About

Fred H. Gage is a professor at the Salk Institute for Biological Studies, where he holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. His research concentrates on the plasticity, adaptability, and diversity of the brain, with a focus on understanding how genes and environment influence brain function and disease. Gage demonstrated that neurogenesis occurs in the adult human brain and that environmental enrichment and physical exercise can enhance this process. His lab has shown that neural stem cells exist in the adult hippocampus and can give rise to physiologically active neurons, and that mobile DNA elements are active during neurogenesis, contributing to genomic mosaicism in the brain. Recently, he led a team at the Salk Institute that received significant funding to analyze the interactions between proteins, genes, epigenetics, inflammation, and metabolism in the aging brain, aiming to uncover mechanisms of cognitive decline and develop new therapies for diseases such as Alzheimer’s. Gage’s work also involves modeling neurological and psychiatric diseases using human stem cells, reprogramming patient cells into induced pluripotent stem cells and neurons to study disease progression and mechanisms, including depression and autism. His discoveries include the lifelong capacity of the human brain to generate new neurons, the enhancement of neurogenesis through exercise and cognitive enrichment, and the use of stem cell technologies to identify early dysfunctions in neurons derived from individuals with schizophrenia. Gage has received numerous awards and honors for his contributions to neuroscience and stem cell research.

Research topics

• Biology
• Genetics
• Neuroscience
• Cell biology
• Medicine
• Computer Science
• Immunology
• Computational biology
• Internal medicine
• Biochemistry
• Cancer research
• Evolutionary biology
• Psychology
• Virology
• Zoology
• Ophthalmology

Selected publications

• Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patients

  npj Parkinson s Disease · 2022 · 61 citations

  Senior authorCorresponding
  • Neuroscience
  • Medicine
  • Psychology

  Several mutations that cause Parkinson's disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.

  PublisherOA PDFDOI

• A nomenclature consensus for nervous system organoids and assembloids

  Nature · 2022 · 283 citations

  • Computer Science
  • Computational biology
  • Biology
  DOI

• Altered Neuronal Support and Inflammatory Response in Bipolar Disorder Patient-Derived Astrocytes

  Stem Cell Reports · 2021 · 45 citations

  Senior authorCorresponding
  • Biology
  • Neuroscience
  • Immunology

  Bipolar disorder (BD) is characterized by cyclical mood shifts. Studies indicate that BD patients have a peripheral pro-inflammatory state and alterations in glial populations in the brain. We utilized an in vitro model to study inflammation-related phenotypes of astrocytes derived from induced pluripotent stem cells (iPSCs) generated from BD patients and healthy controls. BD astrocytes showed changes in transcriptome and induced a reduction in neuronal activity when co-cultured with neurons. IL-1β-stimulated BD astrocytes displayed a unique inflammatory gene expression signature and increased secretion of IL-6. Conditioned medium from stimulated BD astrocytes reduced neuronal activity, and this effect was partially blocked by IL-6 inactivating antibody. Our results suggest that BD astrocytes are functionally less supportive of neuronal excitability and this effect is partially mediated by IL-6. We confirmed higher IL-6 in blood in a distinct cohort of BD patients, highlighting the potential role of astrocyte-mediated inflammatory signaling in BD neuropathology.

  PublisherOA PDFDOI

• Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients

  Cell stem cell · 2021 · 244 citations

  Senior authorCorresponding
  • Biology
  • Neuroscience
  • Cell biology
  PublisherOA PDFDOI

• The role of retrotransposable elements in ageing and age-associated diseases

  Nature · 2021 · 427 citations

  • Biology
  • Evolutionary biology
  • Genetics
  PublisherOA PDFDOI

• Cytoplasmic synthesis of endogenous <i>Alu</i> complementary DNA via reverse transcription and implications in age-related macular degeneration

  Proceedings of the National Academy of Sciences · 2021 · 63 citations

  • Biology
  • Genetics
  • Cell biology

  replication cycle shunt as potential therapies for a major cause of blindness.

  DOI

• Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism

  Proceedings of the National Academy of Sciences · 2020 · 67 citations

  • Biology
  • Genetics
  • Neuroscience

  loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.

  DOI

• Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis

  Cell stem cell · 2020 · 183 citations

  • Biology
  • Cancer research
  • Virology
  DOI

Recent grants

• NIH Grant P30NS072031

  NIH · $8.4M · 2017

• NIH Grant P01NS028121

  NIH · $25.0M · 2006

• NIH Grant R01MH088485

  NIH · $1.5M · 2013

• NIH Grant R03TW006130

  NIH · $163k · 2005

• Dynamics of activity-induced transcription in single dentate granule cells

  NIH · $3.8M · 2017–2028

Frequent coauthors

• Kristen Brennand

  138 shared

• John R. Kelsoe

  University of California, San Diego

  125 shared

• Mark A. Frye

  122 shared

• Caroline M. Nievergelt

  University of California, San Diego

  121 shared

• Martin Alda

  Dalhousie University

  121 shared

• Ketil J. Øedegaard

  Novartis (Norway)

  116 shared

• Joseph R. Calabrese

  University School

  116 shared

• Michael J. McCarthy

  Loyola University Chicago

  116 shared

Awards & honors

• Ogawa-Yamanaka Stem Cell Prize, 2024
• Taylor International Prize in Medicine, 2024
• W.M. Keck Foundation Award, 2024
• The International Society for Stem Cell Research Achievement…
• ARCS Foundation Scientist of the Year, 2018

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