Rakez Kayed - US grants

The pathological aggregation of the microtubule-associated protein tau and its subsequent accumulation into neurofibrillary tangles (NFTs) and other hyperphosphorylated tau-containing inclusions are defining histopathological features of Alzheimer?s disease (AD) and several other neurodegenerative disorders collectively known as tauopathies. These diseases affect millions of people in the United States and exact enormous personal and financial costs on those afflicted and their loved ones. However, while amyloid-? (A?) and tau aggregates in the brain are the common pathological hallmarks of AD, the disease is heterogeneous with different comorbid pathologies and symptom progression rates. Recent studies suggest that NFTs are not the most toxic tau entities in tauopathies; rather tau oligomers?soluble intermediates between monomers and NFTs?have emerged as an important drug target due to their toxicity, seeding potency, and ability to propagate a specific abnormal tau conformation and thus initiate widespread tau pathology. Our data suggest that oligomers composed of different proteins might give rise to increased and diverse tau oligomerization, resulting in different pathologies and phenotypes that sometimes overlap with other neurodegenerative diseases. The dynamic and hydrophobic nature of tau oligomers allows for the formation of heterogeneous populations of aggregates that include distinct tau oligomeric conformers (strains). In this proposal we will test the tau oligomeric strain hypothesis in AD by defining strain characteristics and potential mechanisms of strain formation and propagation. Specific aim 1 will test the hypothesis that diverse tau oligomeric strains are found in AD brain and CSF. Specific aim 2 will test the hypothesis that brain-derived tau oligomeric strains arise from cross-seeding other amyloidogenic proteins and propagate pathology in vivo. This research proposal will yield useful results with great potential to advance the development of diagnostic and therapeutic applications to target toxic tau oligomers in AD. The elucidation of different tau oligomeric strains and their roles in disease progression may reveal novel therapeutic strategies and identify upstream drug targets for treating AD. Moreover, a better understanding of tau strains could help identify useful approaches for screening the best drug candidates. Finally, it could provide novel insights into the design of future clinical trials and introduce the exciting possibility of personalized medicine to treat AD and other tauopathies.

Parkinson?s disease and related synucleinopathies afflict 10% of those older than age 65. Since there are currently no effective treatments, it is essential that we find a way to prevent or treat these devastating neurodegenerative diseases. The pathological hallmark of synucleinopathies such as Parkinson?s disease is the deposition of insoluble aggregates of misfolded ?-synuclein; however, mounting evidence suggests that soluble aggregates of ?-synuclein (e.g., oligomers) are a key causal agent in synucleinopathies. An emerging concept in neurodegenerative disease research and diagnosis is that disease pathology overlaps or even forms a continuum of pathologies. For example, concomitance of ?-synuclein and tau pathology in Parkinson?s disease and dementia with Lewy bodies is not rare; in fact, several studies report co-localization of ?-synuclein and tau. Thus, it has been put forth that soluble aggregates of ?-synuclein and tau contribute to secondary symptoms and clinical heterogeneity in these dementing disorders and that ?-synuclein and tau interaction is essential for the full development of pathology and neurotoxicity. Despite the outstanding efforts of many investigators, the relationship between ?-synuclein and tau aggregation in synucleinopathies remains unresolved. Moreover, the role and mechanisms of neurotoxicity remain largely unknown. Finally, the ability to detect ?-synuclein and tau oligomers in early stage disease and exploit them as therapeutic targets for synucleinopathies remains largely unexplored. In this MPI, R01 proposal, we will test the exciting hypothesis that tau and ?-synuclein oligomers synergize to promote neurotoxicity. This project utilizes a diversity of state-of-the-art conceptual and technical approaches from a multidisciplinary and highly collaborative team to address the important problem of identifying mechanisms specific to ?-synuclein toxicity, the role of tau oligomerization and targeting these entities through immunotherapy. Aim 1 will test whether ?-synuclein and tau oligomers synergize to induce motor, learning, and memory deficits in vivo. Aim 2 will test whether ?-synuclein and tau synergize to promote neurotoxicity as well as investigate specific mechanisms. Aim 3 will determine the contribution of ?-synuclein posttranslational modifications to ?-synuclein and tau oligomer neurotoxicity. These aims integrate highly specialized transgenic animals, protein biochemistry, mass spectrometry-based proteomics, and Drosophila genetics. Our proposal, if successful, will provide much needed novel molecular insight into the mechanisms of neurotoxicity in synucleinopathies that may prove crucial in moving forward to a disease modifying therapy.

PROJECT SUMMARY/ABSTRACT Progressive accumulation of microtubule-associated protein (tau) is a defining feature of Alzheimer's disease (AD) and a number of other disorders termed tauopathies. Recent studies from our laboratories, confirmed by others, demonstrated that tau oligomers constitute distinctly toxic and pathologically significant tau species able to spread in tauopathy brain, likely through inter-synaptic transmission. However, precise investigation of tau oligomer spreading is hindered by the complexity of the neuronal network. Methods to effectively diagnose AD and other tauopathies at early stages and monitor their progress are also lacking. In addition to cognitive abnormalities, AD patients show visual anomalies. In this application, we will test the hypothesis that tau pathology in the retina may predict tau-related dysfunction in the brain, making it an excellent platform to study the propagation of tau oligomeric strains, detect and monitor the progression of AD and other tau-related disorders, and evaluate the efficacy of our newly developed tau oligomer-specific monoclonal antibodies (TOMAs) at targeting different tau oligomeric strains. Outcomes from this study will provide clear pathways of oligomer spreading and aid in the development of novel approaches to monitor and treat tauopathies.

PROJECT SUMMARY/ABSTRACT Alzheimer?s disease (AD) is the most common and severe age-associated neurodegenerative dementia of our times for which there is no cure. Synaptic dysfunction induced by the dysfunctional targeting toxic oligomers of both Ab and Tau (the two hallmark amyloids in AD) is recognized as one of the earliest events in AD, driving initial cognitive decline and clinical manifestation. Preventing such oligomer disrupting action on synapses would thus be an effective and comprehensive therapy for AD, blocking the combined driving toxicity of both A? and tau. However, a strategy to achieve this important goal remains elusive. In the present project we wish to address this critical knowledge gap by testing the hypothesis that activation of calcineurin (CN) mediates the synergistic effect of A? and tau oligomers on synapses. CN is a CNS-abundant phosphatase critically involved in synaptic function and memory formation. CN activity is abnormally increased the brain of AD patients as well as tg mouse models of AD, and inhibition of CN with FK506 (an FDA-approved immunosuppressant drug) protects synapses from A? oligomers and restores memory in transgenic AD mouse models. Most notably, we showed that the incidence of AD in solid organ transplant recipients chronically treated with FK506 is dramatically reduced as compared to the general population. This is highly significant in light of recent evidence showing that overexpression of hTau induces elevated CN in the CNS, and that tau oligomers induce synaptic deficits and memory dysfunction in synergy with A? oligomers, strongly suggesting that the two species impinge upon a common molecular target mediating their combined key role in AD onset and clinical progression. We propose that such common target is CN and that CN inhibition is an effective approach to block the combined toxicity of tau and A? oligomers that drive AD. In the present project will employ in vitro, ex vivo and in vivo models and autopsy human brain specimens to mechanistically test our hypothesis by characterizing the role of CN in mediating the disruptive effects of tau oligomers (Aim 1) and by establishing CN as the common target mediating the combined, synergistic impact of tau and Ab oligomers on synaptic and memory function (Aim 2). At the completion of the proposed studies we will have documented a previously unappreciated role of CN as the point of molecular convergence of the toxic oligomers of the two amyloid proteins that hallmark AD neuropathology, tau and A?, and illustrated the beneficial effects of FK506 in preventing their combined toxicity. Given the translational value of FK506 (an FDA-approved drug) this discovery will have a substantial impact in the field by promoting the development of an innovative treatment concept for AD centered on simultaneous blockade of tau and A? toxic species, a strategy expected to be effective in humans as suggested by the resilience to AD of transplanted patients chronically treated with FK506.

PROJECT SUMMARY Tau aggregation is a shared pathology of Alzheimer's disease and related dementias known as tauopathies. Because each disorder develops a unique combination of aggregate polymorphisms and co-morbidities that may influence the course and severity of disease, elucidating the relationship between tau aggregate structure and biological activity has become a high priority in the field. Advances to date have been limited, however, by the lack of rigorously standardized aggregate preparations from each form of tauopathy and by the absence of tools needed to selectively detect their presence in biological models and clinical specimens. The proposed Interdisciplinary Research Network on Biologically Active Tau Aggregate Polymorphs seeks to address this need by (1) isolating a full range of biologically active tau aggregates from authentic Alzheimer's disease, Corticobasal Degeneration, Progressive Supranuclear Palsy, and Pick's disease brain tissue, (2) establishing their structures through biophysical analysis, (3) developing probe sets for their selective detection, and (4) disseminating reliably vetted samples and lab-ready protocols for their handling and storage to the broader research community. In accomplishing these goals, the network will support research into the molecular basis of tauopathy pathogenesis and catalyze efforts toward creating novel diagnostic and therapeutic strategies specifically tailored against toxic tau aggregate polymorphs.

Project Summary/Abstract We proposed creating a highly collaborative pre- and post-doctoral training program in the pathophysiology of Alzheimer?s disease and other related neoconservative disorders. Our program is dedicated on advancing pre- and post-doctoral fellows into independent research scientists at research intensive universities and health- related research laboratories. Our trainees will be mentored by members of the Mitchell Center for Neurodegenerative Diseases at the University of Texas Medical Branch ? Galveston. Our highly collaborative faculty reach across multiple departments allowing them to employ a number of experimental approaches to the problems associated with Alzheimer's disease. Our training program incorporates cellular animal models, disease progression mechanisms and pharmacological manipulations, immunotherapeutic approaches targeting tau and amyloid oligomers, synaptic electrophysiology and, DNA damage and repair in neurodegeneration, genetics of synaptic development and degeneration, molecular mechanisms in cognitive resilience, and metabolic determinants of neurodegeneration. A strength of our training program is the investment UTMB has made in developing this highly collaborative team as demonstrated by our joint publications and funded grants. Our four pre-and three post-doctoral trainees will be closely mentored throughout their training. Our pre-doctoral trainees will be required to take several new courses devoted to the cellular signaling in neurodegeneration and the biochemistry and biophysics of amyloid proteins, while our post-doctoral trainees will participate in a certificate program in advanced biomedical research strategies. All trainees will participate in seminars, community building events, journal clubs and active collaborative research training. We have proposed a framework that will enable us to train and mentor both pre- and post-doctoral trainees on their way to becoming independent scientist to help address the Alzheimer?s medical needs of the country.