplanted the amyloid cascade.” Despite the emerging understanding of the role played by AβOs in AD pathogenesis, AβOs have not yet received the clinical attention given to amyloid plaques, which have been at the core of major attempts at therapeutics and diagnostics but are no longer regarded as the most pathogenic form of Aβ. However, if the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, diagnostics, etiology, model systems, oligomers, prions, receptors, structure-function, tau, therapeutics

DOI: 10.3233/JAD-179941

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S567-S610, 2018

Authors: Gulisano, Walter | Maugeri, Daniele | Baltrons, Marian A. | Fà, Mauro | Amato, Arianna | Palmeri, Agostino | D’Adamio, Luciano | Grassi, Claudio | Devanand, D.P. | Honig, Lawrence S. | Puzzo, Daniela | Arancio, Ottavio

Article Type: Review Article

Abstract: The “Amyloid Cascade Hypothesis” has dominated the Alzheimer’s disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms …between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies. Show more

Keywords: Amyloid-β peptide, amyloid-β protein precursor, oligomers, synaptic dysfunction, tau

DOI: 10.3233/JAD-179935

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S611-S631, 2018

Authors: Mormino, Elizabeth C. | Papp, Kathryn V.

Article Type: Review Article

Abstract:  The aberrant accumulation of the amyloid protein is a critical and early event in the Alzheimer’s disease (AD) cascade. Given the early involvement of this pathological process, it is not surprising that many clinically normal (CN) older individuals demonstrate evidence of abnormal Aβ at postmortem examination and in vivo using either CSF or PET imaging. Converging evidence across multiple research groups suggests that the presence of abnormal Aβ among CN individuals is associated with elevated risk of future clinical impairment and cognitive decline. Amyloid positivity in conjunction with biomarkers of neuronal injury offers further insight into which CN are …most at risk for short-term decline. Although in its infancy, tau PET has demonstrated early increases among Aβ+ that will likely be an important indicator of risk among CN. Overall, the detection of early Aβ among CN individuals has provided an important opportunity to understand the contributions of this pathology to age-related cognitive decline and to explore early intervention with disease modifying strategies. Show more

Keywords: Aging, amyloid, biomarkers, cognitive decline, early detection, memory, PET

DOI: 10.3233/JAD-179928

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S633-S646, 2018

Authors: Santana, Isabel | Baldeiras, Inês | Santiago, Beatriz | Duro, Diana | Freitas, Sandra | Pereira, Miguel Tábuas | Almeida, Maria Rosário | Oliveira, Catarina Resende

Article Type: Research Article

Abstract: The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer’s disease (AD), but this mandatory “amyloid-first pathway” has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% …with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n  = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42 , and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1–18.0, p  = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7–9.3, p  = 0.141; SNAP: HR = 3.1, 95% CI = 1.1–9.6; p  = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative “neurodegeneration-first pathway” for further investigation. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid biomarkers, mild cognitive impairment, neurodegeneration

DOI: 10.3233/JAD-179908

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S647-S657, 2018

Authors: Nguyen, Phuong H. | del Castillo-Frias, Maria P. | Berthoumieux, Olivia | Faller, Peter | Doig, Andrew J. | Derreumaux, Philippe

Article Type: Research Article

Abstract: Targeting the early oligomers formed by the amyloid-β (Aβ) peptide of 40 and 42 amino acids is considered one promising therapeutic approach for Alzheimer’s disease (AD). In vitro experiments and computer simulations are often used in synergy to reveal the modes of interactions of drugs. In this account, we present our contribution to understanding how small molecules bind to Aβ40 /Aβ42 peptides, based either on extensive coarse-grained and all-atom simulations, or a variety of experimental techniques. We conclude by offering several perspectives on the future of this field to design more efficient drugs.

Keywords: Aβ oligomers, all-atom/coarse-grained models, Alzheimer’s disease, amyloid simulations, cell-based assays, drugs, in vitro studies

DOI: 10.3233/JAD-179902

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S659-S672, 2018