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Jorge J. Palop, PhD

TitleAssistant Professor
InstitutionUniversity of California San Francisco
DepartmentNeurology
Address1650 Owens St.
San Francisco CA 94158
Phone415-734-2661
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    Mechanisms of Network and Interneuron Dysfunction in Alzheimer’s Disease

    Our laboratory seeks to understand the neuronal processes underlying cognitive impairments in neurodegenerative disorders, such as Alzheimer’s disease (AD), and in neuropsychiatric conditions associated with abnormal synchronization of neuronal networks, such as schizophrenia, autism, and epilepsy. We aim to identify molecular, circuit, and network mechanisms of cognitive dysfunction and to develop novel therapeutic approaches to restore brain functions in AD and related disorders. We are particularly focused on understanding the role of impaired inhibitory interneurons in network hypersynchrony, altered oscillatory brain rhythms, and cognitive dysfunction in AD.

    To study these complex diseases, my laboratory primarily uses mouse models that recapitulate key aspects of the cognitive dysfunction and pathology of these conditions to dissect network and circuits mechanisms of brain dysfunction in mouse models of AD. We use electroencephalography (EEG), local field potentials (LFP), and single-unit recordings to assess neuron activity in vivo, optogenetic approaches to modulate interneuron function in vivo, genetic and pharmacological manipulations to manipulate specific pathways in vivo, and behavioral assessment to determine the cognitive consequences of our mechanistic interventions.

    Areas de investigation

    Network hypersynchrony in AD and related mouse models: We discovered that mouse models of AD (hAPP mice) develop aberrant patterns of neuronal network activity, including epileptiform activity and non-convulsive seizures, that result in profound anatomical and physiological alterations in learning and memory centers (e.g., calbindin depletions). These unexpected findings may be related to the epileptic phenotype of many pedigrees of patients with early-onset familial AD and to the hyperactivation of neuronal networks in patients with sporadic AD and amyloid-positive nondemented subjects. Thus, network abnormalities leading to, or induced by, A? accumulation appear to be a relatively early pathogenic event in AD. These results prompted the field to reexamine the effects of abnormal patterns of network activity on cognitive dysfunction in AD. We are investigating mechanisms of network hypersynchronization in AD and testing novel therapies to prevent such deficits.

    Altered interneuron dysfunction and oscillatory rhythms in cognitive disorders: Inhibitory interneurons regulate oscillatory rhythms and network synchrony that are required for cognitive functions and disrupted in AD. We are currently focused on understanding the role of inhibitory interneurons and oscillatory brain rhythms in cognitive functions in health and disease. We discovered that impaired inhibitory interneurons lead to altered oscillatory activity, network hypersynchrony, and cognitive deficits in mouse models of AD. Importantly, cognitive performance in AD mouse models was improved when interneuron-dependent oscillatory brain activity was enhanced by restoration of Nav1.1 levels in endogenous inhibitory interneurons. We are currently profiling inhibitory interneuron cell types in mouse models of AD to identify potential molecular mechanisms of interneuron dysfunction and potential targets of intervention. We are also dissecting the circuit and neuron alterations in behaving mouse models of AD using single-unit recordings and optogenetic approaches. Thus, we are identifying molecular and circuit mechanisms of brain dysfunction and exploring the therapeutic implications of enhancing inhibitory functions and/or restoring oscillatory rhythms in brain disorders associated with abnormal synchronization of neuronal networks, such as AD, schizophrenia, autism, or epilepsy.

    Interneuron cell-based therapy in AD and related models: During brain development, embryonic interneuron precursors are generated in the medial ganglionic eminence (MGE) and retain a remarkable capacity for migration and integration in adult host brains, where they fully mature into functional inhibitory interneurons. Thus, MGE, or MGE-like, precursors provide a great opportunity for cell-based therapy in animal models of neurological disorders linked to impaired inhibitory function. We discovered that transplanting Nav1.1-overexpressing, but not wildtype, MGE-derived interneurons enhanced behavior-related modulation of gamma oscillatory activity, reduced network hypersynchrony, and improved cognitive function in hAPP mice. Interestingly, Nav1.1-deficient interneuron transplants were sufficient to cause behavioral abnormalities in wild-type mice, indicating the key functional role of interneurons and Nav1.1 for cognitive functions. These findings highlight the potential of Nav1.1 and inhibitory interneurons as a therapeutic target in AD and that disease-specific molecular optimization of cell transplants may be required to ensure therapeutic benefits in different conditions.

    Translational focus: We hope to translate our basic research to develop novel treatments. We are evaluating the therapeutic potential of interneuron-based interventions by using cell-based therapy and pharmacology. We established formal partnerships with major pharmaceutical and biotechnology companies to develop compounds or identify targets that enhance interneuron function or restore brain rhythms in models of AD and epilepsy. We are currently developing small molecule Nav1.1 activators that increase Nav1.1 currents and interneuron-dependent gamma oscillations in vitro and in vivo to develop novel therapies for conditions with impaired interneuron function, including AD and Dravet syndrome.

    Our current short- and long-term research questions include:
    • Does epileptiform activity or network hypersynchrony contribute to AD pathology and cognitive dysfunction in AD and related mouse models?
    • Do impaired inhibitory interneurons contribute to altered oscillatory activity and network hypersynchrony?
    • Can we identify small-molecule Nav1.1 activators to enhance gamma oscillations in vivo?
    • Do inhibitory interneuron cell types have altered molecular profile in AD and related mouse models?
    • What are the functional alterations of principal and interneuron cell types in vivo at the single-cell level in mouse models of AD?
    • Are synaptic depression and aberrant excitatory neuronal activity mechanistically related?
    • What are the molecular mechanisms of hAPP/A?-induced epileptiform activity and interneuron dysfunction?
    • Is hAPP/A? part of a homeostatic mechanism controlling neuronal activity, and is it dysregulated in AD?
    • Can we restore cognitive function in AD by enhancing interneuron function?


    Collapse Research 
    Collapse Research Activities and Funding
    Restoring Brain Functions in Alzheimer Models with Interneuron Transplants
    NIH/NIA R01AG047313May 15, 2014 - Apr 30, 2019
    Role: Principal Investigator

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    Collapse Bibliographic 
    Collapse Publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
    List All   |   Timeline
    1. Martinez-Losa M, Tracy TE, Ma K, Verret L, Clemente-Perez A, Khan AS, Cobos I, Ho K, Gan L, Mucke L, Alvarez-Dolado M, Palop J. Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease. Neuron. 2018 Apr 04; 98(1):75-89.e5. PMID: 29551491.
      View in: PubMed
    2. Scharfman HE, Kanner AM, Friedman A, Blümcke I, Crocker CE, Cendes F, Diaz-Arrastia R, Förstl H, Fenton AA, Grace AA, Palop J, Morrison J, Nehlig A, Prasad A, Wilcox KS, Jette N, Pohlmann-Eden B. Epilepsy as a Network Disorder (2): What can we learn from other network disorders such as dementia and schizophrenia, and what are the implications for translational research? Epilepsy Behav. 2018 Jan; 78:302-312. PMID: 29097123.
      View in: PubMed
    3. Newman JC , Kroll F , Ulrich S, Palop J, Verdin E.Ketogenic diet or BHB improves epileptiform spikes, memory, survival in Alzheimer's model. bioRxiv, 136226. 2017.
    4. Palop J, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016 12; 17(12):777-792. PMID: 27829687.
      View in: PubMed
    5. Schachtrup C, Ryu JK, Mammadzada K, Khan AS, Carlton PM, Perez A, Christian F, Le Moan N, Vagena E, Baeza-Raja B, Rafalski V, Chan JP, Nitschke R, Houslay MD, Ellisman MH, Wyss-Coray T, Palop J, Akassoglou K. Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-ß signaling and astrocyte functions. Nat Neurosci. 2015 Aug; 18(8):1077-80. PMID: 26120963; PMCID: PMC4878404.
    6. Heng MY, Lin ST, Verret L, Huang Y, Kamiya S, Padiath QS, Tong Y, Palop J, Huang EJ, Ptácek LJ, Fu YH. Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model. J Clin Invest. 2013 Jun; 123(6):2719-29. PMID: 23676464; PMCID: PMC3668844.
    7. Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop J, Mucke L. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc Natl Acad Sci U S A. 2012 Oct 16; 109(42):E2895-903. PMID: 22869752; PMCID: PMC3479491.
    8. Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I, Mucke L, Palop J. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 2012 Apr 27; 149(3):708-21. PMID: 22541439; PMCID: PMC3375906.
    9. Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop J, Noebels JL, Mucke L. Amyloid-ß/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci. 2011 Jan 12; 31(2):700-11. PMID: 21228179; PMCID: PMC3325794.
    10. Palop J, Roberson ED, Cobos I. Step-by-step in situ hybridization method for localizing gene expression changes in the brain. Methods Mol Biol. 2011; 670:207-30. PMID: 20967593.
      View in: PubMed
    11. Palop J, Mucke L, Roberson ED. Quantifying biomarkers of cognitive dysfunction and neuronal network hyperexcitability in mouse models of Alzheimer's disease: depletion of calcium-dependent proteins and inhibitory hippocampal remodeling. Methods Mol Biol. 2011; 670:245-62. PMID: 20967595.
      View in: PubMed
    12. Harris JA, Devidze N, Verret L, Ho K, Halabisky B, Thwin MT, Kim D, Hamto P, Lo I, Yu GQ, Palop J, Masliah E, Mucke L. Transsynaptic progression of amyloid-ß-induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron. 2010 Nov 04; 68(3):428-41. PMID: 21040845; PMCID: PMC3050043.
    13. Peebles CL, Yoo J, Thwin MT, Palop J, Noebels JL, Finkbeiner S. Arc regulates spine morphology and maintains network stability in vivo. Proc Natl Acad Sci U S A. 2010 Oct 19; 107(42):18173-8. PMID: 20921410; PMCID: PMC2964216.
    14. Buttini M, Masliah E, Yu GQ, Palop J, Chang S, Bernardo A, Lin C, Wyss-Coray T, Huang Y, Mucke L. Cellular source of apolipoprotein E4 determines neuronal susceptibility to excitotoxic injury in transgenic mice. Am J Pathol. 2010 Aug; 177(2):563-9. PMID: 20595630; PMCID: PMC2913361.
    15. Palop J, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci. 2010 Jul; 13(7):812-8. PMID: 20581818; PMCID: PMC3072750.
    16. Gittis AH, Nelson AB, Thwin MT, Palop J, Kreitzer AC. Distinct roles of GABAergic interneurons in the regulation of striatal output pathways. J Neurosci. 2010 Feb 10; 30(6):2223-34. PMID: 20147549; PMCID: PMC2836801.
    17. Sun B, Halabisky B, Zhou Y, Palop J, Yu G, Mucke L, Gan L. Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer's Disease. Cell Stem Cell. 2009 Dec 04; 5(6):624-33. PMID: 19951690; PMCID: PMC2823799.
    18. Palop J, Mucke L. Synaptic depression and aberrant excitatory network activity in Alzheimer's disease: two faces of the same coin? Neuromolecular Med. 2010 Mar; 12(1):48-55. PMID: 19838821; PMCID: PMC3319077.
    19. Palop J, Mucke L. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol. 2009 Apr; 66(4):435-40. PMID: 19204149; PMCID: PMC2812914.
    20. Sanchez-Mejia RO, Newman JW, Toh S, Yu GQ, Zhou Y, Halabisky B, Cissé M, Scearce-Levie K, Cheng IH, Gan L, Palop J, Bonventre JV, Mucke L. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Nat Neurosci. 2008 Nov; 11(11):1311-8. PMID: 18931664; PMCID: PMC2597064.
    21. Meilandt WJ, Yu GQ, Chin J, Roberson ED, Palop J, Wu T, Scearce-Levie K, Mucke L. Enkephalin elevations contribute to neuronal and behavioral impairments in a transgenic mouse model of Alzheimer's disease. J Neurosci. 2008 May 07; 28(19):5007-17. PMID: 18463254; PMCID: PMC3315282.
    22. Palop J, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 06; 55(5):697-711. PMID: 17785178.
      View in: PubMed
    23. Cheng IH, Scearce-Levie K, Legleiter J, Palop J, Gerstein H, Bien-Ly N, Puoliväli J, Lesné S, Ashe KH, Muchowski PJ, Mucke L. Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem. 2007 Aug 17; 282(33):23818-28. PMID: 17548355.
      View in: PubMed
    24. Roberson ED, Scearce-Levie K, Palop J, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 04; 316(5825):750-4. PMID: 17478722.
      View in: PubMed
    25. Chin J, Massaro CM, Palop J, Thwin MT, Yu GQ, Bien-Ly N, Bender A, Mucke L. Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic mice and humans with Alzheimer's disease. J Neurosci. 2007 Mar 14; 27(11):2727-33. PMID: 17360894.
      View in: PubMed
    26. Deipolyi AR, Fang S, Palop J, Yu GQ, Wang X, Mucke L. Altered navigational strategy use and visuospatial deficits in hAPP transgenic mice. Neurobiol Aging. 2008 Feb; 29(2):253-66. PMID: 17126954.
      View in: PubMed
    27. Palop J, Chin J, Mucke L. A network dysfunction perspective on neurodegenerative diseases. Nature. 2006 Oct 19; 443(7113):768-73. PMID: 17051202.
      View in: PubMed
    28. Chin J, Palop J, Puoliväli J, Massaro C, Bien-Ly N, Gerstein H, Scearce-Levie K, Masliah E, Mucke L. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease. J Neurosci. 2005 Oct 19; 25(42):9694-703. PMID: 16237174.
      View in: PubMed
    29. Palop J, Chin J, Bien-Ly N, Massaro C, Yeung BZ, Yu GQ, Mucke L. Vulnerability of dentate granule cells to disruption of arc expression in human amyloid precursor protein transgenic mice. J Neurosci. 2005 Oct 19; 25(42):9686-93. PMID: 16237173.
      View in: PubMed
    30. Cheng IH, Palop J, Esposito LA, Bien-Ly N, Yan F, Mucke L. Aggressive amyloidosis in mice expressing human amyloid peptides with the Arctic mutation. Nat Med. 2004 Nov; 10(11):1190-2. PMID: 15502844.
      View in: PubMed
    31. Chin J, Palop J, Yu GQ, Kojima N, Masliah E, Mucke L. Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. J Neurosci. 2004 May 12; 24(19):4692-7. PMID: 15140940.
      View in: PubMed
    32. Palop J, Jones B, Kekonius L, Chin J, Yu GQ, Raber J, Masliah E, Mucke L. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Natl Acad Sci U S A. 2003 Aug 05; 100(16):9572-7. PMID: 12881482; PMCID: PMC170959.
    33. López-García C, Varea E, Palop J, Nacher J, Ramirez C, Ponsoda X, Molowny A. Cytochemical techniques for zinc and heavy metals localization in nerve cells. Microsc Res Tech. 2002 Mar 01; 56(5):318-31. PMID: 11877810.
      View in: PubMed
    34. Nacher J, Palop J, Ramirez C, Molowny A, Lopez-Garcia C. Early histological maturation in the hippocampus of the guinea pig. Brain Behav Evol. 2000 Jun; 56(1):38-44. PMID: 11025343.
      View in: PubMed
    35. Nacher J, Ramírez C, Palop J, Molowny A, Luis de la Iglesia JA, López-García C. Radial glia and cell debris removal during lesion-regeneration of the lizard medial cortex. Histol Histopathol. 1999 Jan; 14(1):89-101. PMID: 9987654.
      View in: PubMed
    36. Nacher J, Ramírez C, Palop J, Artal P, Molowny A, López-García C. Microglial cells during the lesion-regeneration of the lizard medial cortex. Histol Histopathol. 1999 Jan; 14(1):103-17. PMID: 9987655.
      View in: PubMed
    37. Sanchez-Andres JV, Palop J, Ramirez C, Nacher J, Molowny A, Lopez-Gracia C. Zinc-positive presynaptic boutons of the rabbit hippocampus during early postnatal development. Brain Res Dev Brain Res. 1997 Nov 12; 103(2):171-83. PMID: 9427481.
      View in: PubMed