Abstract:[Editorial Materials]

Abstract:[Editorial Materials]

Abstract:Alzheimer's disease (AD) is a genetically complex disorder, and the pathophysiological process of AD is thought to begin many years before the diagnosis of AD dementia. This long pre-dementia phase of AD would provide a critical opportunity for therapeutic intervention. Therefore, pre-dementia stage of AD, including mild cognitive impairment (MCI) and pre-MCI, have attracted great interest and become a focus of the research for AD．Many genes have been reported to contribute to the disease susceptibility. So far, the apolipoprotein E gene (APOE) ε4 allele is considered as an only undisputed genetic risk factor for sporadic AD (SAD). A large number of studies aimed to help uncover the remaining disease-related loci in recent decades, but the genetic researches associated with conversion of pre-MCI, MCI to AD dementia are still rare. Here we provide a review on some main AD candidate genes.

Abstract:Post-transcriptional regulation plays a central role in the development and maintenance of the nervous system. Defects in post-transcriptional regulation lead to neurodegenerative diseases. Mounting evidence suggests that the impaired post-transcriptional regulation of associated genes contribute to the neurodegenerative process, such as Alzheimer's disease (AD). This review discusses the role of disruption of alternative splicing regulation of the human tau gene (MAPT) and alterations of microRNA expression in the pathogenesis of neurodegeneration including AD. A brief overview is provided for the role and the mechanism of post-transcriptional regulation in AD pathogenesis.

Abstract:Aβ is the major components of amyloid plaque deposition in the brain, and is considered to be the initiating factor for the pathogenesis of Alzheimer's disease(AD). β-amyloid precursor protein cleaving enzyme 1 (BACE1) is one of the important enzymes in the Aβ production. The process of maturation and expression of BACE1 is regulated by a variety of factors. Some of the pathological changes of early onset of AD such as ischemia, hypoxia, inflammation and stress are considered to be BACE1 related. Many BACE1 and Aβ related cytokines in the fluids may become potential biomarkers, which would provide ideas for early clinical diagnosis of AD.

Abstract:Alzheimer′s disease(AD), which is characterized with acquired deterioration of cognitive functioning and neuronal loss, is the most common neurodegenerative disease in the elderly population. However, the pathogenesis of AD is still unclear. The accumulation of β-amyloid protein(Aβ) in the brains has been associated with pathogenesis of AD. Studies have shown that astrocytes, the most abundant cells in the central nervous system (CNS), play an important role in the cause and progression of AD by regulating the metabolism of Aβ. The present paper reviews the production, internalization and degradation of Aβ in astrocytes. Our goal is to provide updated views of the role and mechanism of astrocytes in the metabolism of Aβ and its role in pathogenesis in the early stages of Alzheimer′s disease.

Abstract:Deposition of β amyloid (Aβ) in hippocampus is a crucial progression in the pathophysiology of Alzheimer′s disease (AD). Decreasing its formation and/or increasing its clearance have become a focus of AD therapy. As compared with increased Aβ production, decreased Aβ degradation plays a more important role in AD pathogenesis. Although Aβ can be cleared through transportation to the blood and cerebral spinal fluid pathway, the so-called "vascular system", most Aβ peptide was degraded to small molecules by a kind of protease called Aβ degrading enzyme represented by neprilysin (NEP). In the olderly, mild cognitive impairment and AD patients, the NEP activity is decreased, and the decreased NEP activity is correlated with Aβ content in brain and cognitive function impairment. If NEP activity was increased to degrade Aβ, it may inhibit AD progression and even have disease-modifying potential in AD and NEP thus may behave as a potential drug target for AD therapy.

Abstract:Autophagy is a main pathway that clears the dysfunction organelles, misfolding proteins and oxidative lipids. It's important for maintaining life activity and conserved from yeast to mammalian. In the AD neurons the misfolding proteins were not efficiently cleared then accumulated. These caused neurons loss of function even neuron death. This review focuses on the recent progresses on regulation of autophagy and the role of autophagy in Alzheimer's diseases. Autophagy is protective in early stage of AD, although it induces autophagic cell death in late stage of AD. Autophagosome may be the main site for Aβ production and clearance. Presenilin 1 which is the key proteinase in γ-secrectase also plays a role in lysosomal acidification which is a key step for autophagic degradation. Tau may be involved in autophagosome trafficking and autophagosome-lysosome fusion. mTOR and AMPK sensing nutrients and energy in cells also regulate autophagy.

Abstract:Alzheimer's disease (AD) is the most common cause of dementia among the elderly people. The prevailing hypothesis for the pathological progression of AD is the β-amyloid peptide (Aβ) cascade hypothesis: oligomeric forms of Aβ with cytotoxicity are the main cause of neuronal death in the brain of the AD patients. Thus, the inhibition of Aβ production and aggregation as well as improvement of its clearance appear to be the main strategy for drug development. However, the disturbing issue is that no significantly effective approach is available yet although a large number of compounds have been trialed on clinic. It questions the hypothesis that Aβ is the key pathologic factor leading to AD progression. The other possibility of failure is that loss of neural cells is so extensive that any treatment becomes not available when cognitive symptoms are apparent. New diagnostic ways may help to identify individuals before substantial neural damage has occurred. Treatments could then be attempted to stave off the onset of the disorders or the progression of the disease.

Abstract:This article reviews the relationship between brain aging and Alzheimer's disease (AD). Specific issues addressed include the question of whether AD and brain aging should be conceptually lumped or split, the extent to which AD and brain aging potentially share common molecular mechanisms, whether beta amyloid should be primarily considered a marker of AD or simply brain aging, and the definition of AD itself. A small percentage of individuals with normal antemortem psychometric scores meet the neuropathological criteria for AD termed "preclinical" AD (PCAD). PCAD and control subjects were compared for oxidative stress markers, amyloid beta-peptide, and identification of protein expression differences, and observed a significant increase in highly insoluble monomeric Aβ42, but no significant differences in oligomeric Aβ nor in oxidative stress measurements between controls and PCAD subjects. Expression proteomics identified proteins whose trends in PCAD are indicative of cellular protection, possibly correlating with previous studies showing no cell loss in PCAD.

Abstract:The up-stream molecular causes of Alzheimer's disease (AD) have been discussed from the aspect of carbonyl stress, which represents an important common biochemical process of human aging. Firstly, chemical reactions of carbonyl toxification, induced by free radical oxidative stress and glycation stress, on lipids, carbonhydrates and proteins are elaborated. Secondly, evidences of reactive carbonyls and their effects on cellular structure and functions in AD patients are provided. Finally, detoxification mechanisms against carbonyl stress in brain are analysed and summarized, and strategies based on the mechanism for treating AD, as well as for preventing aging, fatigue and sub-health are also introduced and discussed.

Abstract:Many studies have shown there is a close relationship between metal homeostasis disruption and Alzheimer's disease(AD), but the mechanism needs to be discussed. Recent progresses about these studies are reviewed especially the results in author's laboratory are discussed. Iron and copper homeostasis disruption, oxidative stress，β-amyloid (Aβ), amyloid precursor protein (APP), iron regulatory protein (IRP) and divalent metal transporter 1(DMT1) are discussed in detail. We suggested that the overload of iron and copper might have closer relationship with the oxidative stress damage in the later phase in AD and the deficiency of iron and copper might have closer relationship with the early initiation of AD. The protective effects of natural antioxidant against AD through regulating iron and copper homeostasis disruption and oxidative stress are also discussed. This review may be useful for further research and prevention and therapy of AD.

Abstract:Endoplasmic reticulum (ER) is the protein-folding compartment. When the aggregation of unfolded or misfolded protein in the ER lumen excesses its folding capacity, unfolded protein response (UPR) and ER-associated protein degradation (ERAD) would be activated to eliminate the overload of nascent protein. However, the persistent ER stress would trigger apoptosis pathway and lead to cell death. There exist three pathways in the UPR process, which are mediated by three membrane receptors: PERK, ATF6 or IRE1 respectively. The first activated PERK would down regulates the protein synthesis through the phosphorylation of eukaryotic initiation factor (eIF) 2α (eIF2α) and activate the upstream open reading frame. ATF6 and IRE1 also make the contribution to UPR. Up to now, the most studied neurodegenerative diseases that related to ER stresses are Alzheimer's disease, Parkinson's disease, Vanishing White Matter disease, Pelizaeus-Merzbacher disease, Charcot-Marie-Tooth disease and CAG triplet repeat diseases (as Huntington's disease and Spinocerebellar ataxia).

Abstract:Tau is the most abundant microtubule associated protein. The normal function of Tau is to promote microtubule assembly and stabilize microtubules. In Alzheimer's disease, Tau is abnormally hyperphosphorylated and the hyperphosphorylated Tau accumulates, in the form of paired helical filaments (PHF), in the neuron to form neurofibrillary tangles. Numerous studies indicate that the abnormal Tau modifications play a crucial role in AD neurodegeneration and the cognitive deficits. We have studied systemically the mechanisms underlie Tau hyperphosphorylation and the effects of Tau phosphorylation on cell viability. We found unexpectedly that expression of the hyperphosphorylated Tau, at certain point, renders the cells more resistant to the exogenously induced cell apoptosis, whereas dephosphorylation of Tau promotes cell apoptosis. We also found that persistent Tau hyperphosphorylation and the cellular accumulation damage the neural functions and thus decrease the viability. Based on these findings, we propose that Tau hyperphosphorylation may play a dual role in leading the neurons to abort from an acute apoptosis and at the same time triggering a chronic neurodegeneration, which may explain why the degenerated neurons observed in the postmortem Alzheimer's brain are enriched with the hyperphosphorylated Tau proteins/tangles. It is suggested that proper intervention of Tau hyperphosphorylation may serve as a promising strategy in rescuing cell apoptosis and arresting neurodegeneration in Alzheimer's disease.

Abstract:Neurofibrillary tangles (NFTs) are regarded as one of the major pathological features of Alzheimer's disease, and are composed of misfolded and aggreagted Tau protein with hyperphosphorylation. But the mechanism of Tau hyperphosphorylation still remains to be clarified. This review summarized the roles of endogenous and exogenous factors in the induction of Tau hyperphosphorylation. The level of some factors and the hyperphosphorylation of Tau could be used as biomarkers for the early processing of AD.

Abstract:The decrease of brain estrogen was considered to be closely involved in Alzheimer's disease in women. Moreover, less estrogen receptor β (ERβ) was detected in mitochondrial, nuclear, and cytosolic fractions of female AD brains. The level of brain ERβ in aged rats is also decreased significantly. ERβ depletion impairs learning and memory of mice, while estrogen or ERβ selective agonist could activate the expression of synapse related proteins. ERβ colocalizes with mitochondria in primary neuron, suggesting that ERβ might play roles in regulating mitochondrial function and affect the function of neuron accordingly.

Abstract:Alzheimers's disease (AD) is a continuous pathological physiology process, including pre- MCI(mild cognitive impairment, MCI), MCI and dementia. For the irreversible of the clinical course of AD, finding early and treat right in the stage of preMCI or MCI are very important for slowing down or even reverse the procession of AD. Research shows that type 2 diabetes mellitus (T2DM ) is an independent risk factor for MCI and AD . This manuscript is a brief review of current concepts in the mechanisms potentially linking T2DM with cognitive impairment.

Abstract:There are disturbed circadian rhythm in Alzheimer's disease (AD) patients, which is related to the declined cognitive function. Our group has reported that disturbance of circadian rhythm and melatonin level was an early event in the process of AD, which accompanied with the progression of AD neuropathology. The combined treatment with melatonin and light could delay the impairment of AD cognitive function. In the present review, we will discuss the relationship between disturbed melatonin rhythm and AD.

Abstract:Mild cognitive impairment (MCI) is an intermediate clinical state between normal aging and dementia, and MCI patients are the risk population for the development of Alzheimer's disease (AD). This article firstly introduced the international diagnosis criteria of MCI and its variations and modifications, and based on the previous findings, we proposed an ideal diagnosis model for MCI detection in which outmeasures included both patient's self-report, clinician's judgment and objective behavioral and neuropsychological tests as well as various biomarkers through advanced imaging techniques, cerebrospinal fluid analysis, or even urine endogenous formaldehyde analysis, both cross-sectional comparisons of an individual with the norms and longitudinal changes derived from multi-time point measurements were also involved. We reviewed the recent studies on the neuropsychological impairment characteristics of MCI and the corresponding measurement tools from both cognitive and neuropsychiatric aspects such as MMSE, MoCA, NPI and SCID, and various cognitive intervention methods for MCI were also reviewed. Future research is needed to extend the findings from experimental small samples into community-based large population, as well as from the cross-sectional studies into longitudinal studies, and to adopt multi-detection markers and multi-intervention methods to achieve the optimal effects of early detection and intervention of MCI.

Abstract:Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by impaired memory and other cognitive functions. Previous neuroimaging studies have demonstrated regional structural and functional changes. Recent progressions on multi-modal imaging techniques and human brain connectome methods have allowed us to explore alterations of structural and functional networks in AD. Using these approaches, many studies have discovered AD-related network disruption, including connectivity strength, network efficiency, modular structure and network hubs. These findings provide novel insights into the understanding of AD notion of network disintegration and might lead to uncover disease biomarker for early diagnosis in AD. Most importantly, these findings in AD have been also demonstrated in the individuals at risk for AD (e.g., mild cognitive impairment), suggesting that the neuroimaging studies of AD should be moved into the prodromal stage of AD from the dementia stage.

Abstract:Alzheimer's disease (AD) is a multifactorial complex disease. The failure of recent development of AD therapeutic agents in clinical trials is mainly due to their single-target or single-pathogenic pathway effect. The poor clinical outcome of AD treatment is also due to the late intervention. A large number of neuronal death has already happened at the time of diagnosis. Aiming at the complex diseases with unclear causes and many related factors, the multi-target and multi-link treatment characteristics of traditional Chinese medicine have advantages over the single target treatment. Therefore, we have committed to the research of traditional Chinese medicine in treatment of AD and the development of new drugs since 1995. In this paper, our research results for more than 10 years were reviewed. Our study showed that traditional Chinese medicine formula (Shenwu capsule) and single herb extracts (Tetrahydroxy-stilbene glucoside, Cornel iridoid glycoside, Epimedium flavone and Icariin) could act on the complex pathogenesis of AD at multi-targets and multi-pathways, especially have both neuroprotective and neurotrophic/regenerative effects, and protect mitochondria and synapses, thus have significant features and advantages for the treatment of AD.

Abstract:Deposition of β amyloid (Aβ) in hippocampus is of crucial important in the pathogenesis of Alzheimer’s disease (AD). Recent study indicated that it was the decreased Aβ clearance account for its deposition. Studies showed that apolipoprotein E (ApoE) gene is an influential genetic risk factor for sporadic late-onset AD, but the detailed mechanism how it works is not fully understood. An article published in recent issue of Science (2012 Mar) showed that a retinoid X receptor agonist Bexarotene could rapidly activate ApoE, promot Aβ clearance and correct behavior deficits in transgenic AD moue model. These results clearly demonstrate that ApoE promotes Aβ clearance and provide new insight for AD therapy.