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.     

Lysosomal trafficking defects link Parkinson's disease with Gaucher's disease

Lysosomal dysfunction has been implicated in multiple diseases, including lysosomal storage disorders such as Gaucher's disease, in which loss‐of‐function mutations in the GBA1 gene encoding the lysosomal hydrolase β‐glucocerebrosidase result in lipid substrate accumulation. In Parkinson's disease, α‐synuclein accumulates in Lewy bodies and neurites contributing to neuronal death. Previous clinical and genetic evidence has demonstrated an important link between Parkinson's and Gaucher's disease, as GBA1 mutations and variants increase the risk of Parkinson's and Parkinson's patients exhibit decreased β‐glucocerebrosidase activity. Using human midbrain neuron cultures, we have found that loss of β‐glucocerebrosidase activity promotes α‐synuclein accumulation and toxicity, whereas α‐synuclein accumulation further contributes to decreased lysosomal β‐glucocerebrosidase activity by disrupting β‐glucocerebrosidase trafficking to lysosomes. Moreover, α‐synuclein accumulation disrupts trafficking of additional lysosomal hydrolases, further contributing to lysosomal dysfunction and neuronal dyshomeostasis. Importantly, promoting β‐glucocerebrosidase activity reduces α‐synuclein accumulation and rescues lysosomal and neuronal dysfunction, suggesting that β‐glucocerebrosidase may be an important therapeutic target for advancing drug discovery in synucleinopathies including Parkinson's disease. © 2016 International Parkinson and Movement Disorder Society.     

Correlation of striatal dopamine transporter imaging with post mortem substantia nigra cell counts

Dopamine transporter imaging is widely used for the differential diagnosis of parkinsonism. Only limited data are available on the relationship between striatal dopamine transporter binding and dopaminergic cell loss in the substantia nigra (SN). We analyzed postmortem SN cell counts in patients who had previously undergone dopamine transporter single‐photon emission computed tomography (SPECT). Pathological diagnoses included Parkinson's disease (n = 1), dementia with Lewy bodies (n = 2), multiple system atrophy (n = 1), corticobasal degeneration (n = 2), atypical parkinsonism with multiple pathological conditions (n = 1), Alzheimer's disease (n = 1), and Creutzfeldt‐Jakob disease (n = 1). [¹²³I]β‐CIT SPECT had been performed in all subjects using a standardized protocol on the same triple‐head gamma camera. The density of neuromelanin‐containing and tyrosine hydroxylase–positive substantia nigra neurons/mm² was evaluated in paraffin‐embedded tissue sections by morphometric methods. Mean disease duration at the time of dopamine transporter imaging was 2.3 years, and the mean interval from imaging to death was 29.3 months (range, 4‐68 months). Visual analysis of dopamine transporter images showed reduced striatal uptake in all seven patients with neurodegenerative parkinsonism, but not in Alzheimer's and Creutzfeldt‐Jakob disease cases. Averaged [(right+left)/2] striatal uptake was highly correlated with averaged SN cell counts (r_s = 0.98, P < 0.0005 for neuromelanin‐ and r_s = 0.96, P < 0.0005 for tyrosine hydroxylase–positive cells). Similar strong correlations were found in separate analyses for the right and left sides. Striatal dopamine transporter binding highly correlated with postmortem SN cell counts, confirming the validity of dopamine transporter imaging as an excellent in vivo marker of nigrostriatal dopaminergic degeneration. © 2014 International Parkinson and Movement Disorder Society     

Lithium and Autophagy

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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.     

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.     

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.     

Differential regulation of AKT, MAPK and GSK3β during C2-ceramide-induced neuronal death

Evidence has implicated apoptosis as a mechanism underlying cell demise in diverse neurodegenerative diseases including Parkinson's disease (PD). Endogenous toxins and other stress signals activate the sphingomyelin pathway increasing the levels of ceramide, an important regulator of cell death.In the present paper we have analysed the contribution of PI3K/AKT-GSK3β and MAPK (ERK and JNK) pathways to cell death in a catecholaminergic cell line following exposure to C₂-ceramide. We also explored the potential neuroprotective action of insulin-like growth factor-1 (IGF-1) and neurotrophin-3 (NT3).We demonstrated that C₂-ceramide-induced cell death is associated to an early decrease in phosphorylation (inhibition) of PI3K/AKT and ERK, followed by phosphorylation (activation) of JNK and de-phosphorylation (activation) of glycogen synthase kinase-3 beta (GSK3β). NT3 and IGF-1 increased survival at early time points, but only IGF-1 is capable to attenuate C₂-ceramide-mediated neuronal death, and this neuroprotection is associated to strong and permanent activation of AKT and inhibition of GSK3β.In conclusion, C₂-ceramide initiates a series of events including an early inactivation of PI3K/AKT and ERK pathways followed by activation of JNK and activation of GSK3β and neuronal death, changes that are counteracted by IGF-1.     

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the GABA_A receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases. Neuroactive steroids regulate many physiological functions, such as the stress response, puberty, the ovarian cycle, pregnancy and reward. Their levels are altered in several neuropsychiatric and neurological diseases and both preclinical and clinical studies emphasise a therapeutic potential of neuroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. However, direct administration of neuroactive steroids has several challenges, including pharmacokinetics, low bioavailability, addiction potential, safety and tolerability, which limit its therapeutic use. Therefore, modulation of neurosteroidogenesis to restore the altered endogenous neuroactive steroid tone may represent a better therapeutic approach. This review summarises recent approaches that target the neuroactive steroid biosynthetic pathway at different levels aiming to promote neurosteroidogenesis. These include modulation of neurosteroidogenesis through ligands of the translocator protein 18 kDa and the pregnane xenobiotic receptor, as well as targeting of specific neurosteroidogenic enzymes such as 17β‐hydroxysteroid dehydrogenase type 10 or P450 side chain cleavage. Enhanced neurosteroidogenesis through these targets may be beneficial not only for neurodegenerative diseases, such as Alzheimer's disease and age‐related dementia, but also for neuropsychiatric diseases, including alcohol use disorders.     

Sevoflurane neurotoxicity in neonatal rats is related to an increase in the GABAAR α1/GABAAR α2 ratio

Exposure of neonatal rat to sevoflurane leads to neurodegeneration and deficits of spatial learning and memory in adulthood. However, the underlying mechanisms remain unclear. The type A γ‐aminobutyric acid receptor (GABA_AR) is a target receptor for sevoflurane. The present study intends to investigate the changes in GABA_AR α1/α2 expression and its relationship with the neurotoxicity effect due to sevoflurane in neonatal rats. After a dose–response curve was constructed to determine minimum alveolar concentration (MAC) and safety was guaranteed in our 7‐day‐old neonatal rat pup mode, we conducted two studies among the following groups: (A) the control group; (B) the sham anesthesia group; and (C) the sevoflurane anesthesia group and all three groups were treated in the same way as the model. First, poly(ADP‐ribose) polymerase‐1 protein (PARP‐1) expression was determined in the different brain areas at 6 hr after anesthesia. Second, the expression of PARP‐1 and GABA_AR α1/GABA_AR α2 in the hippocampus area was tested by Western blotting at 6 hr, 24 hr, and 72 hr after anesthesia in all three groups. After 4 hr, with 0.8 MAC (2.1%) sevoflurane anesthesia, the PARP‐1 expression was significantly higher in the hippocampus than the other brain areas (p < .05). Compared with Groups A and B, the expression of PARP‐1 in the hippocampus of Group C significantly increased at 6 hr after sevoflurane exposure (216% ± 15%, p < .05), and the ratio of the α1/α2 subunit of GABA_AR surged at 6 hr (126% ± 6%), 24 hr (127% ± 8%), and 72 hr (183% ± 22%) after sevoflurane exposure in the hippocampus (p < .05). Our study showed that sevoflurane exposure of 0.8 MAC (2.1%)/4 hr was a suitable model for 7‐day‐old rats. And the exposure to sevoflurane could induce the apoptosis of neurons in the early stage, which may be related to the transmission from GABA_AR α2 to GABA_AR α1.     

Neuroprotective Effects of Lithium: Implications for the Treatment of Alzheimer’s Disease and Related Neurodegenerative Disorders

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Calcitonin gene‐related peptide (CGRP): A novel target for Alzheimer's disease

Alzheimer's disease (AD) is leading cause of death among older characterized by neurofibrillary tangles, oxidative stress, progressive neuronal deficits, and increased levels of amyloid‐β (Aβ) peptides. Cholinergic treatment could be the best suitable physiological therapy for AD. Calcitonin gene‐related peptide (CGRP) is a thirty‐seven‐amino acid regulatory neuropeptide resulting from different merging of the CGRP gene, which also includes adrenomedullin, amylin, calcitonin, intermedin, and calcitonin receptor‐stimulating peptide. It is a proof for a CGRP receptor within nucleus accumbens of brain that is different from either the CGRP₁ or CGRP₂ receptor in which it demonstrates similar high‐affinity binding for salmon calcitonin, CGRP, and amylin, a possession which is not shared by any extra CGRP receptors. Binding of CGRP to its receptor increases activated cAMP‐dependent pkA and PI3 kinase, resulting in N‐terminal fragments that are shown to exert complex inhibitory as well facilitator actions on nAChRs. Fragments such as CGRP1‐4, CGRP1‐5, and CGRP1‐6 rapidly as well as reversibly improve agonist sensitivity of nAChRs without straight stimulating those receptors and produce the Ca²⁺‐induced intracellular Ca²⁺ mobilization. Renin–angiotensin–aldosterone system (RAAS)‐activated angiotensin‐type (AT4) receptor is also beneficial in AD. It has been suggested that exogenous administration of CGRP inhibits infiltration of macrophages and expression of various inflammatory mediators such as NFkB, IL‐1b, TNF‐α, iNOS, matrix metalloproteinase (MMP)‐9, and cell adhesion molecules like intercellular adhesion molecule (ICAM)‐1 which attenuates consequence of inflammation in AD. Donepezil, a ChEI, inhibits acetylcholinesterase and produces angiogenesis and neurogenesis, in the dentate gyrus of the hippocampus of WT mice after donepezil administration. However, none of the results discovered in CGRP‐knockout mice and WT mice exposed to practical denervation. Therefore, selective agonists of CGRP receptors may become the potential candidates for treatment of AD.     

A novel antibody targeting sequence 31–35 in amyloid β protein attenuates Alzheimer's disease‐related neuronal damage

Amyloid β protein (Aβ) plays a critical role in pathogenesis of Alzheimer's disease (AD). Our previous studies indicated that the sequence 31–35 in Aβ molecule is an effective active center responsible for Aβ neurotoxicity in vivo and in vitro. In the present study, we prepared a novel antibody specifically targeting the sequence 31–35 of amyloid β protein, and investigated the neuroprotection of the anti‐Aβ_31–35 antibody against Aβ_1–42‐induced impairments in neuronal viability, spatial memory, and hippocampal synaptic plasticity in rats. The results showed that the anti‐Aβ_31–35 antibody almost equally bound to both Aβ_31–35 and Aβ_1–42, and pretreatment with the antibody dose‐dependently prevented Aβ_1–42‐induced cytotoxicity on cultured primary cortical neurons. In behavioral study, intracerebroventricular (i.c.v.) injection of anti‐Aβ_31–35 antibody efficiently attenuated Aβ_1–42‐induced impairments in spatial learning and memory of rats. In vivo electrophysiological experiments further indicated that Aβ_1–42‐induced suppression of hippocampal synaptic plasticity was effectively reversed by the antibody. These results demonstrated that the sequence 31–35 of Aβ may be a new therapeutic target, and the anti‐Aβ_31–35 antibody could be a novel immunotheraputic approach for the treatment of AD. © 2016 Wiley Periodicals, Inc.     

Altered levels and distribution of amyloid precursor protein and its processing enzymes in Niemann‐Pick type C1‐deficient mouse brains

Niemann‐Pick type C (NPC) disease is an autosomal recessive neurodegenerative disorder characterized by intracellular accumulation of cholesterol and glycosphingolipids in many tissues including the brain. The disease is caused by mutations of either NPC1 or NPC2 gene and is accompanied by a severe loss of neurons in the cerebellum, but not in the hippocampus. NPC pathology exhibits some similarities with Alzheimer's disease, including increased levels of amyloid β (Aβ)‐related peptides in vulnerable brain regions, but very little is known about the expression of amyloid precursor protein (APP) or APP secretases in NPC disease. In this article, we evaluated age‐related alterations in the level/distribution of APP and its processing enzymes, β‐ and γ‐secretases, in the hippocampus and cerebellum of Npc1^−/− mice, a well‐established model of NPC pathology. Our results show that levels and expression of APP and β‐secretase are elevated in the cerebellum prior to changes in the hippocampus, whereas γ‐secretase components are enhanced in both brain regions at the same time in Npc1^−/− mice. Interestingly, a subset of reactive astrocytes in Npc1^−/− mouse brains expresses high levels of APP as well as β‐ and γ‐secretase components. Additionally, the activity of β‐secretase is enhanced in both the hippocampus and cerebellum of Npc1^−/− mice at all ages, while the level of C‐terminal APP fragments is increased in the cerebellum of 10‐week‐old Npc1^−/− mice. These results, taken together, suggest that increased level and processing of APP may be associated with the development of pathology and/or degenerative events observed in Npc1^−/− mouse brains. © 2010 Wiley‐Liss, Inc.     

Val8‐GLP‐1 remodels synaptic activity and intracellular calcium homeostasis impaired by amyloid β peptide in rats

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD) in the elderly. Glucagon‐like peptide‐1 (GLP‐1), a modulator in T2DM therapy, has been shown to have neuroprotective properties. However, the native GLP‐1 can be rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV); the neuroprotective mechanism of GLP‐1 in the central nervous system is still an open question, and whether GLP‐1 can prevent amyloid β (Aβ)‐induced synaptic dysfunction and calcium disorder is still unclear. The present study, by using patch clamp and calcium imaging techniques, investigated the effects of Val⁸‐GLP‐1(7–36), a GLP‐1 analogue with profound resistance to DPP IV, on the excitatory and inhibitory synaptic transmission and intracellular calcium concentration ([Ca²⁺]_i) in the absence or presence of Aβ1–40. The results showed that 1) Aβ1–40 significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal neurons of rat brain slices; 2) Val⁸‐GLP‐1(7–36) did not affect the activity of miniature postsynaptic currents but effectively protected against the Aβ1–40‐induced decrease in mEPSC and mIPSC frequency; 3) Aβ1–40 significantly increased [Ca²⁺]_i in primary neuronal cultures; and 4) Val⁸‐GLP‐1(7–36) alone did not change the intracellular calcium level but prevented Aβ1–40‐induced persistent elevation of [Ca²⁺]_i. These findings demonstrate for the first time that central application of Val⁸‐GLP‐1(7–36) could protect against Aβ‐induced synaptic dysfunction and intracellular calcium overloading, suggesting that the neuroprotection of GLP‐1 may be involved in the remodeling of synaptic activity and intracellular calcium homeostasis in the brain. © 2013 Wiley Periodicals, Inc.     

The gaseous mediator,hydrogen sulphide,inhibits in vitro motor patterns in the human,rat and mouse colon and jejunum

Abstract Hydrogen sulphide (H₂S) has been recently proposed as a transmitter in the brain and peripheral tissues. Its role in the gastrointestinal tract is still unknown despite some data which suggest an involvement mediating smooth muscle relaxation. The aim of this study was to investigate the effect of this gas on intestinal segments from mouse jejunum and colon, and muscular strips from the human and rat colon. In isolated segments of mouse colon and jejunum, bath applied sodium hydrogen sulphide (NaHS) (a H₂S donor) caused a concentration‐dependent inhibition of spontaneous motor complexes (MCs) (IC₅₀ 121 μmol L^?1 in the colon and 150 μmol L^?1 in the jejunum). This inhibitory effect of NaHS on MCs was (i) unaffected by tetrodotoxin (TTX), capsaicin, pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate and N‐nitro‐l ‐arginine suggesting a non‐neural effect and (ii) significantly reduced by apamin 3 μmol L^?1. NaHS concentration‐dependently inhibited the spontaneous motility in strips from human colon (IC₅₀ 261 μmol L^?1) and rat colon (IC₅₀ 31 μmol L^?1). The inhibitory effect of NaHS on colonic strips was (i) unaffected by the neural blocker TTX (1 μmol L^?1) with IC₅₀ 183 μmol L^?1 for the human colon and of 26 μmol L^?1 for the rat colon and (ii) significantly reduced by glybenclamide (10 μmol L^?1), apamin (3 μmol L^?1) and TEA (10 mmol L^?1) with IC₅₀ values of 2464, 1307 and 2421 μmol L^?1 for human strips, and 80, 167 and 674 μmol L^?1 for rat strips respectively. We conclude that H₂S strongly inhibits in vitro intestinal and colonic motor patterns. This effect appears to be critically dependent on K channels particularly apamin‐sensitive SK channels and glybenclamide‐sensitive K (ATP) channels.     

Dynamics of β‐adrenergic/cAMP signaling and morphological changes in cultured astrocytes

The morphology of astrocytes, likely regulated by cAMP, determines the structural association between astrocytes and the synapse, consequently modulating synaptic function. β‐Adrenergic receptors (β‐AR), which increase cytosolic cAMP concentration ([cAMP]_i), may affect cell morphology. However, the real‐time dynamics of β‐AR‐mediated cAMP signaling in single live astrocytes and its effect on cell morphology have not been studied. We used the fluorescence resonance energy transfer (FRET)‐based cAMP biosensor Epac1‐camps to study time‐dependent changes in [cAMP]_i; morphological changes in primary rat astrocytes were monitored by real‐time confocal microscopy. Stimulation of β‐AR by adrenaline, noradrenaline, and isoprenaline, a specific agonist of β‐AR, rapidly increased [cAMP]_i (～15 s). The FRET signal response, mediated via β‐AR, was faster than in the presence of forskolin (twofold) and dibutyryl‐cAMP (>35‐fold), which directly activate adenylyl cyclase and Epac1‐camps, respectively, likely due to slow entry of these agents into the cytosol. Oscillations in [cAMP]_i have not been recorded, indicating that cAMP‐dependent processes operate in a slow time domain. Most Epac1‐camps expressing astrocytes revealed a morphological change upon β‐AR activation and attained a stellate morphology within 1 h. The morphological changes exhibited a bell‐shaped dependency on [cAMP]_i. The 5–10% decrease in cell cross‐sectional area and the 30–50% increase in cell perimeter are likely due to withdrawal of the cytoplasm to the perinuclear region and the appearance of protrusions on the surface of astrocytes. Because astrocyte processes ensheath neurons, β‐AR/cAMP‐mediated morphological changes can modify the geometry of the extracellular space, affecting synaptic, neuronal, and astrocyte functions in health and disease. GLIA 2014;62:566–579     

REVIEW: Curcumin and Alzheimer's Disease

Curcumin has a long history of use as a traditional remedy and food in Asia. Many studies have reported that curcumin has various beneficial properties, such as antioxidant, antiinflammatory, and antitumor. Because of the reported effects of curcumin on tumors, many clinical trials have been performed to elucidate curcumin's effects on cancers. Recent reports have suggested therapeutic potential of curcumin in the pathophysiology of Alzheimer's disease (AD). In in vitro studies, curcumin has been reported to inhibit amyloid‐β‐protein (Aβ) aggregation, and Aβ‐induced inflammation, as well as the activities of β‐secretase and acetylcholinesterase. In in vivo studies, oral administration of curcumin has resulted in the inhibition of Aβ deposition, Aβ oligomerization, and tau phosphorylation in the brains of AD animal models, and improvements in behavioral impairment in animal models. These findings suggest that curcumin might be one of the most promising compounds for the development of AD therapies. At present, four clinical trials concerning the effects of curcumin on AD has been conducted. Two of them that were performed in China and USA have been reported no significant differences in changes in cognitive function between placebo and curcumin groups, and no results have been reported from two other clinical studies. Additional trials are necessary to determine the clinical usefulness of curcumin in the prevention and treatment of AD.     

Ginkgolide B revamps neuroprotective role of apurinic/apyrimidinic endonuclease 1 and mitochondrial oxidative phosphorylation against Aβ25–35‐induced neurotoxicity in human neuroblastoma cells

Accumulating evidence points to roles for oxidative stress, amyloid beta (Aβ), and mitochondrial dysfunction in the pathogenesis of Alzheimer's disease (AD). In neurons, the base excision repair pathway is the predominant DNA repair (BER) pathway for repairing oxidized base lesions. Apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional enzyme with DNA repair and reduction–oxidation activities, has been shown to enhance neuronal survival after oxidative stress. This study seeks to determine 1) the effect of Aβ_25–35 on reactive oxygen species (ROS)/reactive nitrogen species (RNS) levels, 2) the activities of respiratory complexes (I, III, and IV), 3) the role of APE1 by ectopic expression, and 4) the neuromodulatory role of ginkgolide B (GB; from the leaves of Ginkgo biloba). The pro‐oxidant Aβ_25–35 peptide treatment increased the levels of ROS/RNS in human neuroblastoma IMR‐32 and SH‐SY5Y cells, which were decreased after pretreatment with GB. Furthermore, the mitochondrial APE1 level was found to be decreased after treatment with Aβ_25–35 up to 48 hr, and the level was increased significantly in cells pretreated with GB. The oxidative phosphorylation (OXPHOS; activities of complexes I, III, and IV) indicated that Aβ_25–35 treatment decreased activities of complexes I and IV, and pretreatment with GB and ectopic APE1 expression enhanced these activities significantly compared with Aβ_25–35 treatment. Our results indicate that ectopic expression of APE1 potentiates neuronal cells to overcome the oxidative damage caused by Aβ_25–35. In addition, GB has been shown to modulate the mitochondrial OXPHOS against Aβ_25–35‐induced oxidative stress and also to regulate the levels of ROS/RNS in the presence of ectopic APE1. This study presents findings from a new point of view to improve therapeutic potential for AD via the synergistic neuroprotective role played by APE1 in combination with the phytochemical GB. © 2015 Wiley Periodicals, Inc.     

Widespread and abundant α‐synuclein pathology in a neurologically unimpaired subject

The intracytoplasmic aggregation of α‐synuclein (αS) protein is a common denominator for a group of neurodegenerative disorders currently known as synucleinopathies. It is generally assumed that the incorporation of αS protein into compact inclusions compromises the function and viability of its host cell via mechanical disruption. Herein, we report a widespread and abundant αS pathology in an elderly subject, whose medical history gave no indication of any neurodegenerative disease. We compared neuronal and glial components in this neurologically unimpaired subject with a patient with a clinical syndrome of dementia with Lewy bodies (DLB) by using a range of antigenic determinants and an in situ end‐labeling technique. We detected no differences in vascular pathologies, in gliosis, or in apoptosis that would have explained the incompatible clinical end‐points. With respect to the Alzheimer's disease‐related changes, the only differences noted were the β‐amyloid aggregates in the putamen found in the DLB patient alone. Our findings suggest that there must be some currently unidentified factors rather than αS‐positive inclusions that are responsible for the neuronal dysfunction. The αS‐positive inclusions may well represent detoxified reserves that cells can tolerate for years, and thus prevention of their development could actually accelerate the diseases process.