A novel role of microglial NADPH oxidase in mediating extra‐synaptic function of norepinephrine in regulating brain immune homeostasis

Although the peripheral anti‐inflammatory effect of norepinephrine (NE) is well documented, the mechanism by which this neurotransmitter functions as an anti‐inflammatory/neuroprotective agent in the central nervous system (CNS) is unclear. This article aimed to determine the anti‐inflammatory/neuroprotective effects and underlying mechanisms of NE in inflammation‐based dopaminergic neurotoxicity models. In mice, NE‐depleting toxin N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4) was injected at 6 months of lipopolysaccharide (LPS)‐induced neuroinflammation. It was found that NE depletion enhanced LPS‐induced dopaminergic neuron loss in the substantia nigra. This piece of in vivo data prompted us to conduct a series of studies in an effort to elucidate the mechanism as to how NE affects dopamine neuron survival by using primary midbrain neuron/glia cultures. Results showed that submicromolar concentrations of NE dose‐dependently protected dopaminergic neurons from LPS‐induced neurotoxicity by inhibiting microglia activation and subsequent release of pro‐inflammatory factors. However, NE‐elicited neuroprotection was not totally abolished in cultures from β2‐adrenergic receptor (β2‐AR)‐deficient mice, suggesting that novel pathways other than β2‐AR are involved. To this end, It was found that submicromolar NE dose‐dependently inhibited NADPH oxidase (NOX2)‐generated superoxide, which contributes to the anti‐inflammatory and neuroprotective effects of NE. This novel mechanism was indeed adrenergic receptors independent since both (+) and (?) optic isomers of NE displayed the same potency. We further demonstrated that NE inhibited LPS‐induced NOX2 activation by blocking the translocation of its cytosolic subunit to plasma membranes. In summary, we revealed a potential physiological role of NE in maintaining brain immune homeostasis and protecting neurons via a novel mechanism. GLIA 2015;63:1057–1072     

TGF‐β1 Pathway as a New Target for Neuroprotection in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 37 million people worldwide. Current drugs for AD are only symptomatic, but do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of ß‐amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. The identification of the molecular determinants underlying AD pathogenesis is a fundamental step to design new disease‐modifying drugs. Recently, a specific impairment of transforming‐growth‐factor‐β1 (TGF‐β1) signaling pathway has been demonstrated in AD brain. The deficiency of TGF‐β1 signaling has been shown to increase both Aβ accumulation and Aβ‐induced neurodegeneration in AD models. The loss of function of TGF‐ß1 pathway seems also to contribute to tau pathology and neurofibrillary tangle formation. Growing evidence suggests a neuroprotective role for TGF‐β1 against Aβ toxicity both in vitro and in vivo models of AD. Different drugs, such as lithium or group II mGlu receptor agonists are able to increase TGF‐β1 levels in the central nervous system (CNS), and might be considered as new neuroprotective tools against Aβ‐induced neurodegeneration. In the present review, we examine the evidence for a neuroprotective role of TGF‐β1 in AD, and discuss the TGF‐β1 signaling pathway as a new pharmacological target for the treatment of AD.     

[Gly14]‐humanin rescues long‐term potentiation from amyloid β protein‐induced impairment in the rat hippocampal CA1 region in vivo

The novel neuroprotective action of Humanin (HN), especially its derivative [Gly¹⁴]‐humanin (HNG), against Alzheimer's disease (AD)‐related insults has been reported. However, it is still short of electrophysiological evidence for the protection of HN on synaptic plasticity, and the molecular mechanisms that underlie the neuroprotective function of HN remain largely unknown. The present study examined the effects of intracerebroventricular (i.c.v.) injection of HNG on amyloid β (Aβ), a main constituent of senile plaques in the AD brain, induced suppression of long‐term potentiation (LTP) in the rat hippocampal CA1 region in vivo and investigated the possible mechanism of HNG in LTP protection. We found that application of Aβ fragments 25–35 (Aβ25–35) and 31–35 (Aβ31–35) significantly inhibited high frequency stimulation‐induced LTP, while HNG effectively prevented the suppression of LTP induced by Aβ fragments in a dose‐dependent manner. After pretreatment with Genistein, a tyrosine kinase inhibitor, the protective action of HNG on LTP was nearly completely abolished. Therefore, the present study demonstrated for the first time that HNG could protect against the neurotoxic Aβ‐induced hippocampal LTP impairment and the tyrosine kinase pathway was involved in the neuroprotective action of HNG, suggesting that HNG might be one of the promising candidates for the treatment of AD in the future. Synapse 64:83–91, 2010. © 2009 Wiley‐Liss, Inc.     

Colivelin ameliorates amyloid β peptide‐induced impairments in spatial memory,synaptic plasticity,and calcium homeostasis in rats

Amyloid β peptide (Aβ) has been thought to be neurotoxic and responsible for the impairment of learning and memory in Alzheimer's disease (AD). Humanin (HN), a 24 amino acid polypeptide first identified from the unaffected occipital lobe of an AD patient, is believed to be neuroprotective against the AD‐related neurotoxicity. In this study, we investigated the neuroprotective effects of Colivelin (CLN), a novel HN derivative, against Aβ by using behavioral test, in vivo electrophysiological recording, and intracellular calcium imaging. Our results showed that intrahippocampal injection of CLN (0.2 nmol) effectively prevented Aβ25–35 (4 nmol)‐induced deficits in spatial learning and memory of rats in Morris water maze test; the suppression of in vivo hippocampal long term potentiation (LTP) by Aβ25–35 was nearly completely prevented by CLN; in addition, CLN pretreatment also effectively inhibited Aβ25–35–induced calcium overload in primary cultured hippocampal neurons. These results indicate that CLN has significant neuroprotective properties against Aβ, and CLN may holds great promise for the treatment and prevention of AD. © 2014 Wiley Periodicals, Inc.     

Recurrent systemic infections with Streptococcus pneumoniae do not aggravate the course of experimental neurodegenerative diseases

Neurological symptoms of patients suffering from neurodegenerative diseases such as Alzheimer's dementia (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) often worsen during infections. We assessed the disease‐modulating effects of recurrent systemic infections with the most frequent respiratory pathogen, Streptococcus pneumoniae, on the course of AD, PD, and ALS in mouse models of these neurodegenerative diseases [transgenic Tg2576 mice, (Thy1)‐[A30P]αSYN mice, and Tg(SOD1‐G93A) mice]. Mice were repeatedly challenged intraperitoneally with live S. pneumoniae type 3 and treated with ceftriaxone for 3 days. Infection caused an increase of interleukin‐6 concentrations in brain homogenates. The clinical status of (Thy1)‐[A30P]αSYN mice and Tg(SOD1‐G93A) mice was monitored by repeated assessment with a clinical score. Motor performance was controlled by the tightrope test and the rotarod test. In Tg2576 mice, spatial memory and learning deficits were assessed in the Morris water maze. In none of the three mouse models onset or course of the disease as evaluated by the clinical tests was affected by the recurrent systemic infections performed. Levels of α‐synuclein in brains of (Thy1)‐[A30P]αSYN mice did not differ between infected animals and control animals. Plaque sizes and concentrations of Aβ 1–40 and Aβ 1–42 were not significantly different in brains of infected and uninfected Tg2576 mice. In conclusion, onset and course of disease in mouse models of three common neurodegenerative disorders were not influenced by repeated systemic infections with S. pneumoniae, indicating that the effect of moderately severe acute infections on the course of neurodegenerative diseases may be less pronounced than suspected. © 2009 Wiley‐Liss, Inc.     

Simultaneous Manipulation of Multiple Brain Targets by Green Tea Catechins: A Potential Neuroprotective Strategy for Alzheimer and Parkinson Diseases

Current therapeutic approaches for Alzheimer and Parkinson disease (AD and PD, respectively) are merely symptomatic, intended for the treatment of symptoms, but offer only partial benefit, without any disease‐modifying activity. Novel promising strategies suggest the use of antiinflammatory drugs, antioxidants, iron‐complexing molecules, neurotrophic factor delivery, inhibitors of the amyloid precursor protein (APP)‐processing secretases, gamma and beta (that generate the amyloid‐beta peptides, Aβ), anti‐Aβ aggregation molecules, the interference with lipid cholesterol metabolism and naturally occurring plant flavonoids to potentially reverse the course of the diseases. Human epidemiological and new animal data suggest that tea drinking may decrease the incidence of dementia, AD, and PD. In particular, its main catechin polyphenol constituent (‐)‐epigallocatechin‐3‐gallate (EGCG) has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders. In the current article, we review the literature on the impact of the multimodal activities of green tea polyphenols and their neuroprotective effect on AD and PD.     

Mulberroside a protects against ischemic impairment in primary culture of rat cortical neurons after oxygen–glucose deprivation followed by reperfusion

Mulberroside A is a natural polyhydroxylated stilbene compound present at relatively high abundance in the roots and twigs of Morus alba L. It is known for its nephroprotective, hypoglycemic, and antidiabetic effects. Because its metabolite, oxyresveratrol, possessed purported anti‐inflammatory and neuroprotective effects, we proposed that mulberroside A may elicit neuroprotective effects that can be used in the treatment of brain ischemic injury. Therefore, we decided to investigate the pharmacological properties of mulberroside A in primary culture of rat cortical neurons after oxygen–glucose deprivation followed by reperfusion (OGD/R), evaluating its ability to counteract the hypoxia–ischemia impairment. The results showed that mulberroside A elicited neuroprotective effects comparable to nimodipine. The mechanistic studies showed that mulberroside A decreased the expressions of tumor necrosis factor‐α (TNF‐α), interleukin (IL)?1β, and IL‐6 and inhibited the activation of NALP3, caspase‐1, and nuclear factor‐κB and the phosphorylation of extracellular signal‐regulated protein kinases, the c‐Jun N‐terminal kinase, and p38, exhibiting anti‐inflammatory antiapoptotic effects. Our results also further demonstrate that the proinflammatory cytokines of IL‐1β, IL‐6, and TNF‐α are promising targets for treatment of cerebral ischemic injury. Although further investigation is required for its development, all of these findings led us to speculate that mulberroside A is a candidate for the treatment of ischemic stroke, which would act as a multifactorial neuroprotectant. © 2014 Wiley Periodicals, Inc.     

Memantine protects rat cortical cultured neurons against β‐amyloid‐induced toxicity by attenuating tau phosphorylation

It has been suggested that accumulation of beta‐amyloid (Aβ) peptide triggers neurodegeneration, at least in part, via glutamate‐mediated excitotoxicity in Alzheimer’s disease (AD) brain. This is supported by observations that toxicity induced by Aβ peptide in cultured neurons and in adult rat brain is known to be mediated by activation of glutamatergic N‐methyl‐d ‐aspartate (NMDA) receptors. Additionally, recent clinical studies have shown that memantine, a noncompetitive NMDA receptor antagonist, can significantly improve cognitive functions in some AD patients. However, very little is currently known about the potential role of memantine against Aβ‐induced toxicity. In the present study, we have shown that Aβ_1–42‐induced toxicity in rat primary cortical cultured neurons is accompanied by increased extracellular and decreased intracellular glutamate levels. We subsequently demonstrated that Aβ toxicity is induced by increased phosphorylation of tau protein and activation of tau kinases, i.e. glycogen synthase kinase‐3β and extracellular signal‐related kinase 1/2. Additionally, Aβ treatment induced cleavage of caspase‐3 and decreased phosphorylation of cyclic AMP response element binding protein, which are critical in determining survival of neurons. Memantine treatment significantly protected cultured neurons against Aβ‐induced toxicity by attenuating tau‐phosphorylation and its associated signaling mechanisms. However, this drug did not alter either conformation or internalization of Aβ_1–42 and it was unable to attenuate Aβ‐induced potentiation of extracellular glutamate levels. These results, taken together, provide new insights into the possible neuroprotective action of memantine in AD pathology.     

Acyl ghrelin improves cognition,synaptic plasticity deficits and neuroinflammation following amyloid β (Aβ1‐40) administration in mice

Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild‐type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid β peptide 1‐40 (Aβ_1‐40) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aβ_1‐40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y‐maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aβ_1‐40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aβ_1‐40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aβ_1‐40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium‐binding adapter expressing microglial in the rostral hippocampus. Finally, Aβ_1‐40 blocked long‐term potentiation induced by high‐frequency stimulation and this effect could be acutely blocked with co‐administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD.     

Baicalein reduces β‐amyloid and promotes nonamyloidogenic amyloid precursor protein processing in an Alzheimer's disease transgenic mouse model

Baicalein, a flavonoid isolated from the roots of Scutellaria baicalensis, is known to modulate γ‐aminobutyric acid (GABA) type A receptors. Given prior reports demonstrating benefits of GABA_A modulation for Alzheimer's disease (AD) treatment, we wished to determine whether this agent might be beneficial for AD. CHO cells engineered to overexpress wild‐type amyloid precursor protein (APP), primary culture neuronal cells from AD mice (Tg2576) and AD mice were treated with baicalein. In the cell cultures, baicalein significantly reduced the production of β‐amyloid (Aβ) by increasing APP α‐processing. These effects were blocked by the GABA_A antagonist bicuculline. Likewise, AD mice treated daily with i.p. baicalein for 8 weeks showed enhanced APP α‐secretase processing, reduced Aβ production, and reduced AD‐like pathology together with improved cognitive performance. Our findings suggest that baicalein promotes nonamyloidogenic processing of APP, thereby reducing Aβ production and improving cognitive performance, by activating GABA_A receptors. © 2013 Wiley Periodicals, Inc.     

Death‐associated protein kinase (DAPK1) in cerebral cortex of late‐onset Alzheimer's disease patients and aged controls

A. H. Hainsworth, R. C. Allsopp, A. Jim, J. F. Potter, J. Lowe, C. J. Talbot and R. J. Prettyman (2010) Neuropathology and Applied Neurobiology 36, 17–24
Death‐associated protein kinase (DAPK1) in cerebral cortex of late‐onset Alzheimer's disease patients and aged controls Aims: Here our objective was to detect the pro‐apoptotic serine/threonine kinase death‐associated protein kinase (DAPK1) in aged human cerebral cortex and to test the hypothesis that DAPK1 abundance is associated with late‐onset Alzheimer's disease (AD). Methods: Using Western analysis and immunohistochemistry we evaluated post mortem frontal cerebral cortex from patients with severe AD (mean age 76 years, range 66–91, n = 11, all male), and from control cases without serious central nervous system illness (mean age 77 years, range 61–95, n = 12, all male). We also examined brains of Tg2576 transgenic mice (males, aged 16–21 months), a model for chronic amyloid‐induced brain injury. Results: Immunohistochemical labelling showed DAPK1 expression in cortical neurones of human cortex and axonal tracts within subcortical white matter, both in AD and in control brains. Western analysis confirmed DAPK1 expression in all samples, although expression was very low in some control cases. DAPK1 abundance in the AD group was not significantly different from that in controls (P = 0.07, Mann–Whitney test). In brains of Tg2576 mice DAPK1 abundance was very similar to that in wild‐type littermates (P = 0.96, Mann–Whitney test). Conclusion: We found that DAPK1 was expressed in neurones of aged human frontal cortex, both in AD and in control cases.     

Mechanisms and effects of curcumin on spatial learning and memory improvement in APPswe/PS1dE9 mice

Evidence suggests that curcumin, the phytochemical agent in the spice turmeric, might be a potential therapy for Alzheimer's disease (AD). Its antioxidant, anti‐inflammatory properties have been investigated extensively. Studies have also shown that curcumin can reduce amyloid pathology in AD. The underlying mechanism, however, is complex and is still being explored. In this study, we used the APPswe/PS1dE9 double transgenic mice, an AD model, to investigate the effects and mechanisms of curcumin in the prevention and treatment of AD. The water maze test indicated that curcumin can improve spatial learning and memory ability in mice. Immunohistochemical staining and Western blot analysis were used to test major proteins in β‐amyloid aggregation, β‐amyloid production, and β‐amyloid clearance. Data showed that, 3 months after administration, curcumin treatment reduced Aβ₄₀, Aβ₄₂, and aggregation of Aβ‐derived diffusible ligands in the mouse hippocampal CA1 area; reduced the expression of the γ‐secretase component presenilin‐2; and increased the expression of β‐amyloid‐degrading enzymes, including insulin‐degrading enzymes and neprilysin. This evidence suggests that curcumin, as a potential AD therapeutic method, can reduce β‐amyloid pathological aggregation, possibly through mechanisms that prevent its production by inhibiting presenilin‐2 and/or by accelerating its clearance by increasing degrading enzymes such as insulin‐degrading enzyme and neprilysin. © 2013 Wiley Periodicals, Inc.     

Glucosamine exerts a neuroprotective effect via suppression of inflammation in rat brain ischemia/reperfusion injury

We investigated the neuroprotective effect of glucosamine (GlcN) in a rat middle cerebral artery occlusion model. At the highest dose used, intraperitoneal GlcN reduced infarct volume to 14.3% ± 7.4% that of untreated controls and afforded a reduction in motor impairment and neurological deficits. Neuroprotective effects were not reproduced by other amine sugars or acetylated‐GlcN, and GlcN suppressed postischemic microglial activation. Moreover, GlcN suppressed lipopolysaccharide (LPS)‐induced upregulation of proinflammatory mediators both in vivo and in culture systems using microglial or macrophage cells. The anti‐inflammatory effects of GlcN were mainly attributable to its ability to inhibit nuclear factor kappaB (NF‐κB) activation. GlcN inhibited LPS‐induced nuclear translocation and DNA binding of p65 to both NF‐κB consensus sequence and NF‐κB binding sequence of inducible nitric oxide synthase promoter. In addition, we found that GlcN strongly repressed p65 transactivation in BV2 cells using Gal4‐p65 chimeras system. P65 displayed increased O‐GlcNAcylation in response to LPS; this effect was also reversed by GlcN. The LPS‐induced increase in p65 O‐GlcNAcylation was paralleled by an increase in interaction with O‐GlcNAc transferase, which was reversed by GlcN. Finally, our results suggest that GlcN or its derivatives may serve as novel neuroprotective or anti‐inflammatory agents. © 2010 Wiley‐Liss, Inc.     

Microsomal prostaglandin E synthase‐1 is induced in alzheimer's disease and its deletion mitigates alzheimer's disease‐like pathology in a mouse model

Epidemiological studies have suggested that long‐term use of nonsteroidal anti‐inflammatory drugs that inhibit cyclooxygenase (COX) activity can moderate the onset or progression of Alzheimer's disease (AD). Thus it has been suggested that prostaglandin E₂ (PGE₂), a major end‐product of COX, may play a pathogenic role in AD, but the involvement of PGE synthase (PGES), a terminal enzyme downstream from COX, has not been fully elucidated. Here we found that, among three PGES enzymes, only microsomal PGES‐1 (mPGES‐1) is induced, and its expression is associated with β‐amyloid (Aβ) plaques in the cerebral cortex in human AD patients and in Tg2576 mice, a transgenic AD mouse model. Furthermore, to investigate whether mPGES‐1 contributes to AD‐like pathology, we bred mPGES‐1‐deficient mice with Tg2576 mice. We found that mPGES‐1 deletion reduced the accumulation of microglia around senile plaques and attenuated learning impairments in Tg2576 mice. These results indicated that mPGES‐1 is induced in the AD brain and thus plays a role in AD pathology. Blockage of mPGES‐1 could form the basis for a novel therapeutic strategy for patients with AD. Inc. © 2013 Wiley Periodicals, Inc.     

Methyl 3,4‐dihydroxybenzoate protects primary cortical neurons against Aβ25–35‐induced neurotoxicity through mitochondria pathway

Amyloid‐β peptides (Aβ), which can aggregate into oligomers or fibrils in neurons, play a critical role in the pathogenesis of Alzheimer's disease (AD). Methyl 3,4‐dihydroxybenzoate (MDHB), a phenolic acid compound, has been reported to have antioxidative and neurotrophic effects. The present study investigated the neuroprotective effects of MDHB against Aβ‐induced apoptosis in rat primary cortical neutons. The primary cortical neurons were pretreated with different concentrations of MDHB for 24 hr, then incubated with 10 μM Aβ_25–35 for 24 hr. The results showed that Aβ_25–35 could induce neurotoxicity as evidenced by the decreased cell viability and the increased apoptotic rate. In parallel, Aβ_25–35 significantly increased the reactive oxygen species accumulation and decreased mitochondrial membrane potential. However, pretreatment of the primary cortical neurons with MDHB could effectively suppress these cellular events caused by Aβ_25–35 exposure. In addition, MDHB could increase the level of Bcl‐2, decrease the level of Bax, and inhibit the activation of caspase‐9 and caspase‐3 in Aβ_25–35‐treated primary cortical neurons. All these results were beneficial in their protective effect against Aβ‐induced neurotoxicity. Our results suggest that MDHB has a neuroprotective effect that provides a pharmacological basis for its clinical use in the treatment of AD. © 2013 Wiley Periodicals, Inc.     

Locally reduced levels of acidic FGF lead to decreased expression of 28‐kDa calbindin and contribute to the selective vulnerability of the neurons in the entorhinal cortex in Alzheimer's disease

Recent studies demonstrate that a disturbed calcium‐homeostasis leading to increased susceptibility to excitotoxic triggers plays a major role in the neurodegenerative process initiating in layer 2 of the entorhinal cortex (EC2) during Alzheimer's disease (AD). Thus, proteins binding free Ca ¹¹ (i.e. calbindin) and factors regulating these proteins are of great importance for the neuroprotective–neurotoxic balance in the affected brain regions. In the present combined human and in vitro study evidence is provided that altered levels of the acidic fibroblast growth factor (aFGF) and calbindin expression are concomitantly present in EC2 neurons and have interactive effects. A dramatic loss of aFGF‐ and calbindin‐labeled EC2 neurons was found. Further analysis of the surviving EC2 neurons revealed a strong immunoreactivity to calbindin and aFGF. In vitro experiments show that aFGF regulates calbindin expression, because treatment of differentiating neurons with recombinant aFGF increases calbindin expression in a time‐dependent fashion. The data imply that a reduced expression of aFGF in EC2 neurons of AD brains leads to lower levels of calbindin resulting in decreased neuroprotective capacity.     

Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease

Alzheimer's disease (AD) is the most common progressive dementia and is pathologically characterized by brain deposition of amyloid‐β (Aβ) peptide as senile plaques. Inflammatory and immune response pathways are chronically activated in AD patient brains at low levels, and likely play a role in disease progression. Like microglia, activated astrocytes produce numerous acute‐phase reactants and proinflammatory molecules in the AD brain. One such molecule, S100B, is highly expressed by reactive astrocytes in close vicinity of β‐amyloid deposits. We have previously shown that augmented and prolonged activation of astrocytes has a detrimental impact on neuronal survival. Furthermore, we have implicated astrocyte‐derived S100B as a candidate molecule responsible for this deleterious effect. To evaluate a putative relationship between S100B and AD pathogenesis, we crossed transgenic mice overexpressing human S100B (TghuS100B mice) with the Tg2576 mouse model of AD, and examined AD‐like pathology. Brain parenchymal and cerebral vascular β‐amyloid deposits and Aβ levels were increased in bigenic Tg2576‐huS100B mice. These effects were associated with increased cleavage of the β‐C‐terminal fragment of amyloid precursor protein (APP), elevation of the N‐terminal APP cleavage product (soluble APPβ), and activation of β‐site APP cleaving enzyme 1. In addition, double transgenic mice showed augmented reactive astrocytosis and microgliosis, high levels of S100 expression, and increased levels of proinflammatory cytokines as early as 7–9 months of age. These results provide evidence that (over)‐expression of S100B acts to accelerate AD‐like pathology, and suggest that inhibiting astrocytic activation by blocking S100B biosynthesis may be a promising therapeutic strategy to delay AD progression. © 2009 Wiley‐Liss, Inc.     

Kainate‐induced toxicity in the hippocampus: potential role of lithium

Crespo‐Biel N, Camins A, Canudas AM, Pallàs M. Kainate‐induced toxicity in the hippocampus: potential role of lithium.
Bipolar Disord 2010: 12: 425–436. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: We investigated the neuroprotective effects of lithium in an experimental neurodegeneration model gated to kainate (KA) receptor activation. Methods: The hippocampus from KA‐treated mice and hippocampal cell cultures were used to evaluate the pathways regulated by chronic lithium pretreatment in both in vivo and in vitro models. Results: Treatment with KA, as measured by fragmentation of α‐spectrin and biochemically, induced the activation of calpain resulting in p35 cleavage to p25, indicating activation of cyclin‐dependent kinase 5 (cdk5) and glycogen synthase kinase‐3ß (GSK‐3ß) and an increase in tau protein phosphorylation. Treatment with lithium reduced calpain activation and reduced the effects of cdk5 and GSK‐3ß on tau. KA treatment of cultures resulted in neuronal demise. According to nuclear condensed cell counts, the addition of lithium to neuronal cell cultures (0.5–1 mM) a few days before KA treatment had neuroprotective and also antiapoptotic effects. The action of lithium on calpain/cdk5 and GSK‐3ß pathways produced similar results in vivo. As calpain is activated by an increase in intracellular calcium, we showed that lithium reduced calcium concentrations in basal and KA‐treated hippocampal cells, which was accompanied by an increase in NCX3, a Na⁺/Ca²⁺ exchanger pump. Conclusion: A robust neuroprotective effect of lithium in the excitotoxic process induced by KA in mouse hippocampus was demonstrated via modulation of calcium entry and the subsequent inhibition of the calpain pathway. These mechanisms may act in an additive way with other mechanisms previously described for lithium, suggesting that it may be useful as a possible therapeutic strategy for Alzheimer’s disease.     

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Tobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side‐effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side‐effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid‐beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro‐survival factors such as Akt, and the inhibition of pro‐apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD.     

Microglial CX3CR1 production increases in Alzheimer's disease and is regulated by noradrenaline

The loss of noradrenergic neurons and subsequent reduction of brain noradrenaline (NA) levels are associated with the progression of Alzheimer's disease (AD). This seems to be due mainly to the ability of NA to reduce the activation of microglial cells. We previously observed that NA induces the production of the chemokine Fractalkine/CX3CL1 in neurons. The activation of microglial CX3CR1, sole receptor for CX3CL1, reduces the activation of microglia, which is known to largely contribute to the neuronal damage characteristic of AD. Therefore, alterations of CX3CR1 production in microglia could translate into the enhancement or inhibition of CX3CL1 anti‐inflammatory effects. In order to determine if microglial CX3CR1 production is altered in AD and if NA can control it, CX3CR1 expression and synthesis were analyzed in 5xFAD mice and human AD brain samples. In addition, the effects of NA and its reuptake inhibitor reboxetine were analyzed in microglial cultures and mice respectively. Our results indicate that in AD CX3CR1 production is increased in the brain cortex and that reboxetine administration further increases it and enhances microglial reactivity toward amyloid beta plaques. However, direct administration of NA to primary rat microglia or human HMC3 cells inhibits CX3CR1 production, suggesting that microglia responses to NA may be altered in the absence of CX3CL1‐producing neurons or other nonmicroglial external factors.