Bio

Current Role at Stanford


Research Associate Scientist

Supervisors


Education & Certifications


  • B.S., Florida State University, Biological Sciences (1998)
  • Ph.D., Colorado State University, Biochemistry and Molecular Biology (2006)

Publications

Journal Articles


  • Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome NEUROBIOLOGY OF DISEASE Kleschevnikov, A. M., Belichenko, P. V., Gall, J., George, L., Nosheny, R., Maloney, M. T., Salehi, A., Mobley, W. C. 2012; 45 (2): 683-691

    Abstract

    Cognitive impairment in Down syndrome (DS) involves the hippocampus. In the Ts65Dn mouse model of DS, deficits in hippocampus-dependent learning and synaptic plasticity were linked to enhanced inhibition. However, the mechanistic basis of changes in inhibitory efficiency remains largely unexplored, and efficiency of the GABAergic synaptic neurotransmission has not yet been investigated in direct electrophysiological experiments. To investigate this important feature of neurobiology of DS, we examined synaptic and molecular properties of the GABAergic system in the dentate gyrus (DG) of adult Ts65Dn mice. Both GABAA and GABAB receptor-mediated components of evoked inhibitory postsynaptic currents (IPSCs) were significantly increased in Ts65Dn vs. control (2N) DG granule cells. These changes were unaccompanied by alterations in hippocampal levels of GABAA (?1, ?2, ?3, ?5 and ?2) or GABAB (Gbr1a and Gbr1b) receptor subunits. Immunoreactivity for GAD65, a marker for GABAergic terminals, was also unchanged. In contrast, there was a marked change in functional parameters of GABAergic synapses. Paired stimulations showed reduced paired-pulse ratios of both GABAA and GABAB receptor-mediated IPSC components (IPSC2/IPSC1), suggesting an increase in presynaptic release of GABA. Consistent with increased gene dose, the level of the Kir3.2 subunit of potassium channels, effectors for postsynaptic GABAB receptors, was increased. This change was associated with enhanced postsynaptic GABAB/Kir3.2 signaling following application of the GABAB receptor agonist baclofen. Thus, both GABAA and GABAB receptor-mediated synaptic efficiency is increased in the Ts65Dn DG, thus likely contributing to deficient synaptic plasticity and poor learning in DS.

    View details for DOI 10.1016/j.nbd.2011.10.009

    View details for Web of Science ID 000299500200003

    View details for PubMedID 22062771

  • A novel method for producing mono-biotinylated, biologically active neurotrophic factors: An essential reagent for single molecule study of axonal transport JOURNAL OF NEUROSCIENCE METHODS Sung, K., Maloney, M. T., Yang, J., Wu, C. 2011; 200 (2): 121-128

    Abstract

    In this report, we describe a novel method for producing mature and biologically active mono-biotinylated nerve growth factors (mBtNGF) that can be used for single molecule studies of real-time movement of neurotrophins within axons of neurons. We inserted an AviTag sequence into the C-terminal of the full length mouse preproNGF cDNA and cloned the fusion construct into a pcDNA3.1 mammalian expression vector. We also subcloned the Escherichia coli biotin ligase, BirA, into a pcDNA3.1 vector. These two plasmids were then transiently co-expressed in HEK293FT cells. As a result, the AviTag located in the C-terminal of preproNGF was selectively ligated to a single biotin by BirA. The prepro sequence of NGF was subsequently cleaved within the cell. Mature mono-biotinylated NGF (mBtNGF) was secreted into cell culture media and was purified using Ni resin. We carried out activity assays and our results showed that mBtNGF retained biological activities that were comparable to normal NGF purified from mouse sub maxillary glands. We further verified the biotinylation efficiency of mBtNGF and the level of non-biotinylated NGF was virtually undetectable in the final preparation. Finally, by conjugating to quantum-dot streptavidin, mBtNGF was successfully used for single molecule study of axonal NGF trafficking in neurons.

    View details for DOI 10.1016/j.jneumeth.2011.06.020

    View details for Web of Science ID 000295242300004

    View details for PubMedID 21756937

  • Mechanisms of Neuronal Growth Cone Guidance: An Historical Perspective DEVELOPMENTAL NEUROBIOLOGY Maloney, M. T., Bamburg, J. R. 2011; 71 (9): 795-800

    Abstract

    At the distal most aspect of motile extending axons and dendrites lies the growth cone, a hand like macroorganelle of membrane bound cytoskeleton, packed with receptors, adhesion molecules, molecular motors, and an army of regulatory and signaling proteins. Splayed out along the substratum in vitro, the growth cone resembles an open hand with bundles of filamentous actin, barbed ends outstretched, as if fingers extending from a central domain of dynamic microtubule plus ends. The growth cone acts first as a sensory platform, analyzing the environment ahead for the presence of guidance cues, secondly as a mechanical dynamo establishing focal contact with the extracellular matrix to drive processive forward outgrowth, and thirdly as a forward biochemical command center where signals are interrogated to inform turning, extension, retraction, or branching. During his career, Paul Letourneau has made major contributions to our understanding of how growth cones respond to their environment. Here, we will summarize some of these major advances in their historical context. Letourneau's contributions have provided insights into cytoskeletal organization, growth cone dynamics, and signaling pathways. His recent work has described some important molecules and molecular mechanisms involved in growth cone turning. Although much remains to be understood about this important and intriguing structure, Letourneau's contributions have provided us with "growth cone guidance."

    View details for DOI 10.1002/dneu.20908

    View details for Web of Science ID 000294177100009

    View details for PubMedID 21805682

  • Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation MOLECULAR NEURODEGENERATION Davis, R. C., Marsden, I. T., Maloney, M. T., Minamide, L. S., Podlisny, M., Selkoe, D. J., Bamburg, J. R. 2011; 6

    Abstract

    Previously we reported 1 ?M synthetic human amyloid beta1-42 oligomers induced cofilin dephosphorylation (activation) and formation of cofilin-actin rods within rat hippocampal neurons primarily localized to the dentate gyrus.Here we demonstrate that a gel filtration fraction of 7PA2 cell-secreted SDS-stable human A? dimers and trimers (A?d/t) induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human A? oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers. When incubated under tyrosine oxidizing conditions, synthetic human but not rodent A?1-42, the latter lacking tyrosine, acquires a marked increase (620 fold for EC50) in rod-inducing activity. Gel filtration of this preparation yielded two fractions containing SDS-stable dimers, trimers and tetramers. One, eluting at a similar volume to 7PA2 A?d/t, had maximum activity at ~5 nM, whereas the other, eluting at the void volume (high-n state), lacked rod inducing activity at the same concentration. Fractions from 7PA2 medium containing A? monomers are not active, suggesting oxidized SDS-stable A?1-42 dimers in a low-n state are the most active rod-inducing species. A?d/t-induced rods are predominantly localized to the dentate gyrus and mossy fiber tract, reach significance over controls within 2 h of treatment, and are reversible, disappearing by 24 h after A?d/t washout. Overexpression of cofilin phosphatases increase rod formation when expressed alone and exacerbate rod formation when coupled with A?d/t, whereas overexpression of a cofilin kinase inhibits A?d/t-induced rod formation.Together these data support a mechanism by which A?d/t alters the actin cytoskeleton via effects on cofilin in neurons critical to learning and memory.

    View details for DOI 10.1186/1750-1326-6-10

    View details for Web of Science ID 000287299600001

    View details for PubMedID 21261978

  • Mapping Cofilin-Actin Rods in Stressed Hippocampal Slices and the Role of cdc42 in Amyloid-beta-Induced Rods JOURNAL OF ALZHEIMERS DISEASE Davis, R. C., Maloney, M. T., Minamide, L. S., Flynn, K. C., Stonebraker, M. A., Bamburg, J. R. 2009; 18 (1)

    Abstract

    Dissociated hippocampal neurons exposed to a variety of degenerative stimuli form neuritic cofilin-actin rods. Here we report on stimulus driven regional rod formation in organotypic hippocampal slices. Ultrastructural analysis of rods formed in slices demonstrates mitochondria and vesicles become entrapped within some rods. We developed a template for combining and mapping data from multiple slices, enabling statistical analysis for the identification of vulnerable sub-regions. Amyloid-beta (Abeta) induces rods predominantly in the dentate gyrus region, and Abeta-induced rods are reversible following washout. Rods that persist 24 h following transient (30 min) ATP-depletion are broadly distributed, whereas rods formed in response to excitotoxic glutamate localize within and nearby the pyramidal neurons. Time-lapse imaging of cofilin-GFP-expressing neurons within slices shows neuronal rod formation begins rapidly and peaks by 10 min of anoxia. In approximately 50% of responding neurons, Abeta-induced rod formation acts via cdc42, an upstream regulator of cofilin. These new observations support a role for cofilin-actin rods in stress-induced disruption of cargo transport and synaptic function within hippocampal neurons and suggest both cdc42-dependent and independent pathways modulate cofilin activity downstream from Abeta.

    View details for DOI 10.3233/JAD-2009-1122

    View details for Web of Science ID 000269629500004

    View details for PubMedID 19542631

  • Cofilin-mediated neurodegeneration in Alzheimer's disease and other amyloidopathies MOLECULAR NEUROBIOLOGY Maloney, M. T., Bamburg, J. R. 2007; 35 (1): 21-43

    Abstract

    Transport defects may arise in various neurodegenerative diseases from failures in molecular motors, microtubule abnormalities, and the chaperone/proteasomal degradation pathway leading to aggresomal-lysosomal accumulations. These defects represent important steps in the neurodegenerative cascade, although in many cases, a clear consensus has yet to be reached regarding their causal relationship to the disease. A growing body of evidence lends support to a link between neurite transport defects in the very early stages of many neurodegenerative diseases and alterations in the organization and dynamics of the actin cytoskeleton initiated by filament dynamizing proteins in the ADF/cofilin family. This article focuses on cofilin, which in neurons under stress, including stress induced by the amyloid-beta (Abeta) 1-42 peptide, undergoes dephosphorylation (activation) and forms rod-shaped actin bundles (rods). Rods inhibit transport, are sites of amyloid precursor protein accumulation, and contribute to the pathology of Alzheimer's disease. Because rods form rapidly in response to anoxia, they could also contribute to synaptic deficits associated with ischemic brain injury (e.g., stroke). Surprisingly, cofilin undergoes phosphorylation (inactivation) in hippocampal neurons treated with Abeta1-40 at high concentrations, and these neurons undergo dystrophic morphological changes, including accumulation of pretangle phosphorylated-tau. Therefore, extremes in phosphoregulation of cofilin by different forms of Abeta may explain much of the Alzheimer's disease pathology and provide mechanisms for synaptic loss and plaque expansion.

    View details for Web of Science ID 000245958600002

    View details for PubMedID 17519504

  • beta-secretase-cleaved amyloid precursor protein accumulates at actin inclusions induced in neurons by stress or amyloid beta: A feedforward mechanism for Alzheimer's disease JOURNAL OF NEUROSCIENCE Maloney, M. T., Minamide, L. S., Kinley, A. W., Boyle, J. A., Bamburg, J. R. 2005; 25 (49): 11313-11321

    Abstract

    Rod-like inclusions (rods), composed of actin saturated with actin depolymerizing factor (ADF)/cofilin, are induced in hippocampal neurons by ATP depletion, oxidative stress, and excess glutamate and occur in close proximity to senile plaques in human Alzheimer's disease (AD) brain (Minamide et al., 2000). Here, we show rods are found in brains from transgenic AD mice. Soluble forms of amyloid beta (Abeta(1-42)) induce the formation of rods in a maximum of 19% of cultured hippocampal neurons in a time- and concentration-dependent manner. Approximately one-half of the responding neurons develop rods within 6 h or with as little as 10 nM Abeta(1-42). Abeta(1-42) induces the activation (dephosphorylation) of ADF/cofilin in neurons that form rods. Vesicles containing amyloid precursor protein (APP), beta-amyloid cleavage enzyme, and presenilin-1, a component of the gamma-secretase complex, accumulate at rods. The beta-secretase-cleaved APP (either beta-C-terminal fragment of APP or Abeta) also accumulates at rods. These results suggest that rods, formed in response to either Abeta or some other stress, block the transport of APP and enzymes involved in its processing to Abeta. These stalled vesicles may provide a site for producing Abeta(1-42), which may in turn induce more rods in surrounding neurons, and expand the degenerative zone resulting in plaque formation.

    View details for DOI 10.1523/JNEUROSCI.3711-05.2005

    View details for Web of Science ID 000233941900010

    View details for PubMedID 16339026

  • Production and use of replication-deficient adenovirus for transgene expression in neurons NEURONS: METHODS AND APPLICATIONS FOR THE CELL BIOLOGIST Minamide, L. S., Shaw, A. E., Sarmiere, P. D., Wiggan, O., Maloney, M. T., Bernstein, B. W., Sneider, J. M., Gonzalez, J. A., Bamburg, J. R. 2003; 71: 387-416

    Abstract

    Adenoviruses infect a wide range of cell types, do not require integration into the host cell genome, and can be produced as replication-deficient viruses capable of expressing transgenes behind any desired promoter. Thus, they are ideal for use in expressing transgenes in the postmitotic neuron. This chapter describes simplifications in the protocols for making recombinant adenoviruses and their use in expressing transgenes in primary neurons of several different types.

    View details for Web of Science ID 000184574100019

    View details for PubMedID 12884701

Conference Proceedings


  • ADF/Cofilin-Actin Rods in Neurodegenerative Diseases Bamburg, J. R., Bernstein, B. W., Davis, R. C., FLYNN, K. C., Goldsbury, C., Jensen, J. R., Maloney, M. T., Marsden, I. T., Minamide, L. S., Pak, C. W., Shaw, A. E., Whiteman, I., Wiggan, O. BENTHAM SCIENCE PUBL LTD. 2010: 241-250

    Abstract

    Dephosphorylation (activation) of cofilin, an actin binding protein, is stimulated by initiators of neuronal dysfunction and degeneration including oxidative stress, excitotoxic glutamate, ischemia, and soluble forms of beta-amyloid peptide (Abeta). Hyperactive cofilin forms rod-shaped cofilin-saturated actin filament bundles (rods). Other proteins are recruited to rods but are not necessary for rod formation. Neuronal cytoplasmic rods accumulate within neurites where they disrupt synaptic function and are a likely cause of synaptic loss without neuronal loss, as occurs early in dementias. Different rod-inducing stimuli target distinct neuronal populations within the hippocampus. Rods form rapidly, often in tandem arrays, in response to stress. They accumulate phosphorylated tau that immunostains for epitopes present in "striated neuropil threads," characteristic of tau pathology in Alzheimer disease (AD) brain. Thus, rods might aid in further tau modifications or assembly into paired helical filaments, the major component of neurofibrillary tangles (NFTs). Rods can occlude neurites and block vesicle transport. Some rod-inducing treatments cause an increase in secreted Abeta. Thus rods may mediate the loss of synapses, production of excess Abeta, and formation of NFTs, all of the pathological hallmarks of AD. Cofilin-actin rods also form within the nucleus of heat-shocked neurons and are cleared from cells expressing wild type huntingtin protein but not in cells expressing mutant or silenced huntingtin, suggesting a role for nuclear rods in Huntington disease (HD). As an early event in the neurodegenerative cascade, rod formation is an ideal target for therapeutic intervention that might be useful in treatment of many different neurological diseases.

    View details for Web of Science ID 000276412800011

    View details for PubMedID 20088812

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