Danielle Beckman

Alzheimer‐associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation

Alzheimers disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD‐associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α‐P). AβOs further induced eIF2α‐P and activated pro‐inflammatory IKKβ/NF‐κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor‐α (TNF‐α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.

Cross Talk Between Brain Innate Immunity and Serotonin Signaling Underlies Depressive-Like Behavior Induced by Alzheimer's Amyloid-β Oligomers in Mice

Considerable clinical and epidemiological evidence links Alzheimers disease (AD) and depression. However, the molecular mechanisms underlying this connection are largely unknown. We reported recently that soluble Aβ oligomers (AβOs), toxins that accumulate in AD brains and are thought to instigate synapse damage and memory loss, induce depressive-like behavior in mice. Here, we report that the mechanism underlying this action involves AβO-induced microglial activation, aberrant TNF-α signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNF-α and abolished depressive-like behavior induced by AβOs. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, AβOs failed to induce depressive-like behavior in Toll-like receptor 4-deficient mice and in mice harboring a nonfunctional TLR4 variant in myeloid cells. Results establish that AβOs trigger depressive-like behavior via a double impact on brain serotonin levels and microglial activation, unveiling a cross talk between brain innate immunity and serotonergic signaling as a key player in mood alterations in AD. SIGNIFICANCE STATEMENT Alzheimers disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia in the world. Brain accumulation of amyloid-β oligomers (AβOs) is a major feature in the pathogenesis of AD. Although clinical and epidemiological data suggest a strong connection between AD and depression, the underlying mechanisms linking these two disorders remain largely unknown. Here, we report that aberrant activation of the brain innate immunity and decreased serotonergic tonus in the brain are key players in AβO-induced depressive-like behavior in mice. Our findings may open up new possibilities for the development of effective therapeutics for AD and depression aimed at modulating microglial function.

Hippocampal biomarkers of fear memory in an animal model of generalized anxiety disorder

Generalized anxiety disorder (GAD) is highly prevalent and incapacitating. Here we used the Carioca High-Conditioned Freezing (CHF) rats, a previously validated animal model for GAD, to identify biomarkers and structural changes in the hippocampus that could be part of the underlying mechanisms of their high-anxiety profile. Spatial and fear memory was assessed in the Morris water maze and passive avoidance test. Serum corticosterone levels, immunofluorescence for glucocorticoid receptors (GR) in the dentate gyrus (DG), and western blotting for hippocampal brain derived neurotrophic factor (BDNF) were performed. Immunohistochemistry for markers of cell proliferation (bromodeoxiuridine/Ki-67), neuroblasts (doublecortin), and cell survival were undertaken in the DG, along with spine staining (Golgi) and dendritic arborization tracing. Hippocampal GABA release was assessed by neurochemical assay. Fear memory was higher among CHF rats whilst spatial learning was preserved. Serum corticosterone levels were increased, with decreased GR expression. No differences were observed in hippocampal cell proliferation/survival, but the number of newborn neurons was decreased, along with their number and length of tertiary dendrites. Increased expression of proBDNF and dendritic spines was observed; lower ratio of GABA release in the hippocampus was also verified. These findings suggest that generalized anxiety/fear could be associated with different hippocampal biomarkers, such as increased spine density, possibly as a compensatory mechanism for the decreased hippocampal number of neuroblasts and dendritic arborization triggered by high corticosterone. Disruption of GABAergic signaling and BDNF impairment are also proposed as part of the hippocampal mechanisms possibly underlying the anxious phenotype of this model.

Prion protein modulates monoaminergic systems and depressive-like behavior in mice

Background: The prion protein (PrPC) functions as a scaffold for cell surface signaling systems, and plays a role in neurodegenerative diseases that include clinical depression among their symptoms. Results: PrPC-null mice showed depressive-like behavior concomitant with functional changes in monoaminergic systems. Conclusion: PrPC regulates functions of monoaminergic synapses. Significance: PrPC may be involved in major depression and related neuropsychiatric disorders. We sought to examine interactions of the prion protein (PrPC) with monoaminergic systems due to: the role of PrPC in both Prion and Alzheimer diseases, which include clinical depression among their symptoms, the implication of monoamines in depression, and the hypothesis that PrPC serves as a scaffold for signaling systems. To that effect we compared both behavior and monoaminergic markers in wild type (WT) and PrPC-null (PrP−/−) mice. PrP−/− mice performed poorly when compared with WT in forced swimming, tail suspension, and novelty suppressed feeding tests, typical of depressive-like behavior, but not in the control open field nor rotarod motor tests; cyclic AMP responses to stimulation of D1 receptors by dopamine was selectively impaired in PrP−/− mice, and responses to serotonin, but not to norepinephrine, also differed between genotypes. Contents of dopamine, tyrosine hydroxylase, and the 5-HT5A serotonin receptor were increased in the cerebral cortex of PrP−/−, as compared with WT mice. Microscopic colocalization, as well as binding in overlay assays were found of PrPC with both the 5HT5A and D1, but not D4 receptors. The data are consistent with the scaffolding of monoaminergic signaling modules by PrPC, and may help understand the pathogenesis of clinical depression and neurodegenerative disorders.

The Importance of Serotonin in Exercise-Induced Adult Neurogenesis: New Evidence from Tph2−/− Mice

The neurotransmitter serotonin (5-HT) is a well established modulator of adult neurogenesis. In the last decade, several lines of research involving pharmacological enhancement of 5-HT levels, depletion of serotonergic neurons and direct activation of 5-HT receptors have shown consistently that 5-HT

Diazepam Inhibits Electrically Evoked and Tonic Dopamine Release in the Nucleus Accumbens and Reverses the Effect of Amphetamine

Diazepam is a benzodiazepine receptor agonist with anxiolytic and addictive properties. Although most drugs of abuse increase the level of release of dopamine in the nucleus accumbens, here we show that diazepam not only causes the opposite effect but also prevents amphetamine from enhancing dopamine release. We used 20 min sampling in vivo microdialysis and subsecond fast-scan cyclic voltammetry recordings at carbon-fiber microelectrodes to show that diazepam caused a dose-dependent decrease in the level of tonic and electrically evoked dopamine release in the nucleus accumbens of urethane-anesthetized adult male Swiss mice. In fast-scan cyclic voltammetry assays, dopamine release was evoked by electrical stimulation of the ventral tegmental area. We observed that 2 and 3 mg of diazepam/kg reduced the level of electrically evoked dopamine release, and this effect was reversed by administration of the benzodiazepine receptor antagonist flumazenil in doses of 2.5 and 5 mg/kg, respectively. No significant effects on measures of dopamine re-uptake were observed. Cyclic voltammetry experiments further showed that amphetamine (5 mg/kg, intraperitoneally) caused a significant increase in the level of dopamine release and in the half-life for dopamine re-uptake. Diazepam (2 mg/kg) significantly weakened the effect of amphetamine on dopamine release without affecting dopamine re-uptake. These results suggest that the pharmacological effects of benzodiazepines have a dopaminergic component. In addition, our findings challenge the classic view that all drugs of abuse cause dopamine release in the nucleus accumbens and suggest that benzodiazepines could be useful in the treatment of addiction to other drugs that increase the level of dopamine release, such as cocaine, amphetamines, and nicotine.

Reply to Altered Monoaminergic Systems and Depressive-like Behavior in Congenic Prion Protein Knock-out Mice.

Nuvolone and Aguzzi (1) ascribed to the effect of a 129-Sirpa polymorphism, a macrophage phenotype we had previously attributed to PrP, and we acknowledge that comparisons of wild-type and Prnp-null mice are subject to the flanking gene problem, as are many other studies of genetically modified mice. However, our current suggestion of a PrPmonoaminergic link, consistent with the scaffold hypothesis, additionally relies on the binding of PrP to monoaminergic markers.

Brain infusion of α-synuclein oligomers induces motor and non-motor Parkinson’s disease-like symptoms in mice

Abstract Parkinson’s disease (PD) is characterized by motor dysfunction, which is preceded by a number of non‐motor symptoms including olfactory deficits. Aggregation of &agr;‐synuclein (&agr;‐syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of &agr;–syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of &agr;‐syn oligomers (&agr;‐SYOs) in mice and evaluated motor and non‐motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that &agr;‐SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45 days post‐infusion (dpi). &agr;‐ SYO‐infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety‐like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of &agr;‐SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH‐positive cells was also seen in the substantia nigra of &agr;‐SYO‐injected mice compared to control. In conclusion, i.c.v. infusion of &agr;‐SYOs recapitulated some of PD‐associated non‐motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive‐like behavior typical of the disease. Moreover, &agr;‐SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to &agr;‐syn oligomers as the proximal neurotoxins responsible for early non‐motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening.

A roadmap for investigating the role of the prion protein in depression associated with neurodegenerative disease

ABSTRACT The physiological properties of the native, endogenous prion protein (PrPC) is a matter of concern, due to its pleiotropic functions and links to neurodegenerative disorders and cancer. In line with our hypothesis that the basic function of PrPC is to serve as a cell surface scaffold for the assembly of signaling modules, multiple interactions have been identified of PrPC with signaling molecules, including neurotransmitter receptors. We recently reported evidence that PrPC may modulate monoaminergic neurotransmission, as well as depressive-like behavior in mice. Here, we discuss how those results, together with a number of other studies, including our previous demonstration that both inflammatory and behavioral stress modulate PrPC content in neutrophils, suggest a distributed role of PrPC in clinical depression and inflammation associated with neurodegenerative diseases. An overarching understanding of the multiple interventions of PrPC upon physiological events may both shed light on the pathogenesis of, as well as help the identification of novel therapeutic targets for clinical depression, Prion and Alzheimers Diseases.

Training Microglia to Resist Alzheimer's Disease

Alzheimers disease (AD) is a progressive neurodegenerative type of dementia with no effective treatments. In the search for ways to manage AD, nonpharmacological interventions, focused on patient lifestyle, are steadily gaining ground. For instance, recent evidence indicates that cognitive