The neurotoxin DSP-4 dysregulates the locus coeruleus-norepinephrine system and recapitulates molecular and behavioral aspects of prodromal neurodegenerative disease

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer\u27s disease (AD) and Parkinson\u27s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg, one week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms

First observation of Bs -> D_{s2}^{*+} X mu nu decays

Using data collected with the LHCb detector in proton-proton collisions at a centre-of-mass energy of 7 TeV, the semileptonic decays Bs -> Ds+ X mu nu and Bs -> D0 K+ X mu nu are detected. Two structures are observed in the D0 K+ mass spectrum at masses consistent with the known D^+_{s1}(2536) and $D^{*+}_{s2}(2573) mesons. The measured branching fractions relative to the total Bs semileptonic rate are B(Bs -> D_{s2}^{*+} X mu nu)/B(Bs -> X mu nu)= (3.3\pm 1.0\pm 0.4)%, and B(Bs -> D_{s1}^+ X munu)/B(Bs -> X mu nu)= (5.4\pm 1.2\pm 0.5)%, where the first uncertainty is statistical and the second is systematic. This is the first observation of the D_{s2}^{*+} state in Bs decays; we also measure its mass and width.Comment: 8 pages 2 figures. Published in Physics Letters

Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus.

Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer\u27s disease-like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase-cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD

Genetic loss of norepinephrine does not alter adult hippocampal neurogenesis in dopamine beta-hydroxylase deficient mice

Norepinephrine (NE), and specific adrenoceptors, have been reported to influence distinct aspects of adult hippocampal neurogenesis, including latent stem cell activation, progenitor proliferation, and differentiation. These findings are predominantly based on the use of pharmacological approaches in both in vitro and in vivo systems. Here, we sought to assess the consequences of genetic ablation of NE on adult hippocampal neurogenesis, by examining dopamine β hydroxylase knockout (Dbh -/-) mice, which lack NE from birth. We find that Dbh -/- mice exhibit no difference in adult hippocampal progenitor proliferation and survival. Further, the number of immature newborn neurons, labeled using stage-specific developmental markers within the hippocampal neurogenic niche, was also unaltered in Dbh -/- mice. In contrast, the noradrenergic neurotoxin DSP-4, which had previously been shown to reduce adult hippocampal neurogenesis in rats, also resulted in a decline in hippocampal progenitor proliferation in C57/Bl6N mice. These findings indicate that pharmacological lesioning of noradrenergic afferents in adulthood, but not the complete genetic loss of NE from birth, impairs adult hippocampal neurogenesis in mice

The -970 C-T polymorphism does not affect <i>Dbh</i> mRNA abundance.

<p><i>Dbh -/- BT</i> mice carrying either the C allele (2 independent lines, pooled) or the T allele (2 independent lines, pooled) at position -970 were assessed for mRNA abundance in the (A) brain, (B) adrenal, (C) heart, (D) liver, and (E) lung by qRT-PCR. Shown are individual and mean ± SEM threshold cycle numbers (ΔCt) normalized to copy number. N = 6–11 per allele.</p

A human BAC transgene drives specific Dbh expression to the locus coeruleus and adrenal gland.

<p>Shown are representative examples of human dopamine β-hydroxylase (DBH) and mouse tyrosine hydroxylase (TH) mRNA expression in adrenal gland and brain sections from C57Bl6/J wild-type and BAC transgenic mice containing the noradrenergic locus coeruleus (LC, corresponding to Figure 75 in the Mouse Brain Atlas) and the dopaminergic substantia nigra pars compacta/ventral tegmental area (SN/VTA, corresponding to Figure 55 in the Mouse Brain Atlas[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154864#pone.0154864.ref038" target="_blank">38</a>]).</p

A human BAC transgene rescues <i>Dbh -/-</i> developmental, physiological, and behavioral phenotypes.

<p><i>Dbh +/-</i>, <i>Dbh -/-</i>, and <i>Dbh -/- BT</i> littermates were assessed for (A) weaning weight, (B) ptosis, (C) novelty-induced locomotor activity, and (D) seizure susceptibility. Shown is mean ± SEM (A) weight in grams, (B) mm eye opening, (C) ambulations in 30 min, and (D) latency to flurothyl-induced generalized seizure. N = 6–8 per genotype. *p<0.05, **p<0.01, ****p<0.0001.</p

Viable offspring born to a <i>Dbh +/-</i> female by <i>DBH -/-BT</i> male cross^*.

<p>Viable offspring born to a <i>Dbh +/-</i> female by <i>DBH -/-BT</i> male cross^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154864#t001fn001" target="_blank">*</a>}.</p

A human BAC transgene restores normal central and peripheral NE levels to <i>Dbh -/-</i> mice.

<p><i>Dbh +/-</i>, <i>Dbh -/-</i>, and <i>Dbh -/- BT</i> littermates were assessed for tissue NE levels in the (A) brain, (B) heart, and (C) adrenal by HPLC. Shown is mean ± SEM ng of NE per mg tissue. N = 7–9 per genotype.</p