Dr. Rudolph Tanzi is a Professor of Neurology at Harvard Medical School and and the Director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH). He co-discovered three of the first Alzheimer’s disease genes and has identified several others in the Alzheimer’s Genome Project, which he directs. Dr. Tanzi was the keynote speaker of the 2017 Gordon Science Symposium and its annual David Elmaleh Lecture. Below is the summary of his inaugural address titled “Alzheimer’s disease: a story of genes, glia, and germs”.
Alzheimer’s disease (AD) is the most common form of dementia affecting the elderly and is characterized by global cognitive decline. AD is strongly influenced by both genetic factors and lifestyle. While certain rare gene mutations, e.g. in the APP, PSEN1 and PSEN2 genes guarantee onset of AD before 60 years old, most cases of AD (>97%) involve genetic susceptibility factors, e.g. APOE, and lifestyle, e.g. diet, exercise, sleep, intellectual and social engagement, stress levels, and brain trauma. Most recently we have found that low-grade infections, e.g. bacterial, fungal, viral, in the brain may also play a role by rapidly nucleating beta-amyloid deposition as an antimicrobial protection response of the brain's innate immune system. Genetic susceptibility factors have been elucidated over the past decade using genome-wide association studies (GWAS) and more recently by follow up with whole genome sequencing (WGS) and whole exome sequencing (WES). We are now carrying out GWAS using approximately 50 million single nucleotide variants (SNV) from WGS and WES (whole genome sequencing association studies; WGSAS). As AD-linked/associated functional SNVs are identified in these studies, they are being tested in our 3D human stem cell-derived neural culture models of AD, in which we have shown beta-amyloid directly drives tangle formation. Many of the more recently identified AD genes are involved in innate immunity, e.g. CD33, which we first reported in our family-based GWAS in 2008 (along with ADAM10 and ATXN1). To study CD33 and other innate immune-related AD genes, we have incorporated microglia into our 3D neural cultures while also utilizing classic transgenic mouse models.
Magnetic resonance imaging (MRI) provides various methods for imaging anatomical, physiological, and functional information of our body noninvasively. In a conference organized by the Gordon Center, Dr. Sung-Hong Park, from the South Korean university of KAIST, discussed the latest imaging modalities for acceleration of data acquisition in terms of pulse sequences and image reconstructions. These modalities include (i) acquisition of time-of-flight MR angiogram and blood oxygenation level dependent (BOLD) MR venogram, (ii) application of compressed sensing to arterial spin labeling, a non-invasive perfusion MRI technqiue, (iii) simultaneous acquisiton of blood perfusion and magnetization transfer (MT) with 2D inter-slice blood flow and MT effects, and (iv) acceleration of functional MRI with compressed sensing.
Dr. Jordan R. Green is the Director of the MGH IHP Speech and Feeding Disorders Lab, and holds academic appointments in the Departments of Communication Sciences and Disorders at MGH Institutes of Health Professions, and at the Speech & Hearing Biosciences and Technology program at the Harvard Medical School. Dr. Green was the guest speaker at a lecture organized by the MGH Gordon Center. Below is the presentation summary.Progressive motor deterioration due to amyotrophic lateral sclerosis (ALS) leads to the eventual impairment of speech and swallowing function. Despite the devastating consequences of speech impairment to life quality, few options are available to objectively assess the integrity of the speech motor system and to assist impaired oral communication. The long-term goals of current research led by Dr. Green is to derive objective measures of speech performance that can be used to support diagnosis and clinical decision-making, and to develop new pathways of oral communication for the speech impaired (i.e., a real-time articulatory movement-driven speech synthesizer).
Antonia Dimitrakopoulou-Strauss M.D. is Professor of Nuclear Medicine at the German Cancer Research Center. She was the guest speaker at a lecture organized by the MGH Gordon Center. Below is the presentation summary.
Molecular imaging techniques allow a better staging as well as an individualization and optimization of therapy in oncological patients. The availability of new hybrid scanners, like PET-CT and PET-MRI have revolutionized both diagnosis and therapy management and are therefore a unique tool for personalized cancer treatment. Identification of non-responders early in the course of treatment, the choice of the appropriate therapeutic protocol as well as optimal treatment duration are some aspects which can be improved by the use of molecular imaging techniques and can help to avoid side effects and save costs for the health system. Furthermore, therapies with new targeted drugs, like tyrosine kinase inhibitors or immune checkpoint inhibitors require also a tight monitoring for assessment of a therapeutic result and a fast change to another protocol in case of progress. Standardization of response criteria is another important aspect and a prerequisite for a more routine application of molecular imaging for therapy guidance. Furthermore, the development of new tumor-specific tracers will enable a more accurate assessment of a therapeutic result. Numerous peptides targeting receptoractive tumors are in development with a high potential in a large spectrum of tumors for theranostic approaches, like in neuroendocrine tumors and in prostate cancer.
Dr. Anne van de Ven is a Research Assistant Professor at Northeastern University. She was the guest speaker at a lecture organized by the MGH Gordon Center. Below is the presentation summary.
Intravital microscopy allows the visualization of nanoparticle transport across a sequence of multi-scale physical barriers. Data collected using this approach can be used to simulate, predict, and improve nanoparticle designs for drug and contrast agent delivery to solid tumors. Dr. van de Ven presented an integrated framework that combines patient-derived xenografts, exogenous contrast agents, and experimental nanoparticles to study how patient-specific transport parameters can impact nanotherapeutics delivery.
According to Dr. van de Ven, preliminary data suggests that only a subset of patients will be highly amenable to nanotherapy. Using ferumoxytol as a surrogate, she is currently developing MRI techniques to quantify nanoparticle delivery and relate it to therapeutic efficacy in vivo for the personalized selection of therapy.
Dr. Tae Ho Lee is Assistant Professor of Medicine at Harvard Medical School. He was the guest speaker at a lecture organized by the MGH Gordon Center. Below is his presentation summary.
Phosphorylation of proteins is one of the most important post-translational modifications (PTMs) and a key signaling mechanism in diverse physiological and pathological processes. Its deregulation contributes to age-related diseases, notably cancer and Alzheimer’s disease (AD).
AD is characterized by a progressive loss of memory and other cognitive functions. It affects over 44 million people in worldwide and its incidence is expected to triple over the next 30.years. There is therefore an urgent need to understand the mechanisms underlying the degeneration of neuronal cells. The two defining neuropathological features of AD are extracellular senile plaques and intracellular neurofibrillary tangles (NFTs). The senile plaques are made of amyloid-β (Aβ), cleaved products of the amyloid precursor protein (APP), whereas the neurofibrillary tangles mainly consist of the microtubule-associated protein tau. Many hypotheses have been proposed to explain the etiology and pathogenesis of AD and related disorders; two dominant theories focus on increased production of Aβ and dysfunction of tau. However, currently the pathogenic mechanisms are still not fully understood and there is no effective therapy. Therefore, the ability to define regulatory mechanisms controlling APP processing and tau function will be critical for elucidating the pathogenesis and for designing strategies for preventing and/or treating neurodegenerative diseases.
Death-associated protein kinase 1 (DAPK1) is a death domain-containing calcium/ calmodulinregulated serine/threonine kinase and plays an important role in regulating neuronal function. We demonstrated here that DAPK1 expression is dramatically up-regulated in the 75% hippocampi of AD patients compared with age-matched normal subjects. Moreover, we showed that DAPK1 regulates tau toxicity in modulating microtubule assembly and neuronal differentiation, and DAPK1 overexpression increases tau phosphorylation at multiple AD-related sites in cells and animal models. We also found that DAPK1 increases Aβ secretion in a kinase activity-dependent manner. In addition, the levels of insoluble Aβ and amyloidogenic APP processing are significantly reduced in APP-overexpression/DAPK1-knockout mice brain. Finally, we identified novel DAPK1 substrates that are involved in neuronal cell death and AD including N-myc downstream-regulated gene 2 (NDRG2). Together, these results suggest that DAPK1 may be a critical regulator of tau phosphorylation, APP processing, and neuronal cell death and DAPK1 deregulation may contribute to AD progression. Therefore, DAPK1 may serve a potential therapeutic target for AD.
Central nervous system demyelination represents the pathological hallmark of multiple sclerosis (MS) and is thought to contribute to other neurological conditions including traumatic brain injury, stroke and Alzheimer’s disease. The ability to assess demyelination quickly and quantitatively is crucial for the diagnosis and treatment of these diseases. As current imaging approaches for demyelination rely on magnetic resonance imaging, which is neither quantitative nor specific for demyelination, Dr. Pedro Brugarolas set out to develop a PET tracer for demyelination. He described the development of a novel radioligand for brain imaging based on the FDA-approved drug for MS, 4-aminopyridine (4-AP). After demonstrating that C-14 labeled 4-AP localizes to demyelinated areas in mouse models of MS –presumably through binding to exposed potassium channels in demyelinated axons– he designed a fluorinated derivative of 4-AP compatible with with F-18 labeling and PET. Dr. Brugarolas then developed a novel radiochemical method to label this compound and performed PET/CT imaging in rats harboring demyelinated lesions. According to Dr. Pedro Brugarolas, this is the first example of a PET radioligand for potassium channels in the brain potentially opening a new window for looking at brain diseases.
Dr. Pedro Brugarolas is a radiochemist at the University of Chicago. He was the guest speaker of a lecture organized by the Gordon Center and his presentation was titled "[18F]3F4AP: a new PET tracer for imaging brain demyelination."
According to Dr. Sei Kwang Hahn from Pohang University of Science and Technology in South Korea, smart photonic materials have a variety of biomedical applications for biosensing, molecular imaging, surgery and therapies. In a conference organized by the Gordon Center, he discussed his research efforts to develop melanoidin nanoparticles for in vivo noninvasive photoacoustic mapping of sentinel lymph nodes, photoacoustic tomography of gastro-intestinal tracts, and photothermal ablation cancer therapy. Dr. Hahn and his colleagues created biodegradable polymer waveguides and upconversion nanoparticles for photochemical tissue bonding. They also synthesized cell-integrated poly(ethylene glycol) hydrogels for in vivo optogenetic sensing and therapy. Real-time optical readout of encapsulated heat-shock-protein-coupled fluorescent reporter cells made it possible to measure the nanotoxicity of cadmium-based quantum dots in vivo. Using optogenetic cells to produce glucagon-like peptide-1, Dr. Hahn developed smart contact lenses composed of biosensors, drug delivery systems and power sources for the treatment of diabetes as a model disease.