Gesheng Lei

Soluble Aβ levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease.

Amyloid-beta peptide (Aβ) is believed to be central in the pathogenesis of Alzheimers disease (AD) characterized by cognitive deficits. However, it remains uncertain which form(s) of Aβ pathology is responsible for the cognitive deficits in AD. In the present study, the cognitive deficits and the profiles of Aβ pathology were characterized in the 12-month-old APPswe/PS1dE9 double transgenic mice, and their correlations were examined. Compared with non-transgenic littermates, the middle-aged APPswe/PS1dE9 mice exhibited spatial learning and memory deficits in the water maze test and long-term contextual memory deficits in the step-down passive avoidance test. Among the middle-aged APPswe/PS1dE9 mice, hippocampal soluble Aβ1-40 and Aβ1-42 levels were highly correlated with spatial learning deficits and long-term contextual memory deficits, as well as cortical and hippocampal soluble Aβ1-40 and Aβ1-42 levels were strongly correlated with spatial memory deficits. By contrast, no significant correlations were observed between three measures of cognitive functions and amyloid plaque burden (total Aβ plaque load and fibrillar Aβ plaque load), total Aβ levels (Aβ1-40 and Aβ1-42), as well as insoluble Aβ levels (Aβ1-40 and Aβ1-42). Stepwise multiple regression analysis identified hippocampal soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial learning deficits and the long-term contextual memory deficits, as well as hippocampal and cortical soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial memory deficits in transgenic mice. These results demonstrate that cognitive deficits are highly related to the levels of soluble Aβ in middle-aged APPswe/PS1dE9 mice, in which soluble Aβ levels are only a tiny fraction of the amount of total Aβ levels. Consequently, our findings provide further evidence that soluble Aβ might primarily contribute to cognitive deficits in AD, suggesting that reducing the levels of soluble Aβ species would be a therapeutic intervention for AD patients even with large deposits of aggregated, insoluble Aβ.

RETRACTED: S14G-Humanin ameliorates Aβ25-35-induced behavioral deficits by reducing neuroinflammatory responses and apoptosis in mice

Cerebral amyloid-beta protein (Abeta) deposition and associated neuroinflammation and apoptosis are increasingly recognized as an important component leading to cognitive impairment in Alzheimers disease (AD). Humanin (HN) and its derivative, S14G-HN (HNG), are best known for their ability to suppress neuronal death induced by AD-related insults in vitro. Furthermore, limited in vivo studies show that HNG can ameliorate memory impairment induced by intracerebroventricular injection of anti-cholinergic drugs or Abeta25-35. However, the mechanism underlying the in vivo effect remains unclear. In this study, we sought to determine the effects of HNG on neuroinflammatory responses and apoptosis associated with behavioral deficits induced by Abeta25-35 in vivo. Our results indicate that intracerebroventricular injection of aggregated Abeta25-35 induced impairment of learning and memory, markedly elevated numbers of reactive astrocytes, activated microglia, and apoptotic cells, as well as remarkable increased levels of IL-6 and TNFalpha. Moreover, intraperitoneal HNG treatment ameliorated behavioral deficits, and reduced neuroinflammatory responses and apoptotic cells in the brain. Cumulatively, these finding demonstrate for the first time that HNG may have the potential for attenuating Abeta-induced cognitive deficits by reducing inflammatory responses and apoptosis in vivo, which may add to the novel evidence for anti-inflammatory and antiapoptosis properties of HNG in AD treatment.

Multiple inflammatory pathways are involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice

Increased accumulation of amyloid-beta peptide (Aβ) and neuroinflammation is known to exist within the Alzheimers disease (AD) brain. However, it remains unclear which form of Aβ pathologies triggers neuroinflammation and whether increased neuroinflammation contributes to cognitive deficits in AD. In the present study we found that increased inflammatory responses might occur early in preplaque APPswe/PS1dE9 mice, and were significantly enhanced in both early- and late-plaque APPswe/PS1dE9 mice. Correlational analysis revealed that multiple inflammatory indexes significantly correlated with soluble Aβ level, rather than amyloid plaque burden or insoluble Aβ level, in APPswe/PS1dE9 mice. Moreover, multiple inflammatory indexes highly correlated with the impaired spatial learning and memory in APPswe/PS1dE9 mice. Collectively, these results provide evidence that inflammatory responses might be likely triggered by soluble toxic Aβ species. Importantly, we demonstrate for the first time that multiple inflammatory pathways might be involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice, suggesting that a pharmacological approach targeting multiple inflammatory pathways may be a novel promising strategy to prevent or delay AD.

NREM-AHI greater than REM-AHI versus REM-AHI greater than NREM-AHI in patients with obstructive sleep apnea: clinical and polysomnographic features

PurposePrevious studies show a high prevalence of obstructive sleep apnea (OSA) patients with a higher non-rapid eye movement (NREM) apnea–hypopnea index (AHI) (NREM-AHI) than rapid eye movement (REM) AHI (REM-AHI). However, the clinical significance of this phenomenon in patients with OSA is unknown. This study aimed to investigate whether there were significant differences in clinical and polysomnographic features between the NREM-AHI > REM-AHI group and the REM-AHI > NREM-AHI group and to determine whether NREM-AHI > REM-AHI or REM-AHI > NREM-AHI is a specific clinical entity.MethodsOne hundred forty-two patients with OSA, including 114 males and 28 females, were assessed for specific sleep-related complaints using a semistructured clinical questionnaire, for daytime sleepiness using the Epworth Sleepiness Scale (ESS), for depression using the Beck Depression Inventory (BDI), and for health-related quality of life using the Medical Outcomes Study Short-Form 36 Health Survey questionnaire (SF-36). Anthropometric, clinical, and polysomnographic characteristics were examined between patients with NREM-AHI > REM-AHI and those with REM-AHI > NREM-AHI.ResultsA higher NREM-AHI than REM-AHI was found in 54.9% of the 142 patients with OSA. Overall, males predominated in each group, and there were no significant differences in age, body mass index, medical history, and drug intake between the NREM-AHI > REM-AHI group and the REM-AHI > NREM-AHI group. A high occurrence of NREM-AHI > REM-AHI (94.9%) or REM-AHI > NREM-AHI (90.6%) was found in moderate-to-severe cases each group. Although several indexes of OSA were worse in the NREM-AHI > REM-AHI group than in the REM-AHI > NREM-AHI group, no significant differences in specific sleep-related complaints, ESS score, BDI score, the incidence of daytime sleepiness or depression, and scores of sub-dimensions and the total score on SF-36 were present between the two groups. As compared separately, no significant differences in clinical features were observed in the clinical data for males and females between the two groups.ConclusionsOur results show that either NREM-AHI > REM-AHI or REM-AHI > NREM-AHI is more common in moderate-to-severe OSA cases, and there are no significant differences in clinical features between the NREM-AHI > REM-AHI group and the REM-AHI > NREM-AHI group. These findings may suggest that either NREM-AHI > REM-AHI or REM-AHI > NREM-AHI should be considered as a part of the spectrum of OSA, rather than a specific clinical entity.

Aβ20–29 peptide blocking apoE/Aβ interaction reduces full-length Aβ42/40 fibril formation and cytotoxicity in vitro

A key event in the pathogenesis of Alzheimers disease (AD) is the conversion of the peptide beta-amyloid (Abeta) from its soluble monomeric form into various aggregated morphologies in the brain. Apolipoprotein E (apoE) is known to act as a pathological chaperone of Abeta in this process, promoting its fibril formation from soluble Abeta by binding interaction between carboxy-terminal domain of apoE and residues 12-28 of full-length Abeta. Therefore, blocking apoE/Abeta interaction is being actively pursued as a primary therapeutic strategy for AD. Abeta20-29, a short peptide, contains the residues to competitively bind to apoE and may potentially block the interaction between apoE and full-length Abeta. However, little is known whether Abeta20-29 could block apoE/Abeta interaction to play an effective role in reducing full-length Abeta fibrillization and cytotoxicity. Utilizing fluorescence spectroscopic analysis with thioflavin T and electron microscopic study, we show here that Abeta20-29 alone was non-fibrillogenic, and had no direct effects on Abeta1-42 or Abeta1-40 aggregation. Moreover, apoE can directly promote both Abeta1-42 and Abeta1-40 aggregation and fibril formation, while this promoting effect was inhibited when adding Abeta20-29, with a dose-dependent manner. In the series of cell culture experiments, Abeta20-29 alone shows no cytotoxicity to PC12 cells as demonstrated by MTT assay, while co-incubation apoE isoforms and Abeta1-42 or Abeta1-40 shows stronger cytotoxicity as compared to Abeta1-42 or Abeta1-40 alone. When incubated with Abeta20-29, whereas such strong cytotoxic effect was concentration-dependently reduced. Taken together, we demonstrate for the first time that Abeta20-29 has no direct effect on full-length Abeta aggregation, and may competitively block the binding of full-length Abeta to apoE, resulting in an inhibitory effect on apoEs promoting full-length Abeta fibrillogenesis and Abeta-induced cytotoxicity. Our results raise the possibility that Abeta20-29 peptide blocking the interaction between full-length Abeta and apoE isoforms may be effective as a therapeutic agent for AD.

Multiple forms of rhythmic movements in an adolescent boy with rhythmic movement disorder

Rhythmic movement disorder (RMD) refers to a group of stereotyped, repetitive movements involving large muscles, usually occurring prior to the onset of sleep and persisting into sleep. RMD more commonly exhibits only one or two forms of rhythmic movements (RM) in most reported cases. However, multiple RM forms of RMD occurring in a patient in the same night have rarely been reported. In this report, we present the unique case of a 15-year-old boy with RMD affected by multiple forms of RM in the same night, including four known forms (i.e., body rocking, head banging, leg rolling, and rhythmic feet movements) and two new kinds of RM (bilateral rhythmic arm rocking and rhythmic hands movements). Two video-polysomnographic recordings were performed in this patient before starting pharmacologic treatment and after long-term oral clonazepam treatment (1.0mg nightly for 3 months). The characteristics of RMD with multiple RM forms and the effectiveness of clonazepam on the RM episodes and polysomnographic findings observed in our patient are discussed. This report raises the fact that a patient with RMD may present with multiple complex rhythmic movements disrupting sleep, which emphasizes that better understanding of the clinical features of complex rhythmic movements during sleep in primary care settings is essential for early clinical diagnosis and optimal management.

Severe sleep-disordered breathing in a patient with Brown–Vialetto–Van Laere syndrome: Polysomnographic findings

Brown-Vialetto-Van Laere (BVVL) syndrome is a rare disorder with clinical features that include progressive bilateral sensorineural deafness and a variety of cranial nerve impairments. Respiratory compromise has been observed in most familial and sporadic cases; however, few studies have been published regarding sleep-disordered breathing in this syndrome. We report the unique case of a 16-year-old girl with the clinical features of BVVL syndrome who presented with bilateral sensorineural hearing loss and then progressively developed paralysis of the 7th and 9th-12th cranial nerves. More importantly, she presented with the unusual feature of severe sleep-disordered breathing. A polysomnographic study showed evidence of dominant central sleep apnea, and the majority of apneic episodes more likely occurred in stage 2 during NREM sleep. The central sleep apnea was associated with rapid respiratory deterioration and death. This report raises the fact that a patient with BVVL syndrome may present with severe sleep-disordered breathing as a life-threatening condition, which emphasizes the need for greater attention to the early detection of potential sleep-disordered breathing in these afflicted with the BVVL syndrome for optimal clinical management.

Severe bilateral pyramidal tract involvement in a patient with Parry-Romberg syndrome.

Parry-Romberg syndrome (PRS) is a rare clinical entity of unknown etiology, generally characterized by a slow and progressive atrophy that affects 1 side of the face. A variety of neurologic abnormalities have been shown to coexist with PRS. However, few studies regarding pyramidal tract involvement in this disorder have been reported. We report a unique case, in which the patient presented with bilateral pyramidal tract insult and an unusual sequence of disease onset and progression. This case suggests a rarer variant of PRS, and the neurologic findings indicate that the underlying essential neural degeneration may contribute to the processing of pyramidal tract insult or this syndrome.

Delayed parkinsonism with a selective symmetric basal ganglia lesion after manual strangulation

A 21-year-old woman, who experienced manual strangulation, developed delayed parkinsonism associated with a selective symmetric basal ganglia lesion. The patient had recovered completely one year after early combination therapy. This case emphasizes the need for greater attention in detecting early brain injuries in those afflicted with strangulation so as to provide optimal management.

Retraction notice to “S14G-humanin Ameliorates Aβ 25-35-induced Behavioral Deficits by Reducing Neuroinflammatory Responses and Apoptosis in Mice” [Neuropeptides 42/5-6 (2008) 557–567]

This article has been retracted: please see Elsevier Policy on Article animal, whereas panel B is from an HNG treated animal. In Figure 7, Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor and the Authors. There are some inappropriate manipulations or alterations of photographs in this publication. Specifically, in Figure 4, Panels A and B show identical brain sections, 90 degrees rotated. According to the legend, panel A is from a non-treated animal, whereas panel B is from anHNG treated animal. In Figure 5, Panels A and B shownearly identical brain sections, mirrored. A structure present in panel A is absent from panel B. Both panels contain repetitions that could result from deliberate manipulation. According the legend, panel A is from a non-treated