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Open Access Publications from the University of California

Scholarly Works (48 results)

  • Article
  • Peer Reviewed
UC San Francisco Previously Published Works (2016)
The function of neural circuits and networks can be controlled, in part, by modulating the synchrony of their components activities. Network hypersynchrony and altered oscillatory rhythmic activity may contribute to cognitive abnormalities in Alzheimer disease (AD). In this condition, network activities that support cognition are altered decades before clinical disease onset, and these alterations predict future pathology and brain atrophy. Although the precise causes and pathophysiological consequences of these network alterations remain to be defined, interneuron dysfunction and network abnormalities have emerged as potential mechanisms of cognitive dysfunction in AD and related disorders. Here, we explore the concept that modulating these mechanisms may help to improve brain function in these conditions.
    Cover page: Network abnormalities and interneuron dysfunction in Alzheimer disease.
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2016)
    The function of neural circuits and networks can be controlled, in part, by modulating the synchrony of their components' activities. Network hypersynchrony and altered oscillatory rhythmic activity may contribute to cognitive abnormalities in Alzheimer disease (AD). In this condition, network activities that support cognition are altered decades before clinical disease onset, and these alterations predict future pathology and brain atrophy. Although the precise causes and pathophysiological consequences of these network alterations remain to be defined, interneuron dysfunction and network abnormalities have emerged as potential mechanisms of cognitive dysfunction in AD and related disorders. Here, we explore the concept that modulating these mechanisms may help to improve brain function in these conditions.
      Cover page: Network abnormalities and interneuron dysfunction in Alzheimer disease
      • Thesis
      • Peer Reviewed
      UC San Francisco Electronic Theses and Dissertations (2012)

      Many studies of immune responses in neurodegeneration assert that neuroinflammation is a double edged sword - i.e. some aspects of an immune response are beneficial while others are detrimental. In this thesis we investigated two enzymatic cascades that are activated in response to inflammatory stimuli and that we hypothesized were relevant for Huntington's Disease (HD).

      In Chapter 2 we explored the role of the complement cascade in the R6/2 mouse model of HD. The complement cascade is a well characterized immune response mechanism and it is activated in brains of HD patients. Surprisingly, we found that this upregulation of the complement cascade is not mirrored in the R6/2 mouse model of HD, and that genetic deficiency in complement component C3 does not alter disease progression in these mice. This illustrates that normal complement cascade activity is not necessary for disease progression in R6/2 mice, with the caveat that complement activation in HD patients is not faithfully reproduced in this mouse model of HD.

      In Chapter 3 we turned our attention to a pathway known to be relevant in HD, the Kynurenine Pathway. Here, instead of seeking a link between the pathway and HD, we sought to understand how two types of Kynurenine Pathway activity, basal and immune stimulated, are controlled. We employed mice genetically deficient in either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO) because these two enzymes can catalyze the rate-limiting step of the Kynurenine Pathway. We evaluated the contribution of each enzyme to basal and immune stimulated production of several Kynurenine Pathway metabolites that play a role in a variety of highly prevalent diseases, including HD. TDO deficient mice show evidence of several compensatory changes in basal Kynurenine Pathway metabolism. These changes suggest the existence of important unknown mechanisms that regulate basal Kynurenine Pathway metabolism. In contrast, IDO deficient mice appear to be a useful tool for cleanly blocking inflammation induced increases in brain Kynurenine Pathway metabolites without altering basal Kynurenine Pathway metabolism. Both of these results have important implications for development of therapeutics targeting the Kynurenine Pathway.

        Cover page: Immune Activated Pathways in Huntington's Disease
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2021)
        Several lines of evidence implicate the protein tau in the pathogenesis of multiple brain disorders, including Alzheimer's disease, other neurodegenerative conditions, autism, and epilepsy. Tau is abundant in neurons and interacts with microtubules, but its main functions in the brain remain to be defined. These functions may involve the regulation of signaling pathways relevant to diverse biological processes. Informative disease models have revealed a plethora of abnormal tau species and mechanisms that might contribute to neuronal dysfunction and loss, but the relative importance of their respective contributions is uncertain. This knowledge gap poses major obstacles to the development of truly impactful therapeutic strategies. The current expansion and intensification of efforts to translate mechanistic insights into tau-related therapeutics should address this issue and could deliver better treatments for a host of devastating conditions.
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2016)
          Diverse lines of evidence suggest that amyloid-β (Aβ) peptides causally contribute to the pathogenesis of Alzheimer disease (AD), the most frequent neurodegenerative disorder. However, the mechanisms by which Aβ impairs neuronal functions remain to be fully elucidated. Previous studies showed that soluble Aβ oligomers interfere with synaptic functions by depleting NMDA-type glutamate receptors (NMDARs) from the neuronal surface and that overexpression of the receptor tyrosine kinase EphB2 can counteract this process. Through pharmacological treatments and biochemical analyses of primary neuronal cultures expressing wild-type or mutant forms of EphB2, we demonstrate that this protective effect of EphB2 depends on its PDZ-binding motif and the presence of neuronal activity but not on its kinase activity. We further present evidence that the protective effect of EphB2 may be mediated by the AMPA-type glutamate receptor subunit GluA2, which can become associated with the PDZ-binding motif of EphB2 through PDZ domain-containing proteins and can promote the retention of NMDARs in the membrane. In addition, we show that the Aβ-induced depletion of surface NMDARs does not depend on several factors that have been implicated in the pathogenesis of Aβ-induced neuronal dysfunction, including aberrant neuronal activity, tau, prion protein (PrP(C)), and EphB2 itself. Thus, although EphB2 does not appear to be directly involved in the Aβ-induced depletion of NMDARs, increasing its expression may counteract this pathogenic process through a neuronal activity- and PDZ-dependent regulation of AMPA-type glutamate receptors.
            Cover page: Increasing the Receptor Tyrosine Kinase EphB2 Prevents Amyloid-β-induced Depletion of Cell Surface Glutamate Receptors by a Mechanism That Requires the PDZ-binding Motif of EphB2 and Neuronal Activity*
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2011)
            Many neurodegenerative diseases are increasing in prevalence and cannot be prevented or cured. If they shared common pathogenic mechanisms, treatments targeting such mechanisms might be of benefit in multiple conditions. The tau protein has been implicated in the pathogenesis of diverse neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Tau reduction prevents cognitive deficits, behavioral abnormalities and other pathological changes in multiple AD mouse models. Here we examined whether tau reduction also prevents motor deficits and pathological alterations in two mouse models of PD, generated by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) or transgene-mediated neuronal expression of human wildtype α-synuclein. Both models were evaluated on Tau(+/+), Tau(+/-) and Tau(-/-) backgrounds in a variety of motor tests. Tau reduction did not prevent motor deficits caused by 6-OHDA and slightly worsened one of them. Tau reduction also did not prevent 6-OHDA-induced loss of dopaminergic terminals in the striatum. Similarly, tau reduction did not prevent motor deficits in α-synuclein transgenic mice. Our results suggest that tau has distinct roles in the pathogeneses of AD and PD and that tau reduction may not be of benefit in the latter condition.
              Cover page: Tau Reduction Does Not Prevent Motor Deficits in Two Mouse Models of Parkinson's Disease
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2017)

              Background

              Hyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways. This process (excitotoxicity) has been implicated in the pathogenesis of many neurological conditions, ranging from childhood epilepsies to stroke and neurodegenerative disorders such as Alzheimer's disease (AD). Reducing neuronal levels of the microtubule-associated protein tau counteracts network hyperexcitability of diverse causes, but whether this strategy can also diminish downstream excitotoxicity is less clear.

              Methods

              We established a cell-based assay to quantify excitotoxicity in primary cultures of mouse hippocampal neurons and investigated the role of tau in exicitotoxicity by modulating neuronal tau expression through genetic ablation or transduction with lentiviral vectors expressing anti-tau shRNA or constructs encoding wildtype versus mutant mouse tau.

              Results

              We demonstrate that shRNA-mediated knockdown of tau reduces glutamate-induced, NMDA receptor-dependent Ca2+ influx and neurotoxicity in neurons from wildtype mice. Conversely, expression of wildtype mouse tau enhances Ca2+ influx and excitotoxicity in tau-deficient (Mapt -/-) neurons. Reconstituting tau expression in Mapt -/- neurons with mutant forms of tau reveals that the tau-related enhancement of Ca2+ influx and excitotoxicity depend on the phosphorylation of tau at tyrosine 18 (pY18), which is mediated by the tyrosine kinase Fyn. These effects are most evident at pathologically elevated concentrations of glutamate, do not involve GluN2B-containing NMDA receptors, and do not require binding of Fyn to tau's major interacting PxxP motif or of tau to microtubules.

              Conclusions

              Although tau has been implicated in diverse neurological diseases, its most pathogenic forms remain to be defined. Our study suggests that reducing the formation or level of pY18-tau can counteract excitotoxicity by diminishing NMDA receptor-dependent Ca2+ influx.
                Cover page: Phosphorylation of tau at Y18, but not tau-fyn binding, is required for tau to modulate NMDA receptor-dependent excitotoxicity in primary neuronal culture
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2021)
                The protein tau has been implicated in many brain disorders. In animal models, tau reduction suppresses epileptogenesis of diverse causes and ameliorates synaptic and behavioral abnormalities in various conditions associated with excessive excitation-inhibition (E/I) ratios. However, the underlying mechanisms are unknown. Global genetic ablation of tau in mice reduces the action potential (AP) firing and E/I ratio of pyramidal cells in acute cortical slices without affecting the excitability of these cells. Tau ablation reduces the excitatory inputs to inhibitory neurons, increases the excitability of these cells, and structurally alters their axon initial segments (AISs). In primary neuronal cultures subjected to prolonged overstimulation, tau ablation diminishes the homeostatic response of AISs in inhibitory neurons, promotes inhibition, and suppresses hypersynchrony. Together, these differential alterations in excitatory and inhibitory neurons help explain how tau reduction prevents network hypersynchrony and counteracts brain disorders causing abnormally increased E/I ratios.
                  Cover page: Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2013)
                  The microtubule-associated protein tau is expressed throughout the nervous system, most highly in neurons but also in glial cells. Its functions in adult and aging mammals remain to be defined. Previous studies in mouse models found either protective or detrimental effects of genetic tau ablation. Though tau ablation prevented synaptic, network, and cognitive dysfunctions in several models of Alzheimer's disease and made mice more resistant to epileptic seizures, a recent study described a parkinsonian phenotype in aging Tau knockout mice. Here we tested cognition and motor functions in Tau(+/+), Tau(+/-), and Tau(-/-) mice at approximately 1 and 2 years of age. Tau ablation did not impair cognition and caused only minor motor deficits that were much more subtle than those associated with the aging process. Tau ablation caused a mild increase in body weight, which correlated with and might have contributed to some of the motor deficits. However, tau ablation did not cause significant dopaminergic impairments, and dopamine treatment did not improve the motor deficits, suggesting that they do not reflect extrapyramidal dysfunction.
                    Cover page: Age-appropriate cognition and subtle dopamine-independent motor deficits in aged Tau knockout mice
                    • Article
                    • Peer Reviewed
                    UC San Francisco Previously Published Works (2013)
                    We show that a natural behavior, exploration of a novel environment, causes DNA double-strand breaks (DSBs) in neurons of young adult wild-type mice. DSBs occurred in multiple brain regions, were most abundant in the dentate gyrus, which is involved in lea
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