Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases.

Reelin is an extracellular matrix glycoprotein involved in neuronal migration during embryonic brain development and synaptic plasticity in the adult brain. The role of Reelin in the developing central nervous system has been extensively characterized. Indeed, a loss of Reelin or a disruption in its signaling cascade leads to neurodevelopmental defects and is associated with ataxia, intellectual disability, autism, and several psychiatric disorders. In the adult brain, Reelin is critically involved in neurogenesis and synaptic plasticity. Reelin's signaling potentiates glutamatergic and GABAergic neurotransmission, induces synaptic maturation, and increases AMPA and NMDA receptor subunits' expression and activity. As a result, there is a growing literature reporting that a loss of function and/or reduction of Reelin is implicated in numerous neurodegenerative diseases. The present review summarizes the current state of the literature regarding the implication of Reelin and Reelin-mediated signaling during aging and neurodegenerative disorders, highlighting Reelin as a possible target in the prevention or treatment of progressive neurodegeneration.

Central repeat fragment of reelin leads to active reelin intracellular signaling and rescues cognitive deficits in a mouse model of reelin deficiency.

Reelin and its receptor, ApoER2, play important roles in prenatal brain development and postnatally in synaptic plasticity, learning, and memory. Previous reports suggest that reelin's central fragment binds to ApoER2 and receptor clustering is involved in subsequent intracellular signaling. However, limitations of currently available assays have not established cellular evidence of ApoER2 clustering upon binding of the central reelin fragment. In the present study, we developed a novel, cell-based assay of ApoER2 dimerization using a "split-luciferase" approach. Specifically, cells were co-transfected with one recombinant ApoER2 receptor fused to the N-terminus of luciferase and one ApoER2 receptor fused to the C-terminus of luciferase. Using this assay, we directly observed basal ApoER2 dimerization/clustering in transfected HEK293T cells and, significantly, an increase in ApoER2 clustering in response to that central fragment of reelin. Furthermore, the central fragment of reelin activated intracellular signal transduction of ApoER2, indicated by increased levels of phosphorylation of Dab1, ERK1/2, and Akt in primary cortical neurons. Functionally, we were able to demonstrate that injection of the central fragment of reelin rescued phenotypic deficits observed in the heterozygous reeler mouse. These data are the first to test the hypothesis that the central fragment of reelin contributes to facilitating the reelin intracellular signaling pathway through receptor clustering.

Lung infection by Pseudomonas aeruginosa induces neuroinflammation and blood-brain barrier dysfunction in mice.

BACKGROUND: Severe lung infection can lead to brain dysfunction and neurobehavioral disorders. The mechanisms that regulate the lung-brain axis of inflammatory response to respiratory infection are incompletely understood. This study examined the effects of lung infection causing systemic and neuroinflammation as a potential mechanism contributing to blood-brain barrier (BBB) leakage and behavioral impairment. METHODS: Lung infection in mice was induced by instilling Pseudomonas aeruginosa (PA) intratracheally. We determined bacterial colonization in tissue, microvascular leakage, expression of cytokines and leukocyte infiltration into the brain. RESULTS: Lung infection caused alveolar-capillary barrier injury as indicated by leakage of plasma proteins across pulmonary microvessels and histopathological characteristics of pulmonary edema (alveolar wall thickening, microvessel congestion, and neutrophil infiltration). PA also caused significant BBB dysfunction characterized by leakage of different sized molecules across cerebral microvessels and a decreased expression of cell-cell junctions (VE-cadherin, claudin-5) in the brain. BBB leakage peaked at 24 h and lasted for 7 days post-inoculation. Additionally, mice with lung infection displayed hyperlocomotion and anxiety-like behaviors. To test whether cerebral dysfunction was caused by PA directly or indirectly, we measured bacterial load in multiple organs. While PA loads were detected in the lungs up to 7 days post-inoculation, bacteria were not detected in the brain as evidenced by negative cerebral spinal fluid (CSF) cultures and lack of distribution in different brain regions or isolated cerebral microvessels. However, mice with PA lung infection demonstrated increased mRNA expression in the brain of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), chemokines (CXCL-1, CXCL-2) and adhesion molecules (VCAM-1 and ICAM-1) along with CD11b + CD45+ cell recruitment, corresponding to their increased blood levels of white cells (polymorphonuclear cells) and cytokines. To confirm the direct effect of cytokines on endothelial permeability, we measured cell-cell adhesive barrier resistance and junction morphology in mouse brain microvascular endothelial cell monolayers, where administration of IL-1ß induced a significant reduction of barrier function coupled with tight junction (TJ) and adherens junction (AJ) diffusion and disorganization. Combined treatment with IL-1ß and TNFα augmented the barrier injury. CONCLUSIONS: Lung bacterial infection is associated with BBB disruption and behavioral changes, which are mediated by systemic cytokine release.

A novel Reelin construct, R36, recovered behavioural deficits in the heterozygous reeler mouse.

Reelin, a large extracellular glycoprotein, plays a critical role in prenatal brain development and postnatally in synaptic plasticity, learning and memory. Dysregulation of Reelin signalling has been implicated in several neuropsychiatric disorders including schizophrenia, autism, depression and Alzheimer's disease. Previous studies have demonstrated that Reelin's central fragment, R3456, binds to ApoER2, inducing ApoER2 clustering and subsequent intracellular signalling. We previously reported the development of a novel luciferase complementation assay, which we used to demonstrate that R3456 can lead to ApoER2 receptor dimerization. Using this same assay, we explored various smaller fragments and combinations from R3456, and we identified a construct of repeats 3 and 6 (R36), which could still elicit equivalent receptor dimerization. The purpose of this study was to test R36 for biological effects in vitro and in vivo. We show that R36 was capable of initiating intracellular signalling in primary neuronal cultures. In addition, we demonstrate that a single intracerebroventricular injection of R36 protein into a model of Reelin deficiency, the heterozygous reeler mice, can significantly improve cognition. These data support a role for the new construct R36 to enhance the Reelin pathway, and the future possibility of exploring gene therapy approaches with R36 in diseases characterized by reduced levels of Reelin.

Lung infection by P. aeruginosa induces neuroinflammation and blood-brain barrier dysfunction in mice.

Background: Severe lung infection can lead to brain dysfunction and neurobehavioral disorders. The mechanisms that regulate the lung-brain axis of inflammatory response to respiratory infection are incompletely understood. This study examined the effects of lung infection causing systemic and neuroinflammation as a potential mechanism contributing to blood-brain barrier (BBB) leakage and behavioral impairment. Methods: Pneumonia was induced in adult C57BL/6 mice by intratracheal inoculation of Pseudomonas aeruginosa (PA). Solute extravasation, histology, immunofluorescence, RT-PCR, multiphoton imaging and neurological testing were performed in this study. Results: Lung infection caused alveolar-capillary barrier injury as indicated by leakage of plasma proteins across pulmonary microvessels and histopathological characteristics of pulmonary edema (alveolar wall thickening, microvessel congestion, and neutrophil infiltration). PA also caused significant BBB dysfunction characterized by leakage of different sized molecules across cerebral microvessels and a decreased expression of cell-cell junctions (VE-cadherin, claudin-5) in the brain. BBB leakage peaked at 24 hours and lasted for 7 days post-inoculation. Additionally, mice with lung infection displayed hyperlocomotion and anxiety-like behaviors. To test whether cerebral dysfunction was caused by PA directly or indirectly, we measured bacterial load in multiple organs. While PA loads were detected in the lungs up to 7 days post-inoculation, bacteria were not detected in the brain as evidenced by negative cerebral spinal fluid (CSF) cultures and lack of distribution in different brain regions or isolated cerebral microvessels. However, mice with PA lung infection demonstrated increased mRNA expression in the brain of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), chemokines (CXCL-1, CXCL-2) and adhesion molecules (VCAM-1 and ICAM-1) along with CD11b+ cell recruitment, corresponding to their increased blood levels of white cells (polymorphonuclear cells) and cytokines. To confirm the direct effect of cytokines on endothelial permeability, we measured cell-cell adhesive barrier resistance and junction morphology in mouse brain microvascular endothelial cell monolayers, where administration of IL-1ß induced a significant reduction of barrier function coupled with tight junction (TJ) diffusion and disorganization. Combined treatment with IL-1ß and TNFα augmented the barrier injury. Conclusions: These results suggest that lung bacterial infection causes cerebral microvascular leakage and neuroinflammation via a mechanism involving cytokine-induced BBB injury.

Lung infection by P. aeruginosa induces neuroinflammation and blood-brain barrier dysfunction in mice.

Background Severe lung infection can lead to brain dysfunction and neurobehavioral disorders. The mechanisms that regulate the lung-brain axis of inflammatory response to respiratory infection are incompletely understood. This study examined the effects of lung infection causing systemic and neuroinflammation as a potential mechanism contributing to blood-brain barrier (BBB) leakage and behavioral impairment. Methods Pneumonia was induced in adult C57BL/6 mice by intratracheal inoculation of Pseudomonas aeruginosa (PA). Solute extravasation, histology, immunofluorescence, RT-PCR, multiphoton imaging and neurological testing were performed in this study. Results Lung infection caused alveolar-capillary barrier injury as indicated by leakage of plasma proteins across pulmonary microvessels and histopathological characteristics of pulmonary edema (alveolar wall thickening, microvessel congestion, and neutrophil infiltration). PA also caused significant BBB dysfunction characterized by leakage of different sized molecules across cerebral microvessels and a decreased expression of cell-cell junctions (VE-cadherin, claudin-5) in the brain. BBB leakage peaked at 24 hours and lasted for 7 days post-inoculation. Additionally, mice with lung infection displayed hyperlocomotion and anxiety-like behaviors. To test whether cerebral dysfunction was caused by PA directly or indirectly, we measured bacterial load in multiple organs. While PA loads were detected in the lungs up to 7 days post-inoculation, bacteria were not detected in the brain as evidenced by negative cerebral spinal fluid (CSF) cultures and lack of distribution in different brain regions or isolated cerebral microvessels. However, mice with PA lung infection demonstrated increased mRNA expression in the brain of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), chemokines (CXCL-1, CXCL-2) and adhesion molecules (VCAM-1 and ICAM-1) along with CD11b + cell recruitment, corresponding to their increased blood levels of white cells (polymorphonuclear cells) and cytokines. To confirm the direct effect of cytokines on endothelial permeability, we measured cell-cell adhesive barrier resistance and junction morphology in mouse brain microvascular endothelial cell monolayers, where administration of IL-1ß induced a significant reduction of barrier function coupled with tight junction (TJ) diffusion and disorganization. Combined treatment with IL-1ß and TNFα augmented the barrier injury. Conclusions These results suggest that lung bacterial infection causes cerebral microvascular leakage and neuroinflammation via a mechanism involving cytokine-induced BBB injury.

Concentration and proteolysis of CX3CL1 may regulate the microglial response to CX3CL1.

Fractalkine (FKN) is a membrane-bound chemokine that can be cleaved by proteases such as ADAM 10, ADAM 17, and cathepsin S to generate soluble fragments. Studies using different forms of the soluble FKN yield conflicting results in vivo. These observations prompted us to investigate the function and pharmacology of two commonly used isoforms of FKN, a human full-length soluble FKN (sFKN), and a human chemokine domain only FKN (cdFKN). Both are prevalent in the literature and are often assumed to be functionally equivalent. We observed that recombinant sFKN and cdFKN exhibit similar potencies in a cell-based cAMP assay, but binding affinity for CX3CR1 was modestly different. There was a 10-fold difference in potency between sFKN and cdFKN when assessing their ability to stimulate ß-arrestin recruitment. Interestingly, high concentrations of FKN, regardless of cleavage variant, were ineffective at reducing pro-inflammatory microglial activation and may induce a pro-inflammatory response. This effect was observed in mouse and rat primary microglial cells as well as microglial cell lines. The inflammatory response was exacerbated in aged microglia, which is known to exhibit age-related inflammatory phenotypes. We observed the same effects in Cx3cr1-/- primary microglia and therefore speculate that an alternative FKN receptor may exist. Collectively, these data provide greater insights into the function and pharmacology of these common FKN reagents, which may clarify conflicting reports and urge greater caution in the selection of FKN peptides for use in in vitro and in vivo studies and the interpretation of results obtained using these differing peptides.

Reelin central fragment supplementation improves cognitive deficits in a mouse model of Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is characterized by autistic behaviors, childhood seizures, and deficits in learning and memory. FXS has a loss of function of the FMR1 gene that leads to a lack of Fragile X Mental Retardation Protein (FMRP) expression. FMRP is critical for synaptic plasticity, spatial learning, and memory. Reelin is a large extracellular glycoprotein essential for synaptic plasticity and numerous neurodevelopmental processes. Reduction in Reelin signaling is implicated as a contributing factor in disease etiology in several neurological disorders, including schizophrenia, and autism. However, the role of Reelin in FXS is poorly understood. We demonstrate a reduction in Reelin in Fmr1 knock-out (KO) mice, suggesting that a loss of Reelin activity may contribute to FXS. We demonstrate here that Reelin signaling enhancement via a single intracerebroventricular injection of the Reelin central fragment into Fmr1 KO mice can profoundly rescue cognitive deficits in hidden platform water maze and fear conditioning, as well as hyperactivity during the open field. Improvements in behavior were associated with rescued levels of post synaptic marker in Fmr1 KO mice when compared to controls. These data suggest that increasing Reelin signaling in FXS could offer a novel therapeutic for improving cognition in FXS.

Improving Gene Therapy for Angelman Syndrome with Secreted Human UBE3A.

The rare genetic neurodevelopmental disease Angelman syndrome (AS) is caused by the loss of function of UBE3A, a ubiquitin ligase. The disease results in a lifetime of severe symptoms, including intellectual disability and motor impairments for which there are no effective treatments. One avenue of treatment for AS is the use of gene therapy to reintroduce a functional copy of the UBE3A gene. Our group had previously shown that recombinant adeno-associated virus (rAAV) expressing mouse Ube3a could rescue deficits in a mouse model of AS. Here, we expand on this work and show that this approach could be successfully replicated in a second AS model using the human UBE3A gene. Furthermore, we address the challenge of limited vector distribution in the brain by developing a novel modified form of UBE3A. This modified protein, termed STUB, was designed with a secretion signal and a cell-penetrating peptide. This allowed transduced cells to act as factories for the production of UBE3A protein that could be taken up by neighboring non-transduced cells, thus increasing the number of neurons receiving the therapeutic protein. Combining this construct with intracerebroventricular injections to maximize rAAV distribution within the brain, we demonstrate that this novel approach improves the recovery of behavioral and electrophysiological deficits in the AS rat model. More importantly, a comparison of rAAV-STUB to a rAAV expressing the normal human UBE3A gene showed that STUB was a more effective therapeutic. These data suggest that rAAV-STUB is a new potential approach for the treatment of AS.

Portal Glucose Infusion, Afferent Nerve Fibers, and Glucose and Insulin Tolerance of Insulin-Resistant Rats.

BACKGROUND: The role of hepatoportal glucose sensors is poorly understood in the context of insulin resistance. OBJECTIVES: We assessed the effects of glucose infusion in the portal vein on insulin tolerance in 2 rat models of insulin resistance, and the role of capsaicin sensitive nerves in this signal. METHODS: Male Wistar rats, 8 weeks old, weighing 250-275 g, were used. Insulin and glucose tolerance were assessed following a 4-hour infusion of either glucose or saline through catheterization in the portal vein in 3 paradigms. In experiment 1, for diet-induced insulin resistance, rats were fed either a control diet (energy content: proteins = 22.5%, carbohydrates = 64.1%, and lipids = 13.4%) or a high-fat diet (energy content: proteins = 15.3%, carbohydrates = 40.3%, and lipids =44.4%) for 4 months. In experiment 2, for centrally induced peripheral insulin resistance, catheters were inserted in the carotid artery to deliver either an emulsion of triglycerides [intralipid (IL)] or saline towards the brain for 24 hours. In experiment 3, for testing the role of capsaicin-sensitive nerves, experiment 2 was repeated following a periportal treatment with capsaicin or vehicle. RESULTS: In experiment 1, when compared to rats fed the control diet, rats fed the high-fat diet exhibited decreased insulin and glucose tolerance (P ≤ 0.05) that was restored with a glucose infusion in the portal vein (P ≤ 0.05). In experiment 2, infusion of a triglyceride emulsion towards the brain (IL rats) decreased insulin and glucose tolerance and increased hepatic endogenous production when compared to saline-infused rats (P ≤ 0.05). Glucose infusion in the portal vein in IL rats restored insulin and glucose tolerance, as well as hepatic glucose production, to controls levels (P ≤ 0.05). In experiment 3, portal infusion of glucose did not increase insulin tolerance in IL rats that received a periportal pretreatment with capsaicin. CONCLUSIONS: Stimulation of hepatoportal glucose sensors increases insulin tolerance in rat models of insulin resistance and requires the presence of capsaicin-sensitive nerves.

CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases.

Neuroinflammation was initially thought of as a consequence of neurodegenerative disease pathology, but more recently it is becoming clear that it plays a significant role in the development and progression of disease. Thus, neuroinflammation is seen as a realistic and valuable therapeutic target for neurodegeneration. Neuroinflammation can be modulated by neuron-glial signaling through various soluble factors, and one such critical modulator is Fractalkine or C-X3-C Motif Chemokine Ligand 1 (CX3CL1). CX3CL1 is produced in neurons and is a unique chemokine that is initially translated as a transmembrane protein but can be proteolytically processed to generate a soluble chemokine. CX3CL1 has been shown to signal through its sole receptor CX3CR1, which is located on microglial cells within the central nervous system (CNS). Although both the membrane bound and soluble forms of CX3CL1 appear to interact with CX3CR1, they do seem to have different signaling capabilities. It is believed that the predominant function of CX3CL1 within the CNS is to reduce the proinflammatory response and many studies have shown neuroprotective effects. However, in some cases CX3CL1 appears to be promoting neurodegeneration. This review focusses on presenting a comprehensive overview of the complex nature of CX3CL1/CX3CR1 signaling in neurodegeneration and how it may present as a therapeutic in some neurodegenerative diseases but not others. The role of CX3CL1/CXCR1 is reviewed in the context of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), ischemia, retinopathies, spinal cord and neuropathic pain, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy.

CCL2 Overexpression in the Brain Promotes Glial Activation and Accelerates Tau Pathology in a Mouse Model of Tauopathy.

Innate immune activation is a major contributor to Alzheimer's Disease (AD) pathophysiology, although the mechanisms involved are poorly understood. Chemokine C-C motif ligand (CCL) 2 is produced by neurons and glial cells and is upregulated in the AD brain. Transgene expression of CCL2 in mouse models of amyloidosis produces microglia-induced amyloid ß oligomerization, a strong indication of the role of these activation pathways in the amyloidogenic processes of AD. We have previously shown that CCL2 polarizes microglia in wild type mice. However, how CCL2 signaling contributes to tau pathogenesis remains unknown. To address this question, CCL2 was delivered via recombinant adeno-associated virus serotype 9 into both cortex and hippocampus of a mouse model with tau pathology (rTg4510). We report that CCL2 overexpression aggravated tau pathology in rTg4510 as shown by the increase in Gallyas stained neurofibrillary tangles as well as phosphorylated tau-positive inclusions. In addition, biochemical analysis showed a reduction in the levels of detergent-soluble tau species followed by increase in the insoluble fraction, indicating a shift toward larger tau aggregates. Indeed, increased levels of high molecular weight species of phosphorylated tau were found in the mice injected with CCL2. We also report that worsening of tau pathology following CCL2 overexpression was accompanied by a distinct inflammatory response. We report an increase in leukocyte common antigen (CD45) and Cluster of differentiation 68 (CD68) expression in the brain of rTg4510 mice without altering the expression levels of a cell-surface protein Transmembrane Protein 119 (Tmem119) and ionized calcium-binding adaptor molecule 1 (Iba-1) in resident microglia. Furthermore, the analysis of cytokines in brain extract showed a significant increase in interleukin (IL)-6 and CCL3, while CCL5 levels were decreased in CCL2 mice. No changes were observed in IL-1α, IL-1ß, TNF-α. IL-4, Vascular endothelial growth factor-VEGF, IL-13 and CCL11. Taken together our data report for the first time that overexpression of CCL2 promotes the increase of pathogenic tau species and is associated with glial neuroinflammatory changes that are deleterious. We propose that these events may contribute to the pathogenesis of Alzheimer's disease and other tauopathies.

Brain insulin response and peripheral metabolic changes in a Tau transgenic mouse model.

Accumulation of hyper-phosphorylated and aggregated Tau proteins is a neuropathological hallmark of Alzheimer's Disease (AD) and Tauopathies. AD patient brains also exhibit insulin resistance. Whereas, under normal physiological conditions insulin signaling in the brain mediates plasticity and memory formation, it can also regulate peripheral energy homeostasis. Thus, in AD, brain insulin resistance affects both cognitive and metabolic changes described in these patients. While a role of Aß oligomers and APOE4 towards the development of brain insulin resistance emerged, contribution of Tau pathology has been largely overlooked. Our recent data demonstrated that one of the physiological function of Tau is to sustain brain insulin signaling. We postulated that under pathological conditions, hyper-phosphorylated/aggregated Tau is likely to lose this function and to favor the development of brain insulin resistance. This hypothesis was substantiated by observations from patient brains with pure Tauopathies. To address the potential link between Tau pathology and brain insulin resistance, we have evaluated the brain response to insulin in a transgenic mouse model of AD-like Tau pathology (THY-Tau22). Using electrophysiological and biochemical evaluations, we surprisingly observed that, at a time when Tau pathology and cognitive deficits are overt and obvious, the hippocampus of THY-Tau22 mice exhibits enhanced response to insulin. In addition, we demonstrated that the ability of i.c.v. insulin to promote body weight loss is enhanced in THY-Tau22 mice. In line with this, THY-Tau22 mice exhibited a lower body weight gain, hypoleptinemia and hypoinsulinemia and finally a metabolic resistance to high-fat diet. The present data highlight that the brain of transgenic Tau mice exhibit enhanced brain response to insulin. Whether these observations are ascribed to the development of Tau pathology, and therefore relevant to human Tauopathies, or unexpectedly results from the Tau transgene overexpression is debatable and discussed.

Tau, Diabetes and Insulin.

Tau protein which was discovered in 1975 [310] became of great interest when it was identified as the main component of neurofibrillary tangles (NFT), a pathological feature in the brain of patients with Alzheimer's disease (AD) [39, 110, 232]. Tau protein is expressed mainly in the brain as six isoforms generated by alternative splicing [46, 97]. Tau is a microtubule associated proteins (MAPs) and plays a role in microtubules assembly and stability, as well as diverse cellular processes such as cell morphogenesis, cell division, and intracellular trafficking [49]. Additionally, Tau is involved in much larger neuronal functions particularly at the level of synapses and nuclei [11, 133, 280]. Tau is also physiologically released by neurons [233] even if the natural function of extracellular Tau remains to be uncovered (see other chapters of the present book).

[Brain insulin signaling and Tau: impact for Alzheimer's disease and Tauopathies]. / Relation mutuelle entre Tau et signalisation centrale de l'insuline - Quelles conséquences pour la maladie d'Alzheimer et les tauopathies ?

Alzheimer's disease (AD) is a neurodegenerative disease primarily characterized by cognitive deficits and neuropathological lesions such as Tau aggregates and amyloid plaques, but also associated with metabolic and neuroendocrine abnormalities, such as impairment of cerebral insulin. However, the origin of these symptoms and their relationship to pathology and cognitive disorders remain poorly understood. Insulin is a hormone involved in the control of peripheral and central energy homeostasis, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that brain insulin resistance can exacerbate Tau lesions. Conversely, recent data indicate that Tau protein can modulate insulin signalling in the brain, creating a vicious circle precipitating the pathological AD. This review aims to highlight our current understanding of the role of insulin in the brain and its relationship with Tau protein in the context of AD and Tauopathies.

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

Alzheimer disease (AD) is a progressive neurodegenerative disorder mainly characterized by cognitive deficits and neuropathological changes such as Tau lesions and amyloid plaques, but also associated with non-cognitive symptomatology. Metabolic and neuroendocrine abnormalities, such as alterations in body weight, brain insulin impairments, and lower brain glucose metabolism, which often precede clinical diagnosis, have been extensively reported in AD patients. However, the origin of these symptoms and their relation to pathology and cognitive impairments remain misunderstood. Insulin is a hormone involved in the control of energy homeostasis both peripherally and centrally, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that insulin resistance can exacerbate Tau lesions, mainly by disrupting the balance between Tau kinases and phosphatases. On the other hand, the emerging literature indicates that Tau protein can also modulate insulin signalling in the brain, thus creating a detrimental vicious circle. The following review will highlight our current understanding of the role of insulin in the brain and its relation to Tau protein in the context of AD and tauopathies. Considering that insulin signalling is prone to be pharmacologically targeted at multiple levels, it constitutes an appealing approach to improve both insulin brain sensitivity and mitigate brain pathology with expected positive outcome in terms of cognition.

Oligomeric tau-targeted immunotherapy in Tg4510 mice.

BACKGROUND: Finding ways to reverse or prevent the consequences of pathogenic tau in the brain is of considerable importance for treatment of Alzheimer's disease and other tauopathies. Immunotherapy against tau has shown promise in several mouse models. In particular, an antibody with selectivity for oligomeric forms of tau, tau oligomer monoclonal antibody (TOMA), has shown rescue of the behavioral phenotype in several murine models of tau deposition. METHODS: In this study, we examined the capacity of TOMA to rescue the behavioral, histological, and neurochemical consequences of tau deposition in the aggressive Tg4510 model. We treated mice biweekly with 60 µg TOMA i.p. from 3.5 to 8 months of age. RESULTS: Near the end of the treatment, we found that oligomeric tau was elevated in both the CSF and in plasma. Further, we could detect mouse IgG in Tg4510 mouse brain after TOMA treatment, but not after injection with mouse IgG1 as control. However, we did not find significant reductions in behavioral deficits or tau deposits by either histological or biochemical measurements. CONCLUSIONS: These data suggest that there is some exposure of the Tg4510 mouse brain to TOMA, but it was inadequate to affect the phenotype in these mice at the doses used. These data are consistent with other observations that the rapidly depositing Tg4510 mouse is a challenging model in which to demonstrate efficacy of tau-lowering treatments compared to some other preclinical models of tau deposition/overexpression.

Disruption of normal circadian clock function in a mouse model of tauopathy.

Disruption of normal circadian rhythm physiology is associated with neurodegenerative disease, which can lead to symptoms such as altered sleep cycles. In Alzheimer's disease (AD), circadian dysfunction has been attributed to ß-amyloidosis. However, it is unclear whether tauopathy, another AD-associated neuropathology, can disrupt the circadian clock. We have evaluated the status of the circadian clock in a mouse model of tauopathy (Tg4510). Tg4510 mice display a long free-running period at an age when tauopathy is present, and show evidence of tauopathy in the suprachiasmatic nucleus (SCN) of the hypothalamus - the site of the master circadian clock. Additionally, cyclic expression of the core clock protein PER2 is disrupted in the hypothalamus of Tg4510 mice. Finally, disruption of the cyclic expression of PER2 and BMAL1, another core circadian clock protein, is evident in the Tg4510 hippocampus. These results demonstrate that tauopathy disrupts normal circadian clock function both at the behavioral and molecular levels, which may be attributed to the tauopathy-induced neuropathology in the SCN. Furthermore, these results establish the Tg4510 mouse line as a model to study how tauopathy disrupts normal circadian rhythm biology.

Metabolic changes over the course of aging in a mouse model of tau deposition.

Weight loss and food intake disturbances that often precede cognitive decline and diagnosis have been extensively reported in Alzheimer's disease patients. Previously, we observed that transgenic mice overexpressing tau seemed to eat more food yet weigh less than nontransgenic littermates. Thus, the present longitudinal study measured the time course of changes in metabolic state over the lifespan of the tau depositing Tg4510 mouse model of tau deposition. Although body weight was comparable to nontransgenic littermates at 2 months of age, Tg4510 mice weighed less at older ages. This was accompanied by the accumulation of tau pathology and by dramatically increased activity in all phases of the 24-hour cycle. Resting metabolic rate was also increased at 7 months of age. At 12 months near the end of the Tg4510 lifespan, there was a wasting phase, with a considerable decrease of resting metabolic rate, although hyperactivity was maintained. These diverse changes in metabolism in a mouse model of tau deposition are discussed in the context of known changes in energy metabolism in Alzheimer's disease.