While there is a growing body of evidence to indicate that the blood-brain barrier (BBB) is compromised in Alzheimer's disease (AD), there has been little data to support a link between known risk factors for AD and the BBB. My research will attempt to show that the product of the ε4 allele of the APOE gene, a known risk factor for developing AD, somehow fails to maintain the integrity of the BBB, compared to the ε3 allele, and that this BBB failure leads to the chain of events resulting in AD.

Biography

John E. Donahue received his M.D. from Tufts University in 1992. He trained in neurology at Tufts-New England Medical Center and in neuropathology at Rhode Island Hospital. After spending four years at the New Jersey Neuroscience Institute as Director of Neuropathology, he returned to RIH/Brown Medical School in 2003 to practice clinical neuropathology and pursue academic research in neurodegenerative diseases (e.g. Alzheimer's disease) and the blood-brain barrier. Being both a neurologist and neuropathologist enables him to bring a clinical perspective to neuropathology material and an underlying pathologic understanding to clinical material. Translational research in neurodegenerative diseases is ideally-suited for a neurologist-neuropathologist like him. This is a very rare combination in the 21st century; most newly-trained neuropathologists are trained in general anatomic and surgical pathology, not neurology.

Research Description

John E. Donahue, M.D. is a neurologist-neuropathologist who currently studies Alzheimer's disease (AD) and the blood-brain barrier (BBB). He has shown that the heparan sulfate proteoglycan agrin, an important component of the vascular basal lamina, is fragmented in AD brain capillaries. Furthermore, he has also demonstrated that there is an alteration of the distribution of BBB amyloid-beta transporters RAGE (receptor for advanced glycation endproducts) and LRP-1 (low-density lipoprotein receptor-related protein-1) in AD. RAGE, which transports amyloid into the brain, is upregulated in the microvasculature of AD brains, while LRP-1, which transports amyloid out of the brain, is downregulated, leading to a net influx of amyloid into AD brains, further worsening the disease. Given that apolipoprotein E (apoE) is essential for maintaining BBB integrity, and that the apoE4 allele is a known risk factor for AD, Dr. Donahue is currently hypothesizing that the apoE4 allele is not as effective at keeping the BBB sealed, compared with the more common apoE3 allele, thus leading to the chain of events resulting in AD.

Dr. Donahue aims to become an expert in the BBB, to understand that particular anatomic structure and how neurologic function occurs, or does not occur, because of it. The BBB is a very underdeveloped and underappreciated area of neuroscience; less than 5% of abstracts submitted to the Society for Neuroscience annual meeting involve BBB research, yet the BBB is critically important in that its function leads to function of the brain, and its dysfunction leads to dysfunction of the brain.

Awards

1987: Phi Beta Kappa, Tufts University (elected as a junior)
1988: Summa Cum Laude, Tufts University
1992: David L. Kasdon (M'71) Prize, Tufts University School of Medicine (presented to a senior student who has shown interest and outstanding achievement in the neurosciences)
1997: Second place, Gustav Retzius Neuroanatomy Competition (East Coast)
1998: Second place, Gustav Retzius Neuroanatomy Competition (East Coast)
1999: CHAMPION, Gustav Retzius Neuroanatomy Competition (East Coast)
2004-2006: Dean's Teaching Excellence Award for outstanding teaching in Bio 186 (General Pathology) at Brown Medical School
2007-2008: Dean's Teaching Excellence Award for outstanding teaching in Biomed 364 (IMS I: General Pathology) at the Warren Alpert Medical School of Brown University
2009-2010: Certificate of Recognition for exemplary teaching in the pathology lab, Bio 3653 (IMS II: Micro/ID)
2010: Dean's Teaching Excellence Award for outstanding teaching in Bio 3652 (IMS II: Brain Sciences)

Affiliations

American Academy of Neurology (1994-present, current Active Member)
American Association for the Advancement of Science (2005-present, current Professional Member)
American Association of Neuropathologists (1998-present, current Active Member)
American Medical Association (1988-2001)
Brown Brain Science Program/Brown Institute for Brain Science (2006-present)
Children's Oncology Group (COG) (2007-present)
College of American Pathologists (1998-2005)
International Society to Advance Alzheimer Research and Treatment (2008-present, current Professional Member)
Massachusetts Medical Society (1988-present)
Neuroplex, Inc. (New York Society of Neuropathologists) (2000-present)
New York Academy of Sciences (2006-present)
Rhode Island Neurological Society (2009-present)
Rhode Island Pathological Society (2009-present)
Society for Neuroscience (2000-present, current Regular Member)

Funded Research

Title: "Effects of ApoE Genotype on Blood-Brain Barrier Permeability and LRP-1 Expression"
Principal Investigator: John E. Donahue, M.D.
Agency: NIH/NIA
Type: K08 (Alzheimer's Disease Clinical Scientist Development Award)
Number: 1K08AG029147-01
Term: 9/30/06-7/31/09 [no-cost extension year 8/1/09-7/31/10]
Direct Costs: $173,700/year
Total Costs: $562,649
Objectives: 1) Quantitate BBB permeability in human apoE3/E4 and apoE KO transgenic mice utilizing the in situ brain perfusion technique; 2) determine the distribution and quantity of Aβ and its BBB transporters LRP-1 and RAGE in the cerebral microvasculature of those same transgenic mice utilizing immunohistochemistry, ELISA, Western blot, and RT-PCR as appropriate

Teaching Experience

Bio 186 (General Pathology), Brown Medical School: Moderating small-group pathology laboratory sessions for first-year medical students (8-9 students/group), 2004-2006. Received Dean's Teaching Excellence Award in 2004, 2005, and 2006.

Bio 195-196 (Independent Study), Brown University: Accepted two students (Amanda Duffy and Jane Lim) for the fall, 2008 and spring, 2009 semesters and one student (Junghyun "Marco" Kim) for the fall, 2009 and spring, 2010 semesters to do independent study lab research on apoE genotype and blood-brain barrier permeability. Techniques employed included extraction of RNA, DNA, and protein from brain tissues, DNase purification of RNA, cDNA synthesis for Q-PCR, immunohistochemistry, Western blotting, and tracer perfusion of transgenic mouse brains for imaging mass spectrometry analysis. Accepted one student (Jie "Jessica" Pan) for the fall, 2010 and spring, 2011 semesters to study the orbitomedial prefrontal cortex (OMPFC) in healthy young adults, healthy older adults, and Alzheimer disease patients, in conjunction with Dr. Brad Dickerson at Mass. General Hospital, using the FreeSurfer computer program. Also had two other students (Emily Fessler: spring, 2008; and Zachary Gordon: summer, 2008) as volunteers (nonacademic credit).

Bio 262 (Neurologic Pathophysiology), Brown Medical School: Moderating small-group neurology and neuropathology laboratory sessions for second-year medical students (10 students/group), 1998 (two dates in May) and 2004-2005. Helped select neuropathology images for student CD-ROM in 2004. Gave one lecture, "Metabolic Diseases and CNS Tumors" as a substitute for Dr. Stopa in spring, 2004. Revised neuropathology section of syllabus in summer of 2004. Submitted neuropathology test questions, all years.

Bio 350 (Integrated Pathophysiology/Pharmacology: Neurologic Pathophysiology), Brown Medical School: Replacement for Bio 262 beginning in fall semester, 2006. Taught to second-year medical students in fall, 2006.

Bio 3645 (Integrated Medical Sciences I: General Pathology), Warren Alpert Medical School of Brown University: Replacement for Bio 186 beginning in fall semester, 2006. Taught to first-year medical students. Received Dean's Teaching Excellence Award in 2006-7 and 2007-8. Introductory small groups reinstituted in 2009.

Bio 3645 (IMS I: General Pathology): Lecture on "Introduction to Brain Cancer" (12/8/08, 12/7/09, 12/6/10).

Bio 3653 (Integrated Medical Sciences II: Micro/ID), Bio 3662 (IMS III: Cardiovascular), Bio 3663 (IMS III: Pulmonary), and Bio 3673 (IMS IV: Gastroenterology), Warren Alpert Medical School of Brown University: Moderating small-group pathology laboratory sessions for first-year (3653) and second-year (3662, 3663, 3673) medical students (8-9 students/group) beginning in spring, 2009. Received Certificate of Recognition in 2009 and 2010.

Bio 3665 (IMS III: Pathology of Supporting Structures): Lecture on "Diseases of Muscle" (12/8/09).

Co-Director, Bio 3650A/3652 (Integrated Medical Sciences II: Brain Sciences), Warren Alpert Medical School of Brown University: Replacement for Bio 350 beginning in spring semester 2007 and taught to first-year medical students. Co-director beginning in spring semester 2008 with Drs. Edward Feldmann and Glenn Tung. Joined by Drs. N. Steven Potter and Julie Roth with the departure of Dr. Feldmann in 2010. Responsibilities as co-director: 1) Organize brain prosection anatomy lab; 2) Give lectures appropriate to expertise; 3) Solicit/rewrite all exam questions in standard, best answer, multiple-choice USMLE format; 4) Review exams after administration to determine if any questions were inappropriate; 5) Organize and present clinical-pathologic correlation (CPC) case conference; 6) Attend lectures when other co-directors are unable to and whenever possible; 7) Assist with organizing schedule and recruiting lecturers. Received Dean's Teaching Excellence Award in 2010.

Courses Taught

• Brain Sciences (BI3650)
• General Pathology (BI0186)
• Integrated Medical Sciences I (BI0364)
• Neurologic Pathophysiology (BI0262)
• Organ System Pharmacology (BI0350)

Selected Publications

• Silverberg GD, Miller MC, Messier AA, Majmudar S, Machan JT, Donahue JE, Stopa EG, Johanson CE, "Amyloid deposition and influx transporter expression at the blood-brain barrier increase in normal aging," J Neuropathol Exp Neurol 2010; 69: 98-108.(2010)
• Ott BR, Cohen RA, Gongvatana A, Okonkwo OC, Johanson CE, Stopa EG, Donahue JE, Silverberg GD, and the Alzheimer's Disease Neuroimaging Initiative, "Brain ventricular volume and cerebrospinal fluid biomarkers of Alzheimer's disease," J Alzheimers Dis 2010; 20: 647-657. Epub 2010 Feb 24.(2010)
• Brown WD, Bearer EL, Donahue JE, "Chronic active herpes simplex type 2 encephalitis in an asymptomatic immunocompetent child," J Child Neurol 2010; 25: 901-908. Epub 2010 Feb 22.(2010)
• Boxerman JL, Rogg JM, Donahue JE, Machan JT, Goldman MA, Doberstein C, "Preoperative MRI evaluation of pituitary macroadenoma: imaging features predictive of successful transsphenoidal surgery," AJR 2010; 195: 720-728.(2010)
• Silverberg GD, Messier AA, Miller MC, Machan JT, Majmudar S, Stopa EG, Donahue JE, Johanson CE, "Blood-brain barrier amyloid transporter expression decreases as amyloid increases in normal aging," J Neuropathol Exp Neurol 2010; 69: 1034-1043.(2010)
• Chang HJ, Donahue JE, Sciandra KT, Evangelista PT, "Best cases from the AFIP: juvenile ossifying fibroma of the calvaria," Radiographics 2009; 29: 1195-1199.(2009)
• Dewan S, Alvarez VE, Donahue JE, Cielo D, "Intracranial collision metastases of prostate and esophageal carcinoma," J Neurooncol 2009; 95: 147-150. Epub 2009 May 10.(2009)
• Park MC, Goldman MA, Donahue JE, Tung GA, Goel R, Sampath P, "Endonasal ethmoidectomy and bifrontal craniotomy with craniofacial approach for resection of frontalethmoidal osteoma causing tension pneumocephalus," Skull Base 2008; 18: 67-72.(2008)
• Donahue JE, Johanson CE, "Apolipoprotein E, amyloid-beta, and blood-brain barrier permeability in Alzheimer disease," J Neuropathol Exp Neurol 2008; 67: 261-270.(2008)
• Mayrin JV, Donahue JE, Laufgraben MJ, "Visual vignette. Prolactinoma," Endocr Pract 2008; 14: 256.(2008)
• Aboagye-Kumi M, Yango A Jr, Fischer S, Donahue J, Morrissey P, Taylor N, Gautam A, Mendonca C, Kumar S, Gohh R, "Acute disseminated encephalomyelitis in a renal transplant recipient: case report," Transplant Proc 2008; 40: 1751-1753.(2008)
• Miller MC, Tavares R, Johanson CE, Hovanesian V, Donahue JE, Gonzalez L, Silverberg GD, Stopa EG, "Hippocampal RAGE immunoreactivity in early and advanced Alzheimer's disease," Brain Res 2008; 1230C: 273-280. Epub 2008 July 14.(2008)
• Davis JD, Podolanczuk A, Donahue JE, Stopa E, Hennessey JV, Luo LG, Lim Y-P, Stern RA, "Thyroid hormone levels in the prefrontal cortex of post-mortem brains of Alzheimer's disease patients," Curr Aging Sci 2008; 1: 175-181.(2008)
• Blum AS, Tremont GN, Donahue JE, Tung GA, Duncan JA III, Buchbinder BR, Gascon GG, "Landau-Kleffner syndrome with lateral temporal focal cortical dysplasia and mesial temporal sclerosis: a 30-year follow-up," Epilepsy Behav 2007; 10: 495-503. Epub 2007 Mar 7.(2007)
• Bagdasaryan R, Donahue JE, "Granulomatous myositis in association with chronic graft vs. host disease," Med Health R I 2007; 90: 287.(2007)
• Donahue JE, Flaherty SL, Johanson CE, Duncan JA III, Silverberg GD, Miller MC, Tavares R, Yang W, Wu Q, Sabo E, Hovanesian V, Stopa EG, "RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease," Acta Neuropathol (Berl) 2006; 112: 405-415. Epub 2006 Jul 25.(2006)
• Johanson CE, Donahue JE, Spangenberger A, Stopa EG, Duncan JA, Sharma HS, "Atrial natriuretic peptide: its putative role in modulating the choroid plexus-CSF system for intracranial pressure regulation," Acta Neurochir Suppl 2006; 96: 451-456.(2006)
• Park MC, Weaver CE Jr, Donahue JE, Sampath P, "Intracavitary chemotherapy (Gliadel®) for recurrent esthesioneuroblastoma: case report and review of the literature," J Neurooncol 2006; 77: 47-51.(2006)
• Hariharan S, Donahue JE, Garre C, Origone P, Grewal R, "Clinicopathologic and genetic analysis of siblings with NF1 and adult-onset gliomas," J Neurol Sci 2006; 247: 105-108. Epub 2006 May 23.(2006)
• Johanson CE, Donahue JE, Stopa EG, Baird A, "Fibroblast Growth Factor and the Blood-Brain Barrier." In: Kastin AJ (ed.), "Handbook of Biologically Active Peptides." Burlington, MA: Elsevier Academic Press, 2006, pp. 1449-1454.(2006)
• Johanson CE, Silverberg GD, Donahue JE, Duncan JA, Stopa EG, "Choroid Plexus and CSF in Alzheimer's Disease: Altered Expression and Transport of Proteins and Peptides." In: Zheng W, Chodobski A (eds.), "The Blood-Cerebrospinal Fluid Barrier." Boca Raton, FL: CRC Press, 2005, pp. 311-343.(2005)
• Stopa EG, Zipser BD, Donahue JE, "Vascular Basement Membrane Abnormalities and Alzheimer's Disease." In: Paul R, Cohen R, Ott B, Salloway S (eds.), "Vascular Dementia: Cerebrovascular Mechanisms and Clinical Management." Totowa, NJ: Humana Press, Inc., 2005, pp. 257-265.(2005)
• Abubakr A, Wambacq I, Donahue JE, Zappulla R, "The presence of polyglucosan bodies in temporal lobe epilepsy: its role and significance," J Clin Neurosci 2005; 12: 911-914. Epub 2005 Oct 24.(2005)
• Fischer SA, Donahue J, "Pachymeningitis in a Mexican immigrant," Med Health R I 2005; 88: 236.(2005)
• Hariharan S, Zhu J, Nadkarni MA, Donahue JE, "Metastatic lung cancer in the cerebellopontine angles mimicking bilateral acoustic neuroma," J Clin Neurosci 2005; 12: 184-186.(2005)
• Donahue JE, Hanna PA, Hariharan S, "Autopsy-proven Creutzfeldt-Jakob disease in a patient with a negative 14-3-3 assay and nonspecific EEG and MRI," Neurol Sci 2004; 24: 411-413.(2004)
• Donahue JE, Stopa EG, Chorsky RL, King JC, Schipper HM, Tobet SA, Blaustein JD, Reichlin S, "Cells containing immunoreactive estrogen receptor-alpha in the human basal forebrain," Brain Res 2000; 856: 142-151.(2000)
• Donahue JE, Stopa EG, "Benign meningioma," Arch Pathol Lab Med 1999; 123: 855.(1999)
• Donahue JE, Stopa EG, "Multiple neurofibromas in severe neurofibromatosis type 1," Arch Pathol Lab Med 1999; 123: 644-645.(1999)
• Donahue JE, Berzin TM, Rafii MS, Glass DJ, Yancopoulos GD, Fallon JR, Stopa EG, "Agrin in Alzheimer's disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma," Proc Natl Acad Sci U S A 1999; 96: 6468-6472.(1999)
• Tabamo REJ, Donahue JE, "Eastern equine encephalitis: case report and literature review," Med Health R I 1999; 82: 23-26.(1999)
• Donahue JE, Khurana JS, Adelman LS, "Intracerebral hemorrhage in two patients with Down's syndrome and cerebral amyloid angiopathy," Acta Neuropathol (Berl) 1998; 95: 213-216.(1998)
• Donahue JE, Raynor EM, Rutkove SB, "Forearm velocity in carpal tunnel syndrome: when is slow too slow?" Arch Phys Med Rehabil 1998; 79: 181-183. (Published erratum appears on p. 723.)(1998)