Patrizia LoPresti - Academia.edu (original) (raw)

Papers by Patrizia LoPresti

Neurochemistry & neuropharmacology, Oct 4, 2016

Biomedicines

Multiple Sclerosis (MS) is a debilitating disease with typical onset between 20 and 40 years of a... more Multiple Sclerosis (MS) is a debilitating disease with typical onset between 20 and 40 years of age, so the disability associated with this disease, unfortunately, occurs in the prime of life. At a very early stage of MS, the relapsing-remitting mobility impairment occurs in parallel with a progressive decline in cognition, which is subclinical. This stage of the disease is considered the beginning of progressive MS. Understanding where a patient is along such a subclinical phase could be critical for therapeutic efficacy and enrollment in clinical trials to test drugs targeted at neurodegeneration. Since the disease course is uneven among patients, biomarkers are needed to provide insights into pathogenesis, diagnosis, and prognosis of events that affect neurons during this subclinical phase that shapes neurodegeneration and disability. Thus, subclinical cognitive decline must be better understood. One approach to this problem is to follow known biomarkers of neurodegeneration over...

We present evidence thatthemicrotubule- associated protein tauispresent inoligodendrocytes (OLGs)... more We present evidence thatthemicrotubule- associated protein tauispresent inoligodendrocytes (OLGs), thecentral nervous system cells that makemyelin. Byshowing thattauisdistributed inapattern similar tothatofmyelin basic protein, ourresults suggest apossible involvement oftau insomeaspect ofmyelination. Tauprotein hasbeenidentified inOLGsinsitu andinvitro. Ininterfascicular OLGs,tau localization, revealed bymonoclonal antibody Tau-5, was confined tothecell somata. However, incultured ovine OLGs withanexuberant network ofprocesses, tauwasdetected in cell somata, cellular processes, andmembraneexpansions at thetips ofthese processes. Moreover, insuchcultures, tau appeared localized adjacent toorcoincident withmyelin basic protein inmembraneexpansions along andattheendsofthe cellular processes. Thepresence oftaumRNA wasdocu- mentedusingfluorescence insitu hybridization. Thedistri- bution ofthetaumRNAwassimilar tothatofthetauprotein. Western blotanalysis ofcultured OLGsshowedthepresence o...

Oligodendrocytes make a good-sized myelin that surrounds axons and allows humans to walk and see.... more Oligodendrocytes make a good-sized myelin that surrounds axons and allows humans to walk and see. In contrast, when axons do not get enough myelin, axonal function is incapacitated, with resulting deficits in cognition, behavior, and in the ability to move. In order to make sufficient myelin, each oligodendrocyte extends as many as 50 branches to reach all the distant axons. The capacity of each oligodendrocyte to extend these branches relies on the microtubules, which are the oligodendrocyte’s bridges to reach the distant shores, the axons. Microtubule strength is regulated by many factors, including the Tau protein, which is a microtubule-associated protein. The binding of Tau to the microtubules makes the microtubules healthy, which assists oligodendrocytes in reaching the axons with a good-sized myelin.

Cells, 2020

Central nervous system (CNS) neurodegenerative diseases are characterized by faulty intracellular... more Central nervous system (CNS) neurodegenerative diseases are characterized by faulty intracellular transport, cognition, and aggregate regulation. Traditionally, neuroprotection exerted by histone deacetylase (HDAC) inhibitors (HDACi) has been attributed to the ability of this drug class to promote histone acetylation. However, HDAC6 in the healthy CNS functions via distinct mechanisms, due largely to its cytoplasmic localization. Indeed, in healthy neurons, cytoplasmic HDAC6 regulates the acetylation of a variety of non-histone proteins that are linked to separate functions, i.e., intracellular transport, neurotransmitter release, and aggregate formation. These three HDAC6 activities could work independently or in synergy. Of particular interest, HDAC6 targets the synaptic protein Bruchpilot and neurotransmitter release. In pathological conditions, HDAC6 becomes abundant in the nucleus, with deleterious consequences for transcription regulation and synapses. Thus, HDAC6 plays a lead...

Frontiers in Neurology, 2019

Multiple sclerosis (MS) is a complex disease characterized by autoimmune demyelination and progre... more Multiple sclerosis (MS) is a complex disease characterized by autoimmune demyelination and progressive neurodegeneration. Pathogenetic mechanisms of the disease remain largely unknown. Changes in synaptic functions have been reported; however, the significance of such alterations in the disease course remains unclear. Furthermore, the therapeutic potential of targeting synapses is not well-established. Synapses have key signaling elements that regulate intracellular transport and overall neuronal health. Histone deacetylase (HDAC)6 is a microtubule-associated deacetylase. The interaction between HDAC6 and microtubules is augmented by HDAC6 inhibitors. In this study, experimental autoimmune encephalomyelitis (EAE) mice, an animal model of MS, were treated with the HDAC6 inhibitor drug ACY-738 (20 mg/kg) on day 9 and day 10 post-immunization. Mice were assessed for working memory using the cross-maze test at 10 days post-immunization (d.p.i.), whereas disease scores were recorded over approximately 4 weeks post-immunization. We observed that ACY-738 delayed disease onset and reduced disease severity. Most importantly, ACY-738 increased short-term memory in a manner sensitive to disease severity. We induced EAE disease with various amounts of myelin oligodendrocyte glycoprotein (MOG35-55). EAE mice receiving 100 µg of MOG35-55 and treated with ACY-738 had a statistically significant increase in short term-memory compared to naive mice. Additionally, EAE mice receiving 50 µg MOG35-55 and treated with ACY-738 had a statistically significant increase in short term-memory when compared to EAE mice without drug treatment. In contrast, ACY-738 did not change short-term memory in EAE mice immunized with 200 µg of MOG35-55. Because ACY-738 increases short-term memory only with lower amounts of EAE-inducing reagents, we hypothesize that the inflammatory-demyelinating environment induced by higher amount of EAE-inducing reagents overpowers (at day 10 post-immunization) the synaptic molecules targeted by ACY-738. These studies pave the way for developing ACY-738-like compounds for MS patients and for using ACY-738 as a probe to elucidate disease-sensitive changes at the synapses occurring early in the disease course.

Frontiers in Neurology, 2018

Central nervous system (CNS) degeneration occurs during multiple sclerosis (MS) following several... more Central nervous system (CNS) degeneration occurs during multiple sclerosis (MS) following several years of reversible autoimmune demyelination. Progressive CNS degeneration appears later during the course of relapsing-remitting MS (RRMS), although it starts insidiously at disease onset. We propose that there is an early subclinical phase also for primary-progressive (PP) MS. Consensus exists that many different cell types are involved during disease onset. Furthermore, the response to the initial damage, which is specific for each individual, would result in distinct pathological pathways that add complexity to the disease and the mechanisms underlying progressive CNS degeneration. Progressive MS is classified as either active or not active, as well as with or without progression. Different forms of progressive MS might reflect distinct or overlapping pathogenetic pathways. Disease mechanisms should be determined for each patient at diagnosis and the time of treatment. Until individualized and time-sensitive treatments that specifically target the molecular mechanisms of the progressive aspect of the disease are identified, combined therapies directed at anti-inflammation, regeneration, and neuroprotection are the most effective for preventing MS progression. This review presents selected therapeutics in support of the overall idea of a multidimensional therapy applied early in the disease. This approach could limit damage and increase CNS repair. By targeting several cellular populations (i.e., microglia, astrocytes, neurons, oligodendrocytes, and lymphocytes) and multiple pathological processes (e.g., inflammation, demyelination, synaptopathy, and excitatory/inhibitory imbalance) progressive MS could be attenuated. Early timing for such multidimensional therapy is proposed as the prerequisite for effectively halting progressive MS.

Neurochemical Research, 2015

The cytoskeleton protein Tau present in oligodendrocytes (OLGs) promotes cellular process outgrow... more The cytoskeleton protein Tau present in oligodendrocytes (OLGs) promotes cellular process outgrowth and myelination; whereas abnormally hyperphosphorylated Tau has been shown to be present in the most debilitating form of multiple sclerosis and in selective dementias. This research examined the functional consequences of expressing a truncated form of Tau in OLGs during the second postnatal life. In particular, this truncated form of Tau (DTau) retains the Fyn-binding domain but lacks the microtubule-binding domain. Similar to hyperphosphorylated Tau, DTau cannot bind the cytoskeleton and is missorted. The Cre/loxP recombination system was used to generate transgenic (TG) founder lines, which contain a Floxed LacZ-STOP cassette to prevent expression of enhanced green fluorescence protein (EGFP)-DTau. The founder lines were then crossed with a Tamoxifen (TM)-inducible proteolipid protein (PLP)-dependent Cre driver line. Myelin PLP is the major myelin protein in the central nervous system (CNS). TM was given at postnatal day (p) 12 for 3 days, and CNS tissues were collected at p22. Only TG mice with both EGFP-DTau and Cre manifested an overt phenotype of loss of balance and stumbles starting around p18. CNS tissues obtained from TM-treated EGFP-DTau/Cre double transgenic mice had recombined PCR products, GFP, and diminished brain myelin. GFP was expressed in OLGs, but not in neurons or astrocytes. On the contrary, TM-treated TG mice with only one of the two transgenes, i.e., Cre or Tau, did not have recombinant PCR products, GFP, diminished myelin, or abnormal phenotype. Thus, this inducible model shows for the first time that a non-microtubule-associated Tau protein in OLGs elicits both myelin decrease and gait abnormalities, similar to the occurrence in selective demyelinating and neurodegenerative diseases.

Neurochemical research, 2015

Cognitive decline presents a therapeutic challenge for patients with multiple sclerosis (MS), a d... more Cognitive decline presents a therapeutic challenge for patients with multiple sclerosis (MS), a disease characterized by recurrent autoimmune demyelination and by progressive CNS degeneration. Glatiramer acetate (GA, also known as Copolymer 1, Cop-1, or Copaxone), commonly used to treat MS, reduces the frequency of relapses; it has both anti-inflammatory and neuroprotective properties. However, clinical trials have not definitively shown that GA improves cognitive impairment during MS. Using an in vivo animal model of autoimmune demyelination, i.e., relapsing-remitting experimental autoimmune encephalomyelitis (EAE), we tested short-term memory in EAE mice (EAE), in EAE mice treated with GA for 10 days starting at the time of immunization (EAE + GA), and in age-matched healthy, naïve mice (Naïve). Short-term memory was assessed using the cross-maze test at 10, 20, and 30 days post-immunization (d.p.i.); data were analyzed at each time point and over time. At 10 d.p.i., EAE and EAE +...

Bollettino della Società italiana di biologia sperimentale, Jan 30, 1985

Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1992

Treatment of the neuroblastoma cell line SHSY5Y with nerve growth factor (NGF) resulted in limite... more Treatment of the neuroblastoma cell line SHSY5Y with nerve growth factor (NGF) resulted in limited neurite extension, but proliferation continued. However, SHSY5Y cells treated with NGF and a pulse of the DNA polymerase alpha and delta inhibitor aphidicolin showed dramatic neuronal differentiation. Few differentiated cells were observed immediately following the NGF-aphidicolin treatment; however, continued treatment of the cells with NGF in the ensuing week resulted in extension of long neurites (> 400 microns). Neurite extension was not observed for cells treated with aphidicolin alone. Hence, aphidicolin and NGF act synergistically to induce differentiation of SHSY5Y cells. If maintained in NGF, the differentiated cells were stable for at least 1 month and displayed many neuronal characteristics. They were mitotically inactive, and, in contrast to control or NGF-treated cells, the differentiated cells required NGF for survival. The cells expressed multiple microtubule-associat...

In tauopathies, overexpression of tau exon 10 is linked to degeneration and abnormal tau depositi... more In tauopathies, overexpression of tau exon 10 is linked to degeneration and abnormal tau deposition in neurons and oligodendroglia (OLGs). To compare exon 10 expression in normal neurons and OLGs, adult bovine brain was examined for the expression of tau in gray matter and cultured OLGs isolated from white matter. Using exon-specific antibodies, we found that both types of tissues abundantly expressed exon 2 but isolated OLGs had a lower expression of exons 3 and 10 when compared to gray matter. Relative expression of exons 3 and 10 did not change significantly during the in vitro maturation of OLGs for 39 days. Using a panel of well-characterized antibodies against tau, we determined that isolated OLGs contained tau phosphorylated at the Tau-1, 12E8, and PHF-1 but not the AT8, AT100, AT180, and AT270 epitopes. Tau phosphorylation status diminished during in vitro maturation, suggesting that healthy OLG processes require regulated phosphorylation of tau at specific sites. We propose that the tau isoform profile and phosphorylation status contribute to the vulnerability of OLGs in degenerative diseases linked to overexpression of exon 10.

Proceedings of the National Academy of Sciences, 1995

We present evidence that the microtubule-associated protein tau is present in oligodendrocytes (O... more We present evidence that the microtubule-associated protein tau is present in oligodendrocytes (OLGs), the central nervous system cells that make myelin. By showing that tau is distributed in a pattern similar to that of myelin basic protein, our results suggest a possible involvement of tau in some aspect of myelination. Tau protein has been identified in OLGs in situ and in vitro. In interfascicular OLGs, tau localization, revealed by monoclonal antibody Tau-5, was confined to the cell somata. However, in cultured ovine OLGs with an exuberant network of processes, tau was detected in cell somata, cellular processes, and membrane expansions at the tips of these processes. Moreover, in such cultures, tau appeared localized adjacent to or coincident with myelin basic protein in membrane expansions along and at the ends of the cellular processes. The presence of tau mRNA was documented using fluorescence in situ hybridization. The distribution of the tau mRNA was similar to that of th...

Neuroscience Letters, 2001

Oxidative stress is a major mediator of neurodegeneration. In this study, we tested the effects o... more Oxidative stress is a major mediator of neurodegeneration. In this study, we tested the effects of oxidative stress induced by a brief exposure to hydrogen peroxide (H 2 O 2) on the phosphorylation state of the tau protein in oligodendrocytes (OL). Primary oligodendrocyte cultures prepared from newborn rat brains were exposed to millimolar concentrations of H 2 O 2 for up to 15 min, and then incubated in normal medium for up to 12 h. The treatment caused morphological degeneration of OL characterized by the loss of cellular processes apparent approximately 3 h after H 2 O 2 exposure. The morphological degeneration was preceded by a profound dephosphorylation of tau protein revealed by immunoblot using monoclonal tau-1 antibody that recognizes the dephosphorylated epitope. The dephosphorylated form increased dramatically during H 2 O 2 exposure, peaked after 2 h of post-exposure, and returned to the baseline level within 12 h. Total tau protein levels were not changed in the course of the experiment as judged by immunoblotting with phosphorylation-insensitive tau-5 and 46-1 monoclonal antibodies. Our finding demonstrates that oxidative stress induces a rapid but transient dephosphorylation of tau protein that may underlie morphological degeneration of OL.

Molecular Biology of the Cell, 2006

Microtubule-associated protein 1B (MAP1B) is essential for neural development. Besides the abunda... more Microtubule-associated protein 1B (MAP1B) is essential for neural development. Besides the abundant expression in neurons, MAP1B recently was found in myelinating oligodendroglia. Moreover, MAP1B deficiency causes delayed myelin development, suggesting the functional importance of MAP1B in oligodendroglia. However, molecular mechanisms that control MAP1B expression in oligodendroglia remain elusive. We report here that MAP1B mRNA is markedly up-regulated in the oligodendroglia cell line CG4 upon induced differentiation, leading to elevated MAP1B protein production. A coordinated regulation of homeoprotein transcription factors was observed during CG4 cell differentiation, which recapitulates the regulation in neurons that promotes MAP1B transcription. Hence, transcriptional regulation of MAP1B appears to be a common mechanism in both neurons and oligodendroglia. In addition, we found posttranscriptional regulation of MAP1B mRNA by the selective RNA-binding protein QKI in oligodendro...

Journal of Neurochemistry, 2008

are observed in the Fyn-and laminin-2-minus mice. Fynminus mice have a severe myelin deficit in f... more are observed in the Fyn-and laminin-2-minus mice. Fynminus mice have a severe myelin deficit in forebrain at all ages (Sperber et al. 2001), whereas cervical spinal cord has no decrease in myelin content, number of OLGs, or number of myelinated fibers (Sperber et al. 2001). Also, the laminin-2-minus mice have myelin deficit in the brain not the spinal cord (Chun et al. 2003). Recently, Lee et al. (2006) showed that transgenic mice that express a dominant-negative beta1 Integrin protein (lacking the C-terminal tail) have hypomyelinated axons in spinal cords and optic nerves with a significant increase in the number of unmyelinated axons within the spinal cord and optic nerves. In contrast, the corpus callosum has no myelin defects, whereas during remyelination of the corpus callosum the actual percentage of myelinated axons is reduced (Lee et al. 2006). These previous studies provided evidence that integrin-dependent pathways are important during myelination; however, the conditional ablation of the beta 1-integrin gene in oligodendroglial cells did not affect CNS myelination and remyelination (Benninger et al. 2006). Therefore, these results indicate that both integrin-dependent and-independent

Glia, 2014

Myelinogenesis in the mammal nervous system occurs predominantly postnatally. Glatiramer acetate ... more Myelinogenesis in the mammal nervous system occurs predominantly postnatally. Glatiramer acetate (GA), a drug for the treatment for multiple sclerosis (MS), has been shown to induce immunomodulation and neuroprotection in the inflamed CNS in MS and in experimental autoimmune encephalomyelitis (EAE). Here we investigated whether GA can affect myelinogenesis and oligodendrogenesis in the developing nervous system under nonpathological conditions. Towards this end we studied myelination in mice injected daily by GA, at postnatal Days 7-21. Immunohistological and ultrastructural analyses revealed significant elevation in the number of myelinated axons as well as in the thickness of the myelin encircling them and their resulting g-ratios, in spinal cords of GA-injected mice compared with their PBS-injected littermates, at postnatal Day 14. Elevation in myelinated axons was detected also in the peripheral ventral roots of the motor nerves. GA induced also an increase in axonal diameter, implying an effect on the overall development of the nervous system. A prominent elevation in the amount of progenitor oligodendrocytes and their BrdU incorporation, as well as in mature oligodendrocytes indicated that the effect of GA is linked to increased proliferation and differentiation along the oligodendroglial maturation cascade. In addition, elevation in insulin-like growth factor (IGF-1) and brain-derived neurotrophic factor (BDNF) was found in the white matter of the GA-injected mice. Furthermore, a functional advantage in rotating rod test was exhibited by GA-injected mice over their littermates at postnatal Day 21. These cumulative findings corroborate the beneficial effect of GA on oligodendrogenesis and myelination.

Glia, 2002

Oligodendrocytes and neurons derive from the same cell type but develop distinct morphologic and ... more Oligodendrocytes and neurons derive from the same cell type but develop distinct morphologic and functional properties as they mature in vivo. Both cells express tau protein, a developmentally regulated protein in the central nervous system. The regulation of tau has been investigated extensively in neurons but not in oligodendrocytes, so we studied regulation of tau in oligodendrocytes in vivo. The amino-derived tau isoforms consist of isoforms with zero (A0), one (A1), or two (A2) inserts. We examined the developmental regulation of tau mRNA isoforms at the amino domain by comparing tau expression in oligodendrocytes (OLGs) isolated from 1-and 20-day-old rat brain and in age-matched cortex, which abounds in neurons. In the rat brain, myelination peaks at 20 days. By using semiquantitative RT-PCR, we found that OLGs and cortex from 1-day-old rat brain largely had amino-derived tau isoforms with no insert, whereas OLGs from 20-day-old rat brain had similar levels of amino-derived tau isoforms with no insert or with one insert. We also found that 20-day-old OLGs had twofold more tau mRNA levels than younger OLGs. In contrast to OLGs from 20-day-old rat brain, age-matched cortex had comparable levels of A0, A1, and A2 tau amino-derived isoforms. Further, younger and older OLGs had a reciprocal pattern of expression of both carboxy-derived tau mRNA isoforms with either three (3R) or four (4R) repeats. In contrast, younger and older cortex expressed either 3R or 4R tau. This study showed an upregulation of tau mRNA and cell-specific tau mRNA isoform expression in OLGs forming myelin.

Journal of Neurobiology, 1994

To obtain insight into which subpopulations of sensory neurons in dorsal root ganglia are support... more To obtain insight into which subpopulations of sensory neurons in dorsal root ganglia are supported by different neurotrophins, we retrogradely labeled cutaneous and muscle afferents in embryonic day 9 chick embryos and followed their survival in neuron-enriched cultures supplemented with either nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), or neurotrophin-3 (NT-3). We found that NGF is a wide survival factor for subpopulations of both cutaneous and muscle afferents, whereas the survival effects of BDNF and NT-3 are restricted primarily to muscle afferents. We also measured soma size in each neurotrophic factor. These new data show that BDNF- and NT-3-dependent cells appear to be a mixture of two populations of neurons: one small diameter and the other large diameter. In contrast, based on size alone, NGF-dependent cells appear to be a single population of only small-diameter neurons. Thus, BDNF and NT-3 may have some new, previously unreported effects on small-diameter afferent neurons.