Enriched environment prevents memory deficits in type 1 diabetic rats

Studies have shown that an enriched environmental (EE) enhances hippocampal neurogenesis and dendritic branching in rodents, improving the performance in learning and memory task. Diabetes, however, is associated with memory deficits and decreasing in cell proliferation in the hippocampal dentate gyrus (DG), possibly related with higher glucocorticoid levels. Thus, our objective was to investigate the influence of EE on the memory deficits and cell proliferation of diabetic rats. For this, we reared rats for 2 months during early stages of life in standard environments (control rats) or EE. At adulthood, control and EE groups were divided and half of them induced to diabetes by a single injection of streptozotocin, 60 mg/kg, via i.p. Memory deficit was evaluated in these groups in the novel object-placement recognition task 11 days after diabetes induction. BrdU label cells were detected by immunohistochemistry after 3 days of administration to correlate cell proliferation in the DG area and performance in the memory task. Our results showed that EE decreased memory deficits in diabetic-induced rats (p < 0.05). Although cell proliferation in the DG was lower in the diabetic rats, enriched environment did not interfere in this parameter. These findings suggest that enriched environment is able to prevent or delay the development of memory deficits caused by diabetes in rats.     

Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice

The thiazolidinediones, such as rosiglitazone, increase peripheral insulin sensitivity and their use is proposed for the treatment of Alzheimer's disease. However, the mechanisms underlying the potential beneficial effects of rosiglitazone in Alzheimer's disease remain unclear. In previous studies, we observed that Tg2576 Alzheimer mice develop peripheral insulin resistance with age and have much higher serum corticosterone levels than wild-type mice when fasted overnight. We further showed that both of these defects can be ameliorated by rosiglitazone administration. Here, we report that during behavioral testing which involves repetitive overnight fasting, Tg2576 mice administered rosiglitazone exhibited better spatial learning and memory abilities and had lower serum corticosterone levels than untreated Tg2576 mice. When untreated Tg2576 mice were administered metyrapone, a drug that blocks glucocorticoid production, their spatial learning and memory abilities and serum corticosterone levels were similar to those of rosiglitazone-treated mice. We further report here that rosiglitazone attenuated reductions in insulin-degrading enzyme (IDE) mRNA and activity, and reduced amyloid beta-peptide (Abeta)42 levels without affecting amyloid deposition, in the brains of Tg2576 mice. These results demonstrate that rosiglitazone attenuates learning and memory deficits in Tg2576 mice and suggest that the effects of the drug on learning and memory, brain IDE levels, and brain Abeta42 levels in the mice may be due to its glucocorticoid-lowering actions.     

Apple juice prevents oxidative stress induced by amyloid-beta in culture

Increased oxidative stress contributes to the decline in cognitive performance during normal aging and in neurodegenerative conditions such as Alzheimer's disease. Dietary supplementation with fruits and vegetables that are high in antioxidant potential have in some cases compensated for oxidative stress. Herein, we examined whether apple juice could alleviate the neurotoxic consequences of exposure of cultured neuronal cells to amyloid-beta (Abeta), since at least a portion of the neurotoxicity of Abeta is due to oxidative stress. Apple juice concentrate (AJC; 70 degree brix) was diluted into culture medium of SH-SY-5Y human neuroblastoma cells that had been differentiated for 7 days with 5 microM retinoic acid concurrent with the addition of 20 microM Abeta. AJC prevented the increased generation of reactive oxygen species (ROS) normally induced by Abeta treatment under these conditions. AJC also prevented Abeta-induced calcium influx and apoptosis, each of which results in part due to increased ROS. These findings suggest that the antioxidant potential of apple products can prevent Abeta-induced oxidative damage.     

Ascorbic acid prevents water maze behavioral deficits caused by early postnatal methylmalonic acid administration in the rat

Methylmalonic acidemia consists of a group of inherited neurometabolic disorders biochemically characterized by accumulation of methylmalonic acid (MA) and clinically by progressive neurological deterioration whose pathophysiology is not yet fully established. In the present study we investigated the effect of chronic administration (from the 5th to the 28th day of life) of methylmalonic acid (MA) on the performance of adult rats in the Morris water maze task. MA doses ranged from 0.72 to 1.67 μmol/g of body weight as a function of animal age; control rats were treated with the same volume of saline. Chronic postnatal MA treatment had no effect on body weight and in the acquisition of adult rats in the water maze task. However, administration of MA provoked long lasting reversal learning impairment in this task. Motor activity, evaluated by the swim speed in the maze, was not altered by MA administration, indicating no deficit of locomotor activity in rats injected with the metabolite. We also determined the effect of ascorbic acid administered alone or combined with MA on the same behavioral parameters in order to test whether free radicals might be responsible for the behavioral changes observed in MA-treated animals. Ascorbic acid was able to prevent the behavioral alterations provoked by MA. Moreover, the in vitro exposure of hippocampal and striatal preparations to MA revealed that the acid significantly reduced total radical-trapping antioxidant potential (TRAP) and total antioxidant reactivity (TAR) in the striatum, but not in the hippocampus. Furthermore, MA increased the thiobarbituric acid–reactive substances (TBA–RS) measurement in both structures. These data indicate that oxidative stress might be involved in the neuropathology of methylmalonic acidemia and that early MA administration induces long-lasting behavioral deficits, which are possibly caused by oxygen reactive species generation.     

Ascorbic acid prevents water maze behavioral deficits caused by early postnatal methylmalonic acid administration in the rat

Methylmalonic acidemia consists of a group of inherited neurometabolic disorders biochemically characterized by accumulation of methylmalonic acid (MA) and clinically by progressive neurological deterioration whose pathophysiology is not yet fully established. In the present study we investigated the effect of chronic administration (from the 5th to the 28th day of life) of methylmalonic acid (MA) on the performance of adult rats in the Morris water maze task. MA doses ranged from 0.72 to 1.67 micromol/g of body weight as a function of animal age; control rats were treated with the same volume of saline. Chronic postnatal MA treatment had no effect on body weight and in the acquisition of adult rats in the water maze task. However, administration of MA provoked long lasting reversal learning impairment in this task. Motor activity, evaluated by the swim speed in the maze, was not altered by MA administration, indicating no deficit of locomotor activity in rats injected with the metabolite. We also determined the effect of ascorbic acid administered alone or combined with MA on the same behavioral parameters in order to test whether free radicals might be responsible for the behavioral changes observed in MA-treated animals. Ascorbic acid was able to prevent the behavioral alterations provoked by MA. Moreover, the in vitro exposure of hippocampal and striatal preparations to MA revealed that the acid significantly reduced total radical-trapping antioxidant potential (TRAP) and total antioxidant reactivity (TAR) in the striatum, but not in the hippocampus. Furthermore, MA increased the thiobarbituric acid-reactive substances (TBA-RS) measurement in both structures. These data indicate that oxidative stress might be involved in the neuropathology of methylmalonic acidemia and that early MA administration induces long-lasting behavioral deficits, which are possibly caused by oxygen reactive species generation.     

Chronic nicotine reverses working memory deficits caused by lesions of the fimbria or medial basalocortical projection

Nicotine has been found in a variety of studies to improve performance in memory tasks. This study was conducted to determine if chronic nicotine administration is useful in counteracting the working memory deficits seen after lesions of the fimbria or the medial basalocortical projection. Rats were trained to asymptotic performance on a working memory version of the radial-arm maze. Then, they were given knife cut lesions of the fimbria or the medial basalocortical projection or underwent sham surgeries. At the time of surgery, rats in each treatment group were implanted with either nicotine-containing or placebo glass and Silastic pellets. Rats with fimbria or basalocortical lesions showed a significant decline in working memory performance. Chronic nicotine significantly improved choice accuracy in both lesioned and unlesioned rats. Nicotine treatment restored performance of the lesioned rats to control levels. These data show that in addition to improving memory performance in normal rats, nicotine can counteract lesion-induced memory impairments. Nicotine also may be useful for treatment of disease-related memory impairments such as seen in Alzheimer's disease.     

Folate/vitamin-B12 prevents chronic hyperhomocysteinemia-induced tau hyperphosphorylation and memory deficits in aged rats

Hyperhomocysteinemia is associated with an increased risk of Alzheimer's disease (AD). Our previous work has demonstrated that combined folate and vitamin B12 (vit-B12) supplementation prevents tau hyperphosphorylation and memory deficits induced by acute administration of homocysteine in young rats. Here, we further investigated whether folate/vit-B12 supplementation is also effective in aged rats with a chronically high level of homocysteine. 18-month-old rats were injected with homocysteine via the vena caudalis with or without a concurrent folate/vit-B12 supplementation for 28 weeks. We found that hyperhomocysteinemia induced tau hyperphosphorylation and accumulation in hippocampus and cortex. Concurrent signaling changes included the activation of glycogen synthase kinases-3β, cyclin-dependent kinase-5, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38MAPK, and inhibition of protein phosphatase 2A. Although the ability to learn was not affected, the aged rats exhibited significant memory deficits. Folate/vit-B12 supplementation attenuated these biochemical and behavioral correlates. These data demonstrate that folate/vit-B12 supplementation is also effective in a chronic hyperhomocysteinemia model in reversing the AD-like tau pathologies and memory deficits.     

Emotion-discrimination deficits in mild Alzheimer disease.

OBJECTIVE: Mild Alzheimer disease (AD) preferentially affects temporal lobe regions, which represent important structures in memory and emotional processes. This study investigated emotion discrimination in people with mild AD, versus Caretakers. METHODS: Twenty AD subjects and 22 caretakers underwent computerized testing of emotion recognition and differentiation. Performances between groups were compared, controlling for possible effects of age and cognitive abilities. RESULTS: AD subjects showed diminished recognition of happy, sad, fearful, and neutral expressions. They also exhibited decreased differentiation between happy and sad expressions. Controlling for effects of cognitive dysfunction, AD subjects differed on recognition of happy and sad, and differentiation of sad facial expressions, and in error patterns for fearful and neutral faces. CONCLUSIONS: Diminished abilities for emotion discrimination are present in persons with mild AD. In persons with mild AD, who frequently reside in their own home or with close family, this diminished ability may adversely affect social functioning and quality of life.     

Detection of amyloid-beta oligomers in human cerebrospinal fluid by flow cytometry and fluorescence resonance energy transfer

The neuropathology of Alzheimer's disease (AD) has been linked recently to non-fibrillar forms of neurotoxic amyloid-beta (Abeta) oligomers of which high levels are observed in the brain of AD patients. This suggests that Abeta oligomers play a key role in the early events of AD, underlining their potential for the early diagnosis of the disease. We have developed an extremely sensitive assay for the detection of oligomeric and fibrillar structures of Abeta that is based on multiparametric analysis of data obtained by flow cytometry and fluorescence resonance energy transfer (Fret). The assay readily detects Abeta oligomers in human cerebrospinal fluid (CSF) as verified by dot blot of the isolated particles. By measuring 174 CSF samples of non-demented control patients with various neurological disorders a high reliability and reproducibility of the method could be demonstrated.     

Lead exposure through gestation-only caused long-term learning/memory deficits in young adult offspring

Numerous observations in clinical and preclinical studies indicate that the developing brain is particular sensitive to lead (Pb)'s pernicious effects. However, the effect of gestation-only Pb exposure on cognitive functions at maturation has not been studied. We investigated the potential effects of three levels of Pb exposure (low, middle, and high Pb: 0.03%, 0.09%, and 0.27% of lead acetate-containing diets) at the gestational period on the spatial memory of young adult offspring by Morris water maze spatial learning and fixed location/visible platform tasks. Our results revealed that three levels of Pb exposure significantly impaired memory retrieval in male offspring, but only female offspring at low levels of Pb exposure showed impairment of memory retrieval. These impairments were not due to the gross disturbances in motor performance and in vision because these animals performed the fixed location/visible platform task as well as controls, indicating that the specific aspects of spatial learning/memory were impaired. These results suggest that exposure to Pb during the gestational period is sufficient to cause long-term learning/memory deficits in young adult offspring.     

Complex-environment rearing prevents prenatal hypoxia-induced deficits in hippocampal cellular mechanisms necessary for memory consolidation in the adult Wistar rat

Hypoxic episodes in utero can result in enduring and debilitating neurological sequelae that include nonprogressive motor disorders and/or significant learning deficits. The extent of long-term disruption of synaptic function following prenatal hypoxia and its subsequent effect on learning ability, however, remain to be established. Polysialylation of the neural cell adhesion molecule, a cellular event integral to the consolidation of diverse learning paradigms, was used to correlate cellular end points with learning deficits as a consequence of prenatal hypoxia. Pregnant Wistar dams exposed to hypobaric hypoxia during gestational days 10-20 had significantly reduced litter sizes, but the lack of effect on subsequent pup weight gain suggested no gross developmental deficit. By contrast, adult animals with prior in utero hypoxia exhibited significant learning difficulties in both acquisition of a water maze spatial learning task and recall of a passive avoidance paradigm. Learning deficits correlated with a significant reduction in the frequency of polysialylated neurons in the dentate infragranular zone and a blunting of their transient activation 12 hr following task acquisition. Rearing animals with prior prenatal hypoxia in a complex environment, however, eliminated the task acquisition and recall deficits and restored dentate polysialylated cell frequency and their transient posttraining increase.     

Methylene blue prevents neurodegeneration caused by rotenone in the retina

An experimental optic neuropathy model was used to test the hypothesis that methylene blue may protect the retinal ganglion cell layer from neurodegeneration caused by rotenone. Rotenone is a widely used pesticide that inhibits complex I, the first enzyme of the mitochondrial respiratory chain. Complex I dysfunction is linked to the degeneration of retinal ganglion cells in Leber's optic neuropathy. Methylene blue is a reduction-oxidation agent that can act as a powerful antioxidant and also as an enhancer of the electron transport chain, preventing formation of mitochondrial oxygen free radicals and promoting oxygen consumption. The neurodegeneration of the retina was studied in mice with intravitreal microinjection of rotenone alone, or in combination with increasing doses of methylene blue, in one eye, and the vehicle in the contralateral control eye. The effect of rotenone and rotenone plus methylene blue was investigated using two histological stains, complex I and Nissl, and two measurements, morphometric layer thickness and non-biased stereological cell counts. Rotenone induced neurodegeneration in the retinal ganglion cell layer 24 h after injection, as indicated by significant reductions in both the thickness and cell numbers of the retinal ganglion cell layer of eyes microinjected with rotenone as compared to the control eyes. This neurodegeneration was prevented in a dose dependent manner by the injection of methylene blue along with rotenone. It was concluded that rotenone-induced degeneration in the ganglion cell layer can be prevented by intravitreal injection of methylene blue. In vitro experiments showed that methylene blue is both a powerful antioxidant as well as an enhancer of cellular oxygen consumption and is able to reverse the oxidative stress and decrease in oxygen consumption induced by rotenone in brain homogenates. The findings suggest that methylene blue may be a promising neuroprotective agent in optic neuropathy and perhaps other neurodegenerative diseases caused by mitochondrial dysfunction.     

Selective memory and memory deficits in depressed inpatients

We investigated memory impairment and mood-congruent memory bias in depression, using an explicit memory test and an implicit one. Thirty-six severely depressed inpatients that fulfilled DSM-IV criteria for major depressive disorder and 36 healthy controls matched for sex, age, and educational level participated in the study. Explicit memory was assessed with a free recall task and implicit memory with an anagram solution task. Results showed that depressed and controls differed in explicit memory performance, depending on the amount of cognitive distraction between incidental learning and testing. Implicit memory was not affected. In addition, severely depressed patients showed a mood-congruent memory bias in implicit memory but not in explicit memory. The complex pattern of results is discussed with regard to relevant theories of depression.     

Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway

Recent data have revealed that soluble oligomeric amyloid-beta peptide (Abeta) may be the proximate effectors of neuronal injuries and death in Alzheimer's disease (AD) by unknown mechanisms. Consistently, we recently demonstrated the critical role of a redox-sensitive cytosolic calcium-dependent phospholipase A2 (cPLA2)-arachidonic acid (AA) pathway in Abeta oligomer-induced cell death. According to the involvement of oxidative stress and polyunsaturated fatty acids like AA in the regulation of sphingomyelinase (SMase) activity, the present study underlines the role of SMases in soluble Abeta-induced apoptosis. Soluble Abeta oligomers induced the activation of both neutral and acidic SMases, as demonstrated by the direct measurement of their enzymatic activities, by the inhibitory effects of both specific neutral and acidic SMase inhibitors, and by gene knockdown using antisense oligonucleotides. Furthermore, soluble Abeta-mediated activation of SMases and subsequent cell death were found to be inhibited by antioxidant molecules and a cPLA2-specific inhibitor or antisense oligonucleotide. We also demonstrate that sphingosine-1-phosphate is a potent neuroprotective factor against soluble Abeta oligomer-induced cell death and apoptosis by inhibiting soluble Abeta-induced activation of acidic sphingomyelinase. These results suggest that Abeta oligomers induce neuronal death by activating neutral and acidic SMases in a redox-sensitive cPLA2-AA pathway.     

Primary memory and secondary memory in dementia of the Alzheimer type

Abstract

Free recall of word lists was investigated in a sample of 47 patients with dementia of the Alzheimer type (DAT) and 31 normal controls of equivalent age and education. Recall was divided into primary memory (PM) and secondary memory (SM) components based on the number of items intervening between presentation and recall. The findings were as follows: (1) the patients showed a greater deficit on the SM than on the PM measure; (2) there was little evidence of proactive interference in the patient group; (3) the PM and SM measures were independent in the controls but not in the patient group; and, (4) the size of patients' PM deficit increased linearly with increasing items between presentation and attempted recall. These results suggest that the memory disorder of DAT is partially the result of defective PM.     

Codeposition of cystatin C with amyloid-beta protein in the brain of Alzheimer disease patients

Immunohistochemical analysis of brains of patients with Alzheimer disease (AD) revealed that the cysteine proteinase inhibitor cystatin C colocalizes with amyloid beta-protein (Abeta) in parenchymal and vascular amyloid deposits. No evidence of cerebral hemorrhage was observed in any of the brains studied. Immunoelectron microscopy demonstrated dual staining of amyloid fibrils with anti-Abeta and anti-cystatin C antibodies. Cystatin C immunoreactivity was also observed in amyloid deposits in the brain of transgenic mice overexpressing human beta amyloid precursor protein. Massive deposition of the variant cystatin C in the cerebral vessels of patients with the Icelandic form of hereditary cerebral hemorrhage with amyloidosis is thought to be responsible for the pathological processes leading to stroke. Anti-cystatin C antibodies strongly labeled pyramidal neurons within cortical layers most prone to amyloid deposition in the brains of AD patients. Immunohistochemistry with antibodies against the carboxyl-terminus of Abeta(x-42) showed intracellular immunoreactivity in the same neuronal subpopulation. It remains to be established whether the association of cystatin C to Abeta plays a primary role in amyloidogenesis of AD or is a late event in which the protein is bound to the previously formed Abeta amyloid fibrils.     

Apolipoprotein E, amyloid-beta, and blood-brain barrier permeability in Alzheimer disease

There is increasing evidence for blood-brain barrier (BBB) compromise in Alzheimer disease (AD). The presence of the epsilon4 allele of the apolipoprotein E (apoE) gene is a risk factor for sporadic AD. Apolipoprotein E is essential both for maintenance of BBB integrity and for the deposition of fibrillar amyloid-beta (Abeta) that leads to the development of Abeta plaques in AD and to cerebral amyloid angiopathy. This review investigates the relationships between apoE, Abeta, and the BBB in AD. Alterations in the expression and distribution of the BBB Abeta transporters receptor for advanced glycation end-products and low-density lipoprotein receptor-related protein 1 in AD and the potential roles of apoE4 expression in adversely influencing Abeta burden and BBB permeability are also examined. Because both apoE and Abeta are ligands for low-density lipoprotein receptor-related protein 1, all 3 molecules are present in AD plaques, and most AD plaques are located close to the cerebral microvasculature. The interactions of these molecules at the BBB likely influence metabolism and clearance of Abeta and contribute to AD pathogenesis. Therapeutic alternatives targeting apoE/Abeta and sealing a compromised BBB are under development for the treatment of AD.     

Working memory and secondary memory deficits in Alzheimer's disease

The memory loss associated with Alzheimer's Disease (AD) may have multiple cognitive components. Working Memory appears to be impaired due to failures of a Central Executive System. Secondary Memory, on the other hand, is affected due to poor encoding or mediational processes. An analysis of the performance of 71 AD patients on tests related to these neuropsychological constructs revealed that they could indeed be dissociated. In fact, individual patients were identified with significantly different, and unique, patterns of impairment which were consistent with the two-component model. These data, therefore, lend preliminary support for the notion of multiple cognitive impairments being responsible for the memory loss in AD.