Jianting Miao

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.

Early memory deficits precede plaque deposition in APPswe/PS1dE9 mice: involvement of oxidative stress and cholinergic dysfunction.

A large body of evidence has shown that cognitive deficits occur early, before amyloid plaque deposition, suggesting that soluble amyloid-β protein (Aβ) contributes to the development of early cognitive dysfunction in Alzheimer disease (AD). However, the underlying mechanism(s) through which soluble Aβ exerts its neurotoxicity responsible for cognitive dysfunction in the early stage of AD remains unclear so far. In this study, we used preplaque APPswe/PS1dE9 mice ages 2.5 and 3.5 months to examine alterations in cognitive function, oxidative stress, and cholinergic function. We found that only soluble Aβ, not insoluble Aβ, was detected in these preplaque APPswe/PS1dE9 mice. APPswe/PS1dE9 mice 2.5 months of age did not show any significant changes in the measures of cognitive function, oxidative stress, and cholinergic function, whereas 3.5-month-old APPswe/PS1dE9 mice exhibited spatial memory impairment in the Morris water maze, accompanied by significantly decreased acetylcholine (ACh), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) as well as increased malondialdehyde (MDA) and protein carbonyls. In 3.5-month-old preplaque APPswe/PS1dE9 mice, correlational analyses revealed that the performance of impaired spatial memory was inversely correlated with soluble Aβ, MDA, and protein carbonyls, as well as being positively correlated with ACh, ChAT, SOD, and GSH-px; soluble Aβ level was inversely correlated with ACh, ChAT, SOD, and GSH-px, as well as being positively correlated with MDA and protein carbonyls; ACh level showed a significant positive correlation with ChAT, SOD, and GSH-px, as well as a significant inverse correlation with MDA and protein carbonyls. Collectively, this study provides direct evidence that increased oxidative damage and cholinergic dysfunction may be early pathological responses to soluble Aβ and involved in early memory deficits in the preplaque stage of AD. These findings suggest that early antioxidant therapy and improving cholinergic function may be a promising strategy to prevent or delay the onset and progression of AD.

RETRACTED: Neuronal damage, central cholinergic dysfunction and oxidative damage correlate with cognitive deficits in rats with chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion has been identified to be a risk factor for cognitive decline in aging, vascular dementia, and Alzheimers disease. Substantial evidence has shown that chronic cerebral hypoperfusion may cause cognitive impairment, but the underlying neurobiological mechanism is poorly understood so far. In this study, we used a rat model of chronic cerebral hypoperfusion by permanent bilateral common carotid artery occlusion (BCCAO) to investigate the alterations of neuronal damage, glial activation oxidative stress and central cholinergic dysfunction, and their causal relationship with the cognitive deficits induced by chronic cerebral hypoperfusion. We found that BCCAO rats exhibited spatial learning and memory impairments and working memory dysfunction 12 weeks after BCCAO compared with sham-operated rats, simultaneously accompanied by significantly increased neuronal damage and glial cell activation in the cerebral cortex and hippocampus. Twelve weeks of BCCAO treatment in rats resulted in central cholinergic dysfunction and increased oxidative damage compared with sham-operated rats. Correlational analyses revealed that spatial learning and memory impairments and working memory dysfunction were significantly correlated with the measures of neuronal damage, central cholinergic dysfunction and oxidative damage in the cerebral cortex and hippocampus of rats with BCCAO. Moreover, the measures of neuronal damage and central cholinergic dysfunction were significantly correlated with the indexes of oxidative damage in rats with BCCAO. Collectively, this study provides novel evidence that neuronal damage and central cholinergic dysfunction is likely due to increased oxidative stress under the condition of chronic cerebral hypoperfusion. Furthermore, the results of the present study suggest that neuronal damage, central cholinergic dysfunction and oxidative damage in the brain following the reduction of cerebral blood flow could be involved in cognitive deficits induced by chronic cerebral hypoperfusion.

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.

S14G-humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice.

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by clinical cognitive decline and pathological deposition of amyloid-beta protein (Aβ) in the brain. So far, there has been no causative therapy for this devastating disease. S14G-Humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to have strong neuroprotective ability against AD-related insults in vitro and prevent cognitive impairments in Aβ-infused animal models. In addition, a recent study has reported a beneficial effect of intranasal HNG treatment on memory deficit and Aβ accumulation in triple transgenic (3xTg-AD) mice at the early plaque-bearing stage. However, whether HNG treatment has the disease-modifying efficacy on AD with pre-existing well-established amyloid plaque pathology remains unclear. In this study, we employed 9-month-old APPswe/PS1dE9 mice with pre-existing robust amyloid plaque pathology to investigate the effects of chronic HNG treatment on the progression of cognitive dysfunction and Aβ-associated neuropathology. We found that vehicle-treated APPswe/PS1dE9 mice showed impaired spatial learning and memory compared with vehicle- and HNG-treated wild-type mice, while intraperitoneal HNG treatment for 3 months significantly improved spatial learning and memory deficits in APPswe/PS1dE9 mice compared with vehicle control treatment. Coincidental with this, HNG treatment significantly reduced cerebral Aβ plaque deposition, insoluble Aβ levels, and neuroinflammatory responses in APPswe/PS1dE9 mice compared with control treatment. Cumulatively, these findings demonstrate that chronic administration of HNG is able to attenuate cognitive deficits and reduce Aβ loads as well as neuroinflammation in the middle-aged APPswe/PS1dE9 mice even with pre-existing substantial Aβ neuropathology, indicating that HNG has potential as a pharmacotherapeutic intervention in the development of cognitive deficits and neuropathology seen in the cases of established AD.

Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice.

Growing evidence indicates that the activation of c‐Jun N‐terminal kinase (JNK) is implicated in the multiple major pathological features of Alzheimer disease (AD). However, whether specific inhibition of JNK activation could prevent disease progression in adult transgenic AD models at moderate stage remains unknown. Here we first investigated the potential disease‐modifying therapeutic effect of systemic administration of SP600125, a small‐molecule JNK‐specific inhibitor, in middle‐aged APPswe/PS1dE9 mice.

Rutin protects against cognitive deficits and brain damage in rats with chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion is a critical causative factor for the development of cognitive decline and dementia in the elderly, which involves many pathophysiological processes. Consequently, inhibition of several pathophysiological pathways is an attractive therapeutic strategy for this disorder. Rutin, a biologically active flavonoid, protects the brain against several insults through its antioxidant and anti‐inflammatory properties, but its effect on cognitive deficits and brain damage caused by chronic cerebral hypoperfusion remains unknown. Here, we investigated the neuroprotective effect of rutin on cognitive impairments and the potential mechanisms underlying its action in rats with chronic cerebral hypoperfusion.

Protective effect of S14G-humanin against beta-amyloid induced LTP inhibition in mouse hippocampal slices.

Synaptic dysfunction induced by amyloid-beta protein (Abeta) has been shown to play a critical role in cognitive deficits of Alzheimers disease (AD). Currently, however there is no clinical causative therapy for the disease. S14G-humanin (HNG) is best known for its strong neuroprotective ability against AD-related insults in vitro, and several in vivo studies have shown its effectiveness in ameliorating the cognitive impairment, but the precise mechanism of HNG on neuroprotection still remains to be elucidated. The present study examined the effects of HNG on Abeta-induced inhibition of hippocampal long-term potentiation (LTP) in mouse hippocampal slices. The results disclosed that soluble Abeta(25-35) significantly inhibited the induction of early-phase LTP (E-LTP) and late-phase LTP (L-LTP) in the hippocampal CA1 region without affecting the basal synaptic transmission, while HNG significantly ameliorated such inhibition of E-LTP and L-LTP in a dose-dependent manner. In addition, the reduction of phosphorylated CREB trigged by Abeta(25-35) was restored by HNG during L-LTP induction, possibly attributing to the improvement of the L-LTP inhibition. Collectively, our findings add to the evidence that soluble Abeta-induced LTP inhibition may represent an early pathological event of AD, and demonstrate for the first time that HNG may improve LTP inhibition by subneurotoxic concentration of soluble Abeta, suggesting that HNG may have therapeutic potential for Abeta-induced synaptic dysfunction closely associated with cognitive deficits in the early stage of 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.