About

David E. Pleasure is an Emeritus Professor of Neurology at the University of Pennsylvania's Perelman School of Medicine. His research focuses on oligodendroglial development, oligodendroglial excitotoxicity, and peripheral nerve regeneration. His work addresses mechanisms responsible for the death of oligodendroglia in infants with periventricular leukomalacia and in adults with multiple sclerosis, as well as factors controlling the success of peripheral nerve regeneration. Methods used in his research include cell culture, genetically modified mice, and molecular, immunochemical, and immunohistological analyses. He has contributed to understanding the molecular and cellular processes involved in neural development and neurodegenerative conditions.

Research topics

• Biology
• Cell biology
• Neuroscience
• Medicine
• Chemistry

Selected publications

• William King Engel, MD (1930–2025)

  Neurology · 2025-10-07

  articleSenior author
  PublisherDOI

• CSF1R antagonism results in increased supraspinal infiltration in EAE

  Journal of Neuroinflammation · 2024-04-20 · 15 citations

  articleOpen access

  BACKGROUND: Colony stimulating factor 1 receptor (CSF1R) signaling is crucial for the maintenance and function of various myeloid subsets. CSF1R antagonism was previously shown to mitigate clinical severity in experimental autoimmune encephalomyelitis (EAE). The associated mechanisms are still not well delineated. METHODS: To assess the effect of CSF1R signaling, we employed the CSF1R antagonist PLX5622 formulated in chow (PLX5622 diet, PD) and its control chow (control diet, CD). We examined the effect of PD in steady state and EAE by analyzing cells isolated from peripheral immune organs and from the CNS via flow cytometry. We determined CNS infiltration sites and assessed the extent of demyelination using immunohistochemistry of cerebella and spinal cords. Transcripts of genes associated with neuroinflammation were also analyzed in these tissues. RESULTS: In addition to microglial depletion, PD treatment reduced dendritic cells and macrophages in peripheral immune organs, both during steady state and during EAE. Furthermore, CSF1R antagonism modulated numbers and relative frequencies of T effector cells both in the periphery and in the CNS during the early stages of the disease. Classical neurological symptoms were milder in PD compared to CD mice. Interestingly, a subset of PD mice developed atypical EAE symptoms. Unlike previous studies, we observed that the CNS of PD mice was infiltrated by increased numbers of peripheral immune cells compared to that of CD mice. Immunohistochemical analysis showed that CNS infiltrates in PD mice were mainly localized in the cerebellum while in CD mice infiltrates were primarily localized in the spinal cords during the onset of neurological deficits. Accordingly, during the same timepoint, cerebella of PD but not of CD mice had extensive demyelinating lesions, while spinal cords of CD but not of PD mice were heavily demyelinated. CONCLUSIONS: Our findings suggest that CSF1R activity modulates the cellular composition of immune cells both in the periphery and within the CNS, and affects lesion localization during the early EAE stages.

  PublisherOA PDFDOI

• Astroglial conditional <i>Slc13a3</i> knockout is therapeutic in murine Canavan leukodystrophy

  Annals of Clinical and Translational Neurology · 2024-01-28 · 1 citations

  articleOpen accessSenior authorCorresponding

  Canavan disease is a leukodystrophy caused by ASPA mutations that diminish oligodendroglial aspartoacylase activity, and is characterized by markedly elevated brain concentrations of the aspartoacylase substrate N-acetyl-l-aspartate (NAA) and by astroglial and intramyelinic vacuolation. Astroglia express NaDC3 (encoded by SLC13A3), a sodium-coupled transporter for NAA and other dicarboxylates. Astroglial conditional Slc13a3 deletion in aspartoacylase-deficient Canavan disease model mice ("CD mice") reversed brain NAA elevation and improved motor function. These results demonstrate that astroglial NaDC3 contributes to brain NAA elevation in CD mice, and suggest that suppressing astroglial NaDC3 activity would ameliorate human Canavan disease.

  PublisherOA PDFDOI

• Cover Image, Volume 71, Issue 12

  Glia · 2023-10-12

  paratextOpen accessSenior author

  Cover Illustration: Glia of the murine cerebellum at postnatal day 15. Myelin basic protein (green) marks oligodendroglial sheaths, GFAP (red) marks Bergmann glia processes in the molecular layer and astrocytes throughout, and DAPI (blue) marks nuclei. (See Hull, VL, et al. https://doi.org/10.1002/glia.24454)

  PublisherOA PDFDOI

• Pathological <scp>Bergmann</scp> glia alterations and disrupted calcium dynamics in ataxic <scp>Canavan</scp> disease mice

  Glia · 2023-08-23 · 2 citations

  articleOpen accessSenior authorCorresponding

  Abstract Canavan disease (CD) is a recessively inherited pediatric leukodystrophy resulting from inactivating mutations to the oligodendroglial enzyme aspartoacylase (ASPA). ASPA is responsible for hydrolyzing the amino acid derivative N ‐acetyl‐L‐aspartate (NAA), and without it, brain NAA concentrations increase by 50% or more. Infants and children with CD present with progressive cognitive and motor delays, cytotoxic edema, astroglial vacuolation, and prominent spongiform brain degeneration. ASPA‐deficient CD mice ( Aspa nur7/nur7 ) present similarly with elevated NAA, widespread astroglial dysfunction, ataxia, and Purkinje cell (PC) dendritic atrophy. Bergmann glia (BG), radial astrocytes essential for cerebellar development, are intimately intertwined with PCs, where they regulate synapse stability, functionality, and plasticity. BG damage is common to many neurodegenerative conditions and frequently associated with PC dysfunction and ataxia. Here, we report that, in CD mice, BG exhibit significant morphological alterations, decreased structural associations with PCs, loss of synaptic support proteins, and altered calcium dynamics. We also find that BG dysfunction predates cerebellar vacuolation and PC damage in CD mice. Previously, we developed an antisense oligonucleotide (ASO) therapy targeting Nat8l ( N ‐acetyltransferase‐8‐like, “Nat8l ASO”) that inhibits the production of NAA and reverses ataxia and PC atrophy in CD mice. Here, we show that Nat8l ASO administration in adult CD mice also leads to BG repair. Furthermore, blocking astroglial uptake of NAA is neuroprotective in astroglia‐neuron cocultures exposed to elevated NAA. Our findings suggest that restoration of BG structural and functional integrity could be a mechanism for PC regeneration and improved motor function.

  PublisherOA PDFDOI

• Review for "Over-expression of N-acetylaspartate synthase exacerbates pathological energetic deficit and accelerates cognitive decline in the 5xFAD mouse"

  2023-09-18

  peer-review1st authorCorresponding
  PublisherDOI

• Reduction in CD11c+ microglia correlates with clinical progression in chronic experimental autoimmune demyelination

  Neurobiology of Disease · 2021-11-06 · 27 citations

  articleOpen access

  Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease with high variability of clinical symptoms. In most cases MS appears as a relapsing-remitting disease course that at a later stage transitions into irreversible progressive decline of neurologic function. The mechanisms underlying MS progression remain poorly understood. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS. Here we demonstrate that mice that develop mild EAE after immunization with myelin oligodendrocyte glycoprotein 35-55 are prone to undergo clinical progression around 30 days after EAE induction. EAE progression was associated with reduction in CD11c+ microglia and dispersed coalescent parenchymal infiltration. We found sex-dependent differences mediated by p38α signaling, a key regulator of inflammation. Selective reduction of CD11c+ microglia in female mice with CD11c-promoter driven p38α knockout correlated with increased rate of EAE progression. In protected animals, we found CD11c+ microglia forming contacts with astrocyte processes at the glia limitans and immune cells retained within perivascular spaces. Together, our study identified pathological hallmarks of chronic EAE progression and suggests that CD11c+ microglia may regulate immune cell parenchymal infiltration in autoimmune demyelination.

  PublisherDOI

• Therapeutic Potentials of Poly (ADP‐Ribose) Polymerase 1 (PARP1) Inhibition in Multiple Sclerosis and Animal Models: Concept Revisiting

  Advanced Science · 2021-12-21 · 22 citations

  reviewOpen access

  Poly (ADP-ribose) polymerase 1 (PARP1) plays a fundamental role in DNA repair and gene expression. Excessive PARP1 hyperactivation, however, has been associated with cell death. PARP1 and/or its activity are dysregulated in the immune and central nervous system of multiple sclerosis (MS) patients and animal models. Pharmacological PARP1 inhibition is shown to be protective against immune activation and disease severity in MS animal models while genetic PARP1 deficiency studies reported discrepant results. The inconsistency suggests that the function of PARP1 and PARP1-mediated PARylation may be complex and context-dependent. The article reviews PARP1 functions, discusses experimental findings and possible interpretations of PARP1 in inflammation, neuronal/axonal degeneration, and oligodendrogliopathy, three major pathological components cooperatively determining MS disease course and neurological progression, and points out future research directions. Cell type specific PARP1 manipulations are necessary for revisiting the role of PARP1 in the three pathological components prior to moving PARP1 inhibition into clinical trials for MS therapy.

  PublisherOA PDFDOI

• Ablating the Transporter <scp>Sodium‐Dependent Dicarboxylate Transporter 3</scp> Prevents Leukodystrophy in Canavan Disease Mice

  Annals of Neurology · 2021-09-09 · 10 citations

  articleOpen accessSenior authorCorresponding

  Canavan disease is caused by ASPA mutations that diminish brain aspartoacylase activity, and it is characterized by excessive brain storage of the aspartoacylase substrate, N-acetyl-l-aspartate (NAA), and by astroglial and intramyelinic vacuolation. Astroglia and the arachnoid mater express sodium-dependent dicarboxylate transporter (NaDC3), encoded by SLC13A3, a sodium-coupled transporter for NAA and other dicarboxylates. Constitutive Slc13a3 deletion in aspartoacylase-deficient Canavan disease mice prevents brain NAA overaccumulation, ataxia, and brain vacuolation. ANN NEUROL 2021;90:845-850.

  PublisherOA PDFDOI

• Correction to: Olig2 regulates terminal differentiation and maturation of peripheral olfactory sensory neurons

  Cellular and Molecular Life Sciences · 2021-06-22 · 1 citations

  erratumOpen access
  PublisherOA PDFDOI

Recent grants

• Manipulating N-acetyl-L-aspartate to reverse Canavan leukodystrophy

  NIH · $432k · 2020–2023

• NIH Grant G20RR015071

  NIH · $133k · 2001

• NIH Grant P01NS030606

  NIH · $14.6M · 2004

• NIH Grant P01NS011037

  NIH · $14.9M · 2002

• NIH Grant R21NS096004

  NIH · $431k · 2017

Frequent coauthors

• Peter Bannerman

  Shriners Hospitals for Children - Erie

  110 shared

• Takayuki Itoh

  Ochanomizu University

  87 shared

• Fuzheng Guo

  Jilin University

  68 shared

• Robert P. Lisak

  Wayne State University

  67 shared

• Wenbin Deng

  Sun Yat-sen University

  67 shared

• Marc Yudkoff

  Children's Hospital of Philadelphia

  61 shared

• Makoto Horiuchi

  University of Pennsylvania

  57 shared

• Donald H. Silberberg

  50 shared

Education

• MD

  Columbia University College of Physicians and Surgeons

  1963

• BA

  Yale College

  1959