Genistein ameliorates learning and memory deficits in amyloid β(1-40) rat model of Alzheimer's disease

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by increased β-amyloid (Aβ) deposition and neuronal dysfunction leading to impaired learning and recall. Ageing, heredity, and induced oxidative stress are among proposed risk factors. The increased frequency of the disease in women also suggests a role for estrogen in development of AD. In the present study, effects of the phytoestrogen genistein (10mg/kg) on learning and memory impairments was assessed in intrahippocampal Aβ(1-40)-injected rats. The estrogen receptor antagonist fulvestrant was injected intracerebroventricularly in a group of Aβ-lesioned rats. The Aβ-injected animals exhibited the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in the RAM task. Genistein, but not genistein and fulvestrant, significantly improved most of these parameters. Measurements of oxidative stress markers in hippocampal tissue of Aβ-injected rats showed an elevation of malondialdehyde (MDA) and nitrite content, and a reduction of superoxide dismutase (SOD) activity. Genistein significantly attenuated the increased MDA content but did not affect the nitrite content or SOD activity. These results indicate that genistein pretreatment ameliorates Aβ-induced impairment of short-term spatial memory in rats through an estrogenic pathway and by inducing attenuation of oxidative stress.     

阿尔茨海默病发病机制的研究进展

阿尔茨海默病是一种起病隐匿,进行性发展的神经系统退行性疾病。临床上以记忆障碍、失语、失用、失认、视空间损害、执行功能障碍以及人格和行为改变等全面性痴呆表现为特征,病因迄今未明,发病机制复杂。本文对可能的发病机制：遗传因素（包括ApoE基因、早老素-1和早老素-2基因,APP基因、α2巨球蛋白基因、TOMM40基因、COL25A1基因）;Aβ代谢（合成、分解、转运）;神经递质学说;自由基与氧化应激学说;金属离子学说等进行综述。     

Serum beta-amyloid correlates with neuropsychological impairment

AIMS: Evidence suggests a relationship between peripheral Abeta and AD. We hypothesized that higher levels of serum Abeta(1-42) would be associated with memory impairment, thought to occur early in the disease, and rises in serum Abeta(1-40), which occur later, would be associated with impairment in non-memory measures. METHODS: Using a cross-sectional design, we examined the relationship of serum Abeta(1-40), Abeta(1-42), and the ratio of Abeta(1-42/1-40) to neuropsychological measures in 40 cognitively normal controls, 13 MCI subjects, and 25 AD patients. RESULTS: Serum Abeta(1-42) and the ratio of Abeta(1-42/1-40) were significantly higher in the MCI group compared to the controls. A significant relationship in the hypothesized direction (poorer scores associated with higher Abeta(1-40) serum levels) was found between Abeta(1-40) and measures of executive functions across the entire cohort of individuals tested and with measures of language and processing speed in the AD group. Regression analysis found that neuropsychological measures accounted for 26% of the variance in serum Abeta(1-40,) in the MCI/AD but not the controls. Furthermore that language and executive measures were significant predictors. CONCLUSIONS: Results provide preliminary data to partially support our hypotheses and suggest that changes in serum Abeta levels may be attributed to pathological changes within the brain.     

Long-term enrichment enhances the cognitive behavior of the aging neurogranin null mice without affecting their hippocampal LTP

Neurogranin (Ng), a PKC substrate, is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng caused severe deficits in spatial learning and LTP in the hippocampal CA1 region of mice. These Ng-/- mice also exhibit deficits in the amplification of their hippocampal signaling pathways critical for learning and memory. A short-term exposure to an enriched environment failed to improve their behavioral performances. Here, we showed that a long-term enrichment protocol for the aging mice was beneficial to the Ng-/- as well as Ng+/+ and Ng+/- mice in preventing age-related cognitive decline. Enrichment also caused an increase in the hippocampal CREB level of all three genotypes and Ng level of Ng+/+ and Ng+/- mice, but not that of alphaCaMKII or ERK. Interestingly, hippocampal slices of these enriched aging Ng-/- mice, unlike those of Ng+/+ and Ng+/- mice, did not show enhancement in the high frequency stimulation (HFS)-induced LTP in the CA1 region. It appears that the learning and memory processes in these enriched aging Ng-/- mice do not correlate with the HFS-induced LTP, which is facilitated by Ng. These results demonstrated that long-term enrichment for the aging Ng-/- mice may improve their cognitive function through an Ng-independent plasticity pathway.     

Detectable Neuropsychological Differences in Early Preclinical Alzheimer’s Disease: A Meta-Analysis

The development of methods for in vivo detection of cerebral beta amyloid retention and tau accumulation have been increasingly useful in characterizing preclinical Alzheimer’s disease (AD). While the association between these biomarkers and eventual AD has been demonstrated among cognitively intact older adults, the link between biomarkers and neurocognitive ability remains unclear. We conducted a meta-analysis to test the hypothesis that cognitively intact older adults would show statistically discernable differences in neuropsychological performance by amyloid status (amyloid negative = A-, amyloid positive = A+). We secondarily hypothesized a third group characterized by either CSF tau pathology or neurodegeneration, in addition to amyloidosis (A+/N+ or Stage 2), would show lower neuropsychology scores than the amyloid positive group (A+/N- or Stage 1) when compared to the amyloid negative group. Pubmed, PsychINFO, and other sources were searched for relevant articles, yielding 775 total sources. After review for inclusion/exclusion criteria, duplicates, and risk of bias, 61 studies were utilized in the final meta-analysis. Results showed A+ was associated with poorer performance in the domains of global cognitive function, memory, language, visuospatial ability, processing speed, and attention/working memory/executive functions when compared to A-. A+/N+ showed lower performances on memory measures when compared to A+/N- in secondary analyses based on a smaller subset of studies. Results support the notion that neuropsychological measures are sensitive to different stages of preclinical AD among cognitively intact older adults. Further research is needed to determine what constitutes meaningful differences in neuropsychological performance among cognitively intact older adults.     

Stress or no stress: mineralocorticoid receptors in the forebrain regulate behavioral adaptation

Corticosteroid effects on cognitive abilities during behavioral adaptation to stress are mediated by two types of receptors. While the glucocorticoid receptor (GR) is mainly involved in the consolidation of memory, the mineralocorticoid receptor (MR) mediates appraisal and initial responses to novelty. Recent findings in humans and mice suggest that under stress, the MR might be involved in the use of different learning strategies. Here, we used male mice lacking the MR in the forebrain (MR(CaMKCre)), which were subjected to 5-10 min acute restraint stress, followed 30 min later by training trials on the circular hole board. Mice had to locate an exit hole using extra- and intra-maze cues. We assessed performance and the use of spatial and stimulus-response strategies. Non-stressed MR(CaMKCre) mice showed delayed learning as compared to control littermates. Prior stress impaired performance in controls, but did not further deteriorate learning in MR(CaMKCre) mice. When stressed, 20-30% of both MR(CaMKCre) and control mice switched from a spatial to a stimulus-response strategy, which rescued performance in MR(CaMKCre) mice. Furthermore, MR(CaMKCre) mice showed increased GR mRNA expression in all CA areas of the hippocampus and an altered basal and stress-induced corticosterone secretion, which supports their role in the modulation of neuroendocrine activity. In conclusion, our data provide evidence for the critical role of MR in the fast formation of spatial memory. In the absence of forebrain MR spatial learning performance was under basal circumstances impaired, while after stress further deterioration of performance was rescued by switching behavior increasingly to a stimulus-response strategy.     

Gami-Chunghyuldan ameliorates memory impairment and neurodegeneration induced by intrahippocampal Aβ 1-42 oligomer injection

Soluble oligomeric forms of amyloid beta (AβO) are regarded as a main cause of synaptic and cognitive dysfunction in Alzheimer’s disease (AD) and have been a primary target in the development of drug treatments for AD. The present study utilized a mouse model of AD induced by intrahippocampal injection of AβO (10 μM) to investigate the effects of Gami-Chunghyuldan (GCD), a standardized multi-herbal medicinal formula, on the presentation of memory deficits and neurohistological pathogenesis. GCD (10 and 50 mg/kg/day, 5 days, p.o.) improved AβO-induced memory impairment as well as reduced neuronal cell death, astrogliosis, and microgliosis in the hippocampus. In addition, GCD prevented AβO-triggered synaptic disruption and cholinergic fiber loss. These results suggest that GCD may be useful in the prevention and treatment of AD.     

The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease

Alzheimer's disease (AD) is the 3rd most costly disease and the leading cause of dementia. It can linger for many years, but ultimately is fatal, the 6th leading cause of death. Alzheimer's disease (AD) is fatal and affected individuals can sometimes linger many years. Current treatments are palliative and transient, not disease modifying. This article reviews progress in the search to identify the primary AD-causing toxins. We summarize the shift from an initial focus on amyloid plaques to the contemporary concept that AD memory failure is caused by small soluble oligomers of the Aβ peptide, toxins that target and disrupt particular synapses. Evidence is presented that links Aβ oligomers to pathogenesis in animal models and humans, with reference to seminal discoveries from cell biology and new ideas concerning pathogenic mechanisms, including relationships to diabetes and Fragile X. These findings have established the oligomer hypothesis as a new molecular basis for the cause, diagnosis, and treatment of AD.     

Prefrontal cortex or basolateral amygdala lesions blocked the stress-induced inversion of serial memory retrieval pattern in mice

Previous data from our team have shown that pre-test stress in mice reversed the pattern of memory retrieval in a contextual serial spatial task (CSD; Celerier, A., Pierard, C., Rachbauer, D., Sarrieau, A., & Beracochea, D. (2004). Contextual and serial discriminations: A new learning paradigm to assess simultaneously the effects of acute stress on retrieval of flexible or stable information in mice. Learning and Memory, 11, 196-204). The present study is aimed at determining brain areas which might be critically involved in mediating the stress effect on memory retrieval in the CSD task. For that purpose, we studied hereby the effects of ibotenic acid lesions of either the prefrontal cortex (PFC) or the basolateral amygdala (BLA) in Stressed or Non-Stressed Balb/c mice on memory retrieval in the CSD task. In that task, mice learned two successive spatial discriminations (D1 and D2) within two different internal contexts in a four-hole board. The stressor (electric footshocks) was delivered 5 min before test, occurring 24 h after acquisition. During test, mice were relocated either on the floor of the first or of the second discrimination. Results showed that (i) spatial memory was substantial and remained unaffected both by lesions and stress; (ii) Non-Stressed controls as well as Non-Stressed or Stressed PFC and BLA-lesioned mice remembered accurately D1 but not D2; and (iii) in contrast, Stressed controls accurately remembered D2 but not D1. In parallel to behavioral experiments, we also showed that PFC and BLA lesions did not affect the stress-induced increase of plasma corticosterone levels. All together, PFC and BLA integrity are not necessary for retrieval processes per se; in contrast, the PFC and BLA are critically involved in the mediation of the deleterious stress effects on serial order memory retrieval.     

血糖水平对STZ鼠探究行为及学习记忆的影响

为了解不同血糖水平下链脲佐菌素诱导鼠（STZ鼠）探究行为与学习和记忆的变化情况,把60只STZ鼠按血糖水平分成高血糖组、良好血糖组和低血糖组3组,进行延迟时间、探究时间测定和小鼠跳台试验,并与正常对照组比较。结果发现,良好血糖组与正常对照组各检测指标均相近;3组STZ鼠延迟时间、完成迷津作业时间均按血糖值递增;组间差异显著;小鼠跳台试验中高血糖组的错误数最多,24小时后错误数最少,前后差值有组间差异;延迟时间、探究时间与血糖呈显著正相关,错误数差值与血糖呈显著负相关。结果表明,高血糖鼠的探究行为和学习能力最差,但对被动回避学习的记忆保持相对较好。     

Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57BL/6 mice

Recent studies in patients with hippocampal lesions have indicated that the degree of memory impairment is proportional to the extent of damage within the hippocampus. Particularly, patients with damage restricted to the CA1 field demonstrate moderate to severe anterograde amnesia with only slight retrograde amnesia. Comparable results are also seen in other species such as non-human primates and rats; however, the effect of selective damage to CA1 has not yet been characterized in mice. In the present study, we investigated the effects of excitotoxic (NMDA) lesions of dorsal CA1 on several aspects of learning and memory performance in mice. Our data indicate that dorsal CA1 lesioned mice are hyperactive upon exposure to a novel environment, have spatial working memory impairments in the Y-maze spontaneous alternation task, and display deficits in an 8-arm spatial discrimination learning task. Lesioned mice are able to acquire an operant lever-press task but demonstrate extinction learning deficits in this appetitive operant paradigm. Taken together, our results indicate that lesions to dorsal CA1 in mice induce selective learning and memory performance deficits similar to those observed in other species, and extend previous findings indicating that this region of the hippocampus is critically involved in the processing of spatial information and/or the processing of inhibitory responses.     

Psychophysiological mediators of caregiver stress and differential cognitive decline

The authors examined relationships between chronic stress and cognitive decline and whether such relationships were mediated by psychophysiological factors. Ninety-six caregivers of spouses with Alzheimer's disease (AD) were compared with 95 similar noncaregiver spouses. All were free of diabetes. Although the groups started similarly, over 2 years caregivers declined by a small but significant amount (1 raw score point and 4 percentile points, each p<.05) on Shipley Vocabulary. In contrast, noncaregivers did not change. Higher hostile attribution (beta=-.09; p<.05) and metabolic risk (beta=-.10; p<.05) in caregivers mediated the cognitive decline. This is the first study of cognitive decline and mediators in caregivers. This work has implications for caregiver and care-recipient health and for research on cognition, psychophysiology, diabetes, and AD.     

In vitro hippocampal gamma oscillation power as an index of in vivo CA3 gamma oscillation strength and spatial reference memory

Neuronal synchronisation at gamma frequencies (30-100 Hz) has been implicated in cognition and memory. Gamma oscillations can be studied in various in vitro models, but their in vivo validity and their relationship with reference memory remains to be proven. By using the natural variation of wild type C57bl/6J mice, we assessed the relationships between reference memory and gamma oscillations recorded in hippocampal area CA3 in vivo and in vitro. Local field potentials (LFPs) were recorded from area CA3 in behaviourally-characterised freely moving mice, after which hippocampal slices were prepared for recordings in vitro of spontaneous gamma oscillations and kainate-induced gamma oscillations in CA3. The gamma-band power of spontaneous oscillations in vitro correlated with that of CA3 LFP oscillations during inactive behavioural states. The gamma-band power of kainate-induced oscillations correlated with the activity-dependent increase in CA3 LFP gamma-band power in vivo. Kainate-induced gamma-band power correlated with Barnes circular platform performance and object location recognition, but not with object novelty recognition. Kainate-induced gamma-band power was larger in mice that recognised the aversive context, but did not correlate with passive avoidance delay. The correlations between behavioural and electrophysiological measures obtained from the same animals show that the gamma-generating capacity of the CA3 network in vitro is a useful index of in vivo gamma strength and supports an important role of CA3 gamma oscillations in spatial reference memory.     

Hippocampal CA1 spiking during encoding and retrieval: relation to theta phase

The hippocampal theta rhythm is a prominent oscillation in the field potential observed throughout the hippocampus as a rat investigates stimuli in the environment. A recent computational model [Hasselmo, M. E., Bodelon, C., & Wyble, B. P. (2002a). A proposed function for hippocampal theta rhythm: separate phases of encoding and retrieval enhance reversal of prior learning. Neural Computation, 14, 793-817. Neuromodulation, theta rhythm and rat spatial navigation. Neural Networks, 15, 689-707] suggested that the theta rhythm allows the hippocampal formation to alternate rapidly between conditions that promote memory encoding (strong synaptic input from entorhinal cortex to areas CA3 and CA1) and conditions that promote memory retrieval (strong synaptic input from CA3 to CA1). That model predicted that the preferred theta phase of CA1 spiking should differ for information being encoded versus information being retrieved. In the present study, the spiking activity of CA1 pyramidal cells was recorded while rats performed either an odor-cued delayed nonmatch-to-sample recognition memory test or an object recognition memory task based on the animal's spontaneous preference for novelty. In the test period of both tasks, the preferred theta phase exhibited by CA1 pyramidal cells differed between moments when the rat inspected repeated (match) and non-repeated (nonmatch) items. Also in the present study, additional modeling work extended the previous model to address the mean phase of CA1 spiking associated with stimuli inducing varying levels of retrieval relative to encoding, ranging from novel nonmatch stimuli with no retrieval to highly familiar repeated stimuli with extensive retrieval. The modeling results obtained here demonstrated that the experimentally observed phase differences are consistent with different levels of CA3 synaptic input to CA1 during recognition of repeated items.     

The hippocampus and prefrontal cortex are differentially involved in serial memory retrieval in non-stress and stress conditions

We previously showed that 24 h after learning, mice significantly remembered the first (D1) but not the second (D2) discrimination in a serial spatial task and that an acute stress delivered 5 min before the test phase reversed this memory retrieval pattern.A first experiment evaluated the effects of dorsal hippocampus (HPC) or prefrontal cortex (PFC) lesions, these two brain areas being well-known for their involvement in serial and spatial memory processes. For this purpose, six independent groups of mice were used: non-lesioned (controls), PFC or HPC-lesioned animals, submitted or not to an acute stress (electric footshocks; 0.9 mA). Results show that (i) non-stressed controls as well as PFC-lesioned mice (stressed or not) remembered D1 but not D2; (ii) stressed controls and HPC-lesioned mice (stressed or not) remembered D2 but not D1; (iii) stress significantly increased plasma corticosterone in controls and PFC-lesioned mice, but not in HPC-lesioned mice which already showed a significant plasma corticosterone increase in non-stressed condition.Since data from this first experiment showed that stress inhibited the hippocampal-dependent D1 memory retrieval, a second experiment evaluated the behavioral effect of intrahippocampal corticosterone injection in non-stressed mice. Results show that intrahippocampal corticosterone injection induced a reversal of serial memory retrieval pattern similar to that induced by acute stress.Overall, our study shows that (i) in non-stress condition, the emergence of D1 is HPC-dependent; (ii) in stress condition, the emergence of D2 requires the PFC integrity; moreover, intrahippocampal corticosterone injection mimicked the effects of stress in the CSD task.     

Environmental enrichment modifies the PKA-dependence of hippocampal LTP and improves hippocampus-dependent memory

cAMP-dependent protein kinase (PKA) is critical for the expression of some forms of long-term potentiation (LTP) in area CA1 of the mouse hippocampus and for hippocampus-dependent memory. Exposure to spatially enriched environments can modify LTP and improve behavioral memory in rodents, but the molecular bases for the enhanced memory performance seen in enriched animals are undefined. We tested the hypothesis that exposure to a spatially enriched environment may alter the PKA dependence of hippocampal LTP. Hippocampal slices from enriched mice showed enhanced LTP following a single burst of 100-Hz stimulation in the Schaffer collateral pathway of area CA1. In slices from nonenriched mice, this single-burst form of LTP was less robust and was unaffected by Rp-cAMPS, an inhibitor of PKA. In contrast, the enhanced LTP in enriched mice was attenuated by Rp-cAMPS. Enriched slices expressed greater forskolin-induced, cAMP-dependent synaptic facilitation than did slices from nonenriched mice. Enriched mice showed improved memory for contextual fear conditioning, whereas memory for cued fear conditioning was unaffected following enrichment. Our data indicate that exposure of mice to spatial enrichment alters the PKA dependence of LTP and enhances one type of hippocampus-dependent memory. Environmental enrichment can transform the pharmacological profile of hippocampal LTP, possibly by altering the threshold for activity-dependent recruitment of the cAMP-PKA signaling pathway following electrical and chemical stimulation. We suggest that experience-dependent plasticity of the PKA dependence of hippocampal LTP may be important for regulating the efficacy of hippocampus-based memory.     

Enhanced cognitive activity--over and above social or physical activity--is required to protect Alzheimer's mice against cognitive impairment, reduce Abeta deposition, and increase synaptic immunoreactivity

Although social, physical, and cognitive activities have each been suggested to reduce the risk of Alzheimer's disease (AD), epidemiologic studies cannot determine which activity or combination of activities is most important. To address this question, mutant APP transgenic AD mice were reared long-term in one of four housing conditions (impoverished, social, social+physical, or complete enrichment) from 1(1/2) through 9 months of age. Thus, a stepwise layering of social, physical, and enhanced cognitive activity was created. Behavioral evaluation in a full battery of sensorimotor, anxiety, and cognitive tasks was carried out during the final 5 weeks of housing. Only AD mice raised in complete enrichment (i.e., enhanced cognitive activity) showed: (1) protection against cognitive impairment, (2) decreased brain beta-amyloid deposition, and (3) increased hippocampal synaptic immunoreactivity. The protection provided by enhanced cognitive activity spanned multiple cognitive domains (working memory, reference learning, and recognition/identification). Cognitive and neurohistologic benefits of complete enrichment occurred without any changes in blood cytokine or corticosterone levels, suggesting that enrichment-dependent mechanisms do not involve changes in the inflammatory response or stress levels, respectively. These results indicate that the enhanced cognitive activity of complete enrichment is required for cognitive and neurologic benefit to AD mice-physical and/or social activity are insufficient. Thus, our data suggest that humans who emphasize a high lifelong level of cognitive activity (over and above social and physical activities) will attain the maximal environmental protection against AD.