About My Research
Center/Research Area Affiliations
Biography
Dr. Arboleda-Velasquez’s research is focused on the genetics and pathobiology of neurodegenerative diseases of the brain and the retina. He began his career studying brain and retinal small-vessel disease (SVD) during his PhD training at Harvard Medical School and postdoctoral fellowship at Mass Eye and Ear, and recently expanded his research to include mechanisms of resistance to Alzheimer’s disease. Dr. Arboleda-Velasquez’s most significant achievements to date include:
- Showed that Notch signaling, a key regulator of cell fate decisions, plays a central role in the pathophysiology of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; the most common inherited SVD of the brain) and, more generally, in ischemic stroke.
- Showed that pericytes (multifunctional, fibroblast-like cells found in the walls of CNS capillaries) help maintain retinal microvasculature stability in adults, a finding relevant to a retinal SVD called diabetic retinal microangiopathy.
- Discovered a role for the transcription factor Runx1 in aberrant angiogenesis and fibrosis.
- Developed an approach for discovering rare gene variants of large effect contributing to the resistance to neurodegeneration in Alzheimer’s disease – an approach that uncovered the APOE3 Christchurch variant. The APOE3 Christchurch article published in Nature Medicine in November of last year already has 76 citations and has been ranked in the top 5% of all time research outputs scored by Altmetric.
Dr. Arboleda-Velasquez’s early career work on CADASIL, an inherited form of stroke and vascular dementia, took him from the clinical characterization of two families in his home country of Colombia to Harvard Medical School, where he conducted molecular studies of mutant Notch 3 receptors in culture systems. He also generated novel knock-in mouse models that replicated a genotype-phenotype correlation first observed in his CADASIL patients, and leveraged inducible cell ablation studies in mice to provide evidence that pericytes help regulate microvascular stability in adult neural tissues. Dr. Arboleda-Velasquez recently took his CADASIL work towards translational applications by characterizing blood biomarkers linked to the pathobiology of the disease and by establishing the preclinical feasibility of a treatment modality based on Notch 3 signaling normalization using therapeutic antibodies.
Dr. Arboleda-Velasquez’s current research program also encompasses vitreoretinal diseases, with focuses on two relatively uncharted conditions: diabetic retinopathy, the most common cause of permanent blindness in working adults in the US, and proliferative vitreoretinopathy, a severe complication of ocular trauma. To drive innovation towards the discovery of new therapeutic targets, he developed new methods for the primary culture and molecular profiling of human cells derived from surgical specimens from patients with these conditions. These efforts led to: 1) the discovery of Runx1 as a critical mediator of aberrant angiogenesis in proliferative diabetic retinopathy and in the epithelial-to-mesenchymal transition in proliferative vitreoretinopathy; 2) the development of new treatment modalities based on administering small molecule inhibitors of Runx1 as eye drop formulations; and 3) the development of new animal models for proliferative vitreoretinopathy that reproduce the complexity of the human condition.
More recently, he initiated a research program addressing genetic factors underlying resistance to Alzheimer’s disease by leveraging his access to the world’s largest population of patients with familial Alzheimer’s disease caused by the E280A mutation in Presenilin 1 (PSEN1 E280A). Dr. Arboleda-Velasquez is leading a collaborative project to conduct deep phenotyping and genomic and proteomic analyses of subjects with unusually late ages of symptom onset, with the goal of identifying and validating new rare gene variants of large effect capable of conferring resistance to neurodegeneration.
Education
MD, University of Antioquia, Medellin Colombia (2000)
PhD, Harvard Medical School (2009)
Postgraduate Training
Research Fellowship, Schepens Eye Research Institute of Mass. Eye and Ear (2010-2011)
Honors
2015: Young Mentor Award, Harvard Medical School
2015: Leadership Development for Physicians and Scientists Program, Harvard Medical School
2015: Early Career Institute in Neuroscience Travel and Mentoring Minority Award, NINDS-University of Pittsburg
2012: Carl Storm Underrepresented Minority Fellowship, Gordon Research Conference
2011: Society of Neuroscience Scholar Fellow Award
- APOE3 Christchurch modulates ß-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases. Front Mol Neurosci. 2024; 17:1373568.
- The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci. 2023 Dec; 26(12):2104-2121.
- APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation. Alzheimers Dement. 2024 Feb; 20(2):819-836.
- Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer's disease. Nat Commun. 2023 08 23; 14(1):5120.
- Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man. Nat Med. 2023 05; 29(5):1243-1252.
- APOE3 Christchurch modulates tau phosphorylation and ß-catenin/Wnt/Cadherin signaling in induced pluripotent stem cell-derived cerebral organoids from Alzheimer's cases. bioRxiv. 2023 Jan 13.
- Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia. Acta Neuropathol. 2022 09; 144(3):589-601.
- Evidence of beta amyloid independent small vessel disease in familial Alzheimer's disease. Brain Pathol. 2022 11; 32(6):e13097.
- Notch Signaling in Vascular Endothelial and Mural Cell Communications. Cold Spring Harb Perspect Med. 2022 May 09.
- Topical Nanoemulsion of a Runt-related Transcription Factor 1 Inhibitor for the Treatment of Pathologic Ocular Angiogenesis. Ophthalmol Sci. 2022 Sep; 2(3).
- Safe and Effective Disease-Modifying Therapies for Small Blood Vessel Disease in the Brain. Am J Pathol. 2021 11; 191(11):1852-1855.
- Sex Differences in Cognitive Abilities Among Children With the Autosomal Dominant Alzheimer Disease Presenilin 1 E280A Variant From a Colombian Cohort. JAMA Netw Open. 2021 08 02; 4(8):e2121697.
- Specific Abnormalities in White Matter Pathways as Interface to Small Vessels Disease and Cognition in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Individuals. Brain Connect. 2022 02; 12(1):52-60.
- Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases. Am J Pathol. 2021 11; 191(11):1856-1870.
- Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators. Am J Pathol. 2021 07; 191(7):1193-1208.
- Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms. JAMA Ophthalmol. 2021 01 01; 139(1):49-56.
- Global Cardiovascular Risk Profile and Cerebrovascular Abnormalities in Presymptomatic Individuals with CADASIL or Autosomal Dominant Alzheimer's Disease. J Alzheimers Dis. 2021; 82(2):841-853.
- Treatment of Experimental Choroidal Neovascularization via RUNX1 Inhibition. Am J Pathol. 2021 03; 191(3):418-424.
- Topical delivery of a small molecule RUNX1 transcription factor inhibitor for the treatment of proliferative vitreoretinopathy. Sci Rep. 2020 11 30; 10(1):20554.
- TNF-a signaling regulates RUNX1 function in endothelial cells. FASEB J. 2021 02; 35(2):e21155.
- Genetic and nongenetic factors associated with CADASIL: A retrospective cohort study. J Neurol Sci. 2020 Dec 15; 419:117178.
- The INECO Frontal Screening for the Evaluation of Executive Dysfunction in Cerebral Small Vessel Disease: Evidence from Quantitative MRI in a CADASIL Cohort from Colombia - Corrigendum. J Int Neuropsychol Soc. 2020 11; 26(10):1052.
- The INECO Frontal Screening for the Evaluation of Executive Dysfunction in Cerebral Small Vessel Disease: Evidence from Quantitative MRI in a CADASIL Cohort from Colombia. J Int Neuropsychol Soc. 2020 11; 26(10):1006-1018.
- Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study. Lancet Neurol. 2020 06; 19(6):513-521.
- Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020 02 03; 11(1):667.
- Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019 11; 25(11):1680-1683.
- Clinical and research applications of magnetic resonance imaging in the study of CADASIL. Neurosci Lett. 2019 04 17; 698:173-179.
- Event-related potential correlates of recognition memory in asymptomatic individuals with CADASIL. Brain Res. 2019 03 15; 1707:74-78.
- Cognitive performance in asymptomatic carriers of mutations R1031C and R141C in CADASIL. Int J Psychol Res (Medellin). 2018 Jul-Dec; 11(2):46-55.
- Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease. JAMA Neurol. 2018 05 01; 75(5):548-556.
- Effect of Methotrexate on an In Vitro Patient-Derived Model of Proliferative Vitreoretinopathy. Invest Ophthalmol Vis Sci. 2017 08 01; 58(10):3940-3949.
- Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL. J Exp Med. 2017 Aug 07; 214(8):2271-2282.
- Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy. Vision Res. 2017 10; 139:168-176.
- Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis. Diabetes. 2017 07; 66(7):1950-1956.
- Blood biomarkers in a mouse model of CADASIL. Brain Res. 2016 08 01; 1644:118-26.
- Isolation and Transfection of Primary Culture Bovine Retinal Pericytes. Methods Mol Biol. 2016; 1430:107-17.
- Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study. JAMA Neurol. 2015 Aug; 72(8):912-9.
- Characterization of cells from patient-derived fibrovascular membranes in proliferative diabetic retinopathy. Mol Vis. 2015; 21:673-87.
- From pathobiology to the targeting of pericytes for the treatment of diabetic retinopathy. Curr Diab Rep. 2015 Feb; 15(2):573.
- Retinal microangiopathy in a mouse model of inducible mural cell loss. Am J Pathol. 2014 Oct; 184(10):2618-26.
- Notch signaling functions in retinal pericyte survival. Invest Ophthalmol Vis Sci. 2014 Jul 11; 55(8):5191-9.
- Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proc Natl Acad Sci U S A. 2011 May 24; 108(21):E128-35.
- Case records of the Massachusetts General Hospital. Case 12-2009. A 46-year-old man with migraine, aphasia, and hemiparesis and similarly affected family members. N Engl J Med. 2009 Apr 16; 360(16):1656-65.
- Linking Notch signaling to ischemic stroke. Proc Natl Acad Sci U S A. 2008 Mar 25; 105(12):4856-61.
- Delta-like 4 induces notch signaling in macrophages: implications for inflammation. Circulation. 2007 Jun 12; 115(23):2948-56.
- CADASIL: a critical look at a Notch disease. Dev Neurosci. 2006; 28(1-2):5-12.
- Highly conserved O-fucose sites have distinct effects on Notch1 function. J Biol Chem. 2005 Sep 16; 280(37):32133-40.
- CADASIL mutations impair Notch3 glycosylation by Fringe. Hum Mol Genet. 2005 Jun 15; 14(12):1631-9.
- C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology. 2002 Jul 23; 59(2):277-9.
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Cellular and Molecular Basis of Diabetic Retinopathy
Many patients with diabetes develop vascular abnormalities in their retinas—a disease called diabetic retinopathy—that can lead to vision impairment and blindness. Dr. Arboleda-Velasquez is studying the cell signaling mechanisms that control the integrity of the vasculature in a diabetic environment.
There is overwhelming evidence that VEGF, TGFβ, PDGF, Notch, and other molecules that are essential for vascular formation, are also part of the cell signaling circuitry contributing to vessel maintenance and the cellular response to injury and metabolic change. However, very little is known about how different signaling pathways are integrated in the microvasculature cell program and even less is understood about how these cell communication mechanisms are challenged in diabetes.
- Do these signaling molecules operate through the same molecular targets during development and in the adult?
- Which molecules predominate?
- In what order do they function in the process of vascular remodeling in response to a high-glucose environment?
- How can we devise therapeutic approaches through manipulation of a signaling pathway without interfering with the function of other interconnected signaling mechanisms?
Dr. Arboleda-Velasquez uses novel technologies, imaging methods, and enzymes to study cell-cell and protein-protein interactions. It is widely known that catalysis depends on transient interactions between enzymes and their substrates. Scientists have recently taken advantage of this chemistry to design tools for the study of protein-protein and cell-cell interactions. These powerful methods can now be used to visualize known protein-protein interactions, to discover new protein-protein interactions in cell lysates, and even to label and measure protein-protein interactions across intercellular contacts.
Dr. Arboleda Velasquez is currently using these technologies to investigate how a diabetic environment could impact interactions of vascular cells mediated by the Notch signaling pathway. Notch proteins and their ligands help cells to communicate with each other through close range interactions, which could be impaired in diabetic patients as vessels degenerate.
Notch Signaling in Ischemic Cerebral Small-Vessel Disease and CADASIL
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a frequent cause of stroke and cognitive decline in adults with a family history of these conditions.
CADASIL is caused by mutations in a gene called Notch 3. The Notch 3 gene is part of a group of genes that help cells communicate with each other. Cells use these social cues from neighboring cells as useful information to make decisions regarding their fate. However, it is not clear how Notch 3 mutations lead to cell-cell miscommunication and how this leads to stroke.
Dr. Arboleda-Velasquez uses mouse models of CADASIL and culture cells derived from these animals to study how CADASIL mutations affect Notch 3 function and how normal physiology could be restored using genetic manipulations and newly developed drugs. This work may lead to the identification of novel therapeutic targets for CADASIL, as many drugs that modulate Notch signaling are currently under development for other human conditions.