Autophagy is a dynamic cellular pathway involved in the turnover of proteins, protein complexes, and organelles through lysosomal degradation. The integrity of postmitotic neurons is heavily dependent on high basal autophagy compared to non-neuronal cells as misfolded proteins and damaged organelles cannot be diluted through cell division. Moreover, neurons contain the specialized structures for intercellular communication, such as axons, dendrites and synapses, which require the reciprocal transport of proteins, organelles and autophagosomes over significant distances from the soma. Defects in autophagy affect the intercellular communication and subsequently, contributing to neurodegeneration. The presence of abnormal autophagic activity is frequently observed in selective neuronal populations afflicted in common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. These observations have provoked controversy regarding whether the increase in autophagosomes observed in the degenerating neurons play a protective role or instead contribute to pathogenic neuronal cell death. It is still unknown what factors may determine whether active autophagy is beneficial or pathogenic during neurodegeneration. In this review, we consider both the normal and pathophysiological roles of neuronal autophagy and its potential therapeutic implications for common neurodegenerative diseases.
Alzheimer Disease/metabolism/pathology/physiopathology ; Animals ; Autophagy/*physiology ; Humans ; Huntington Disease/metabolism/pathology/physiopathology ; Models, Biological ; Neurodegenerative Diseases/metabolism/*pathology/physiopathology ; Neurons/*cytology ; Parkinson Disease/metabolism/pathology/physiopathology

Appropriate selection and measurement of lead biomarkers of exposure are critically important for health care management purposes, public health decision making, and primary prevention synthesis. Lead is one of the neurotoxicants that seems to be involved in the etiology of psychologies. Biomarkers are generally classified into three groups: biomarkers of exposure, effect, and susceptibility.The main body compartments that store lead are the blood, soft tissues, and bone; the half-life of lead in these tissues is measured in weeks for blood, months for soft tissues, and years for bone. Within the brain, lead-induced damage in the prefrontal cerebral cortex, hippocampus, and cerebellum can lead to a variety of neurological disorders, such as brain damage, mental retardation, behavioral problems, nerve damage, and possibly Alzheimer's disease, Parkinsons disease, and schizophrenia. This paper presents an overview of biomarkers of lead exposure and discusses the neurotoxic effects of lead with regard to children and adults.
Alzheimer Disease ; chemically induced ; metabolism ; pathology ; physiopathology ; psychology ; Animals ; Behavior ; drug effects ; Biomarkers ; metabolism ; Brain ; metabolism ; pathology ; physiopathology ; Brain Diseases ; chemically induced ; pathology ; physiopathology ; Environmental Exposure ; adverse effects ; Humans ; Lead ; pharmacokinetics ; toxicity ; Lead Poisoning ; etiology ; metabolism ; pathology ; physiopathology ; psychology ; Neurotoxicity Syndromes ; etiology ; metabolism ; pathology ; physiopathology ; psychology ; Parkinson Disease, Secondary ; chemically induced ; metabolism ; pathology ; physiopathology ; psychology ; Schizophrenia ; chemically induced ; metabolism ; pathology ; physiopathology

Small ubiquitin-related modifiers (SUMOs) belong to an important class of ubiquitin like proteins. SUMOylation is a post-translational modification process that regulates the functional properties of many proteins, among which are several proteins implicated in neurodegenerative diseases. This study was aimed to investigate the changes of SUMO-1 expression and modification, and the relationship between SUMO-1 and Alzheimer's disease (AD) pathology in APP/PS1 transgenic AD mice. Using Western blot, co-immunoprecipitation and immunofluorescent staining methods, the SUMO-1 expression and modification and its relation to tau, amyloid precursor protein (APP) and β-amyloid protein (Aβ) in the 12-month-old APP/PS1 transgenic AD mice were analyzed. The results showed that: (1) Compared with the normal wild-type mice, the expression and modification of SUMO-1 increased in brain of AD mice, which was accompanied by an increase of ubiquitination; (2) In RIPA soluble protein fraction of cerebral cortex, co-immunoprecipitation analysis showed tau SUMOylated by SUMO-1 increased in AD mice, however, AT8 antibody labeled phosphorylated tau was less SUMOylated whereas PS422 antibody labeled phosphorylated tau was similar to control mice; (3) Double immunofluorescent staining showed that SUMO-1 could distributed in amyloid plaques, appearing that some of SUMO-1 diffused in centre of some plaques and some of SUMO-1 co-localized with AT8 labeled phosphorylated tau forming punctate aggregates around amyloid plaques which was concerned as dystrophic neurites, however, less Aβ, APP and PS422 labeled phosphorylated tau were found co-localized with SUMO-1. These results suggest that SUMO-1 expression and modification increase abnormally in transgenic AD mice, which may participate in modulation of the formation of senile plaques and dystrophic neurites.
Alzheimer Disease ; physiopathology ; Amyloid beta-Peptides ; metabolism ; Amyloid beta-Protein Precursor ; metabolism ; Animals ; Brain ; pathology ; Mice ; Mice, Transgenic ; Neurites ; pathology ; Phosphorylation ; Plaque, Amyloid ; physiopathology ; SUMO-1 Protein ; metabolism ; Sumoylation ; tau Proteins ; metabolism

BACKGROUNDAlzheimer disease (AD) is a neurodegenerative disease related to aging. At present, its pathological mechanisms remain unclear. Family members of the renin-angiotensin system (RAS) play a role in neuronal plasticity, as well as formation of learning and memory. In this study, we explore the effects of altered angiotensin-converting enzyme (ACE), and investigate the possible mechanisms of perindopril, an ACE inhibitor, on brain structure and function in a rat model of AD, as well as the role that ACE plays in AD.

METHODSSixty Sprague-Dawley rats were selected and randomly divided into 3 groups: control, AD, and perindopril. Each group consisted of 20 rats, with 10 rats for determining pathology, and the remaining 10 rats for quantifying ACE activity. The rat AD model was established by stereotactically injecting amyloid beta protein (A-beta) 1-42 into the right hippocampus. Learning and memory functions were tested using the Y-type electric maze. The number and morphology of abnormal neurons were determined by haematoxylin and eosin staining. Amyloid deposition was measured by Congo red staining. Finally, ACE activity was estimated by spectrophotometry.

RESULTSCompared with the control group, the number of times needed to escape electrical stimuli increased (23.70 +/- 3.13, P < 0.001), the number of normal neurons in the CA1 region was reduced (density of 96.5 +/- 32.6/mm, P < 0.001), amyloid deposition was obvious, and ACE activity increased ((34.4 +/- 6.6) nmol x g(-1) x min(-1), P < 0.001) in the AD group. In the perindopril group, the number of times needed to escape electrical stimuli decreased (18.50 +/- 3.66, P < 0.001), the number of abnormal neurons increased (density of CA1 neurons was 180.8 +/- 28.5/mm, P < 0.001), amyloid deposition was reduced, and ACE activity was down-regulated ((26.2 +/- 6.2) nmol x g(-1) x min(-1), P < 0.001).

CONCLUSIONSACE activity increased in the brains of AD rats. Perindopril improved learning and memory in AD rats, which correlated with decreased ACE activity and delayed AD pathogenesis.

Alzheimer Disease ; enzymology ; pathology ; physiopathology ; Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; Animals ; Brain ; drug effects ; enzymology ; pathology ; Disease Models, Animal ; Maze Learning ; drug effects ; physiology ; Neurons ; drug effects ; metabolism ; pathology ; Peptidyl-Dipeptidase A ; metabolism ; Perindopril ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley

BACKGROUNDAmyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in the AD brains, Aβ accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model.

METHODSThe 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aβ (oAβ) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence.

RESULTSIn 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as Iba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAβ (1-42) induced the production of senescence-related protein p16, but not p53 in vitro, which was in line with the in vivo manifestation.

CONCLUSIONSoAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.

Alzheimer Disease ; metabolism ; physiopathology ; Amyloid Precursor Protein Secretases ; genetics ; metabolism ; Amyloid beta-Peptides ; metabolism ; Amyloid beta-Protein Precursor ; metabolism ; Animals ; Aspartic Acid Endopeptidases ; genetics ; metabolism ; Brain ; metabolism ; physiopathology ; Cells, Cultured ; Cellular Senescence ; genetics ; physiology ; Cognition ; physiology ; Cognition Disorders ; metabolism ; physiopathology ; Disease Models, Animal ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurons ; metabolism ; pathology ; Real-Time Polymerase Chain Reaction

OBJECTIVETo observe the effect of a Chinese medicine compound, Naoerkang (NEK), on amyloid-beta peptide (1-42; Aβ(1-42)) and matrix metalloproteinase-9 (MMP-9) expressions in the hippocampus of Alzheimer's disease (AD) model rats.

METHODSA total of 48 male Sprague Dawley (SD) rats were randomly divided into normal control, untreated, and piracetam groups, and low-dose, medium-dose, and high-dose NEK groups, with 8 rats in each group. The 5-μL aggregated Aβ(1-42) (2 μg/μL) were injected into both CA1 areas of the hippocampus in the rats to establish an AD model, whereas the normal control was treated with the same dose of normal saline. The rats in the NEK groups were treated with a high, medium, or low dose of NEK [60 g/(kg·d), 30 g/(kg·d), and 15 g/(kg·d)], respectively, intragastrically for 28 days; piracetam (0.375 g/kg, intragastrically) was consecutively administered in the piracetam group; and normal saline was applied in the normal control and untreated groups. A Y-maze test was used for behavioral study to test the learning and memory abilities. Aβ(1-42) and MMP-9 expressions in the hippocampus was determined immunohistochemically, and the results were analyzed by image acquisition and an analysis system.

RESULTSAggregated Aβ(1-42) induced obvious learning and memory dysfunction, as well as up-regulation of Aβ(1-42) expression in the hippocampus. Compared with those in the normal control group, the learning and memory abilities of rats in the untreated group significantly decreased (P<0.01), and the expression of Aβ(1-42) was significantly increased (P<0.01). Twenty-eight days after different treatments, compared with those in the untreated group, the learning and memory abilities of AD model rats in the piracetam, low-dose, medium-dose and high-dose NEK groups were significantly improved (P<0.01 or P<0.05), and the expression of Aβ(1-42) in the hippocampus decreased (P<0.01 or P<0.05), and MMP-9 increased (P<0.01 or P<0.05), especially in the high-dose NEK group.

CONCLUSIONNEK might play a role of anti-dementia by increasing the expression of MMP-9 in the hippocampus of AD model rats, resulting in the reduction of the quantity of Aβ(1-42) and improvement in learning and memory ability in AD model rats.

Alzheimer Disease ; drug therapy ; metabolism ; pathology ; physiopathology ; Amyloid beta-Peptides ; metabolism ; Animals ; CA1 Region, Hippocampal ; drug effects ; enzymology ; pathology ; physiopathology ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Hippocampus ; drug effects ; metabolism ; pathology ; physiopathology ; Immunohistochemistry ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Memory ; drug effects ; Rats ; Rats, Sprague-Dawley

The plant viral protease, NIa, has a strict substrate specificity for the consensus sequence of Val-Xaa-His-Gln, with a scissoring property after Gln. We recently reported that NIa efficiently cleaved the amyloid-beta (Abeta) peptide, which contains the sequence Val-His-His-Gln in the vicinity of the cleavage site by alpha-secretase, and that the expression of NIa using a lentiviral system in the brain of AD mouse model reduced plaque deposition levels. In the present study, we investigated whether exogenous expression of NIa in the brain of AD mouse model is beneficial to the improvement of cognitive deficits. To address this question, Lenti-NIa was intracerebrally injected into the brain of Tg-APPswe/PS1dE9 (Tg-APP/PS1) mice at 7 months of age and behavioral tests were performed 15-30 days afterwards. The results of the water maze test indicated that Tg-APP/PS1 mice which had been injected with Lenti-GFP showed an increased latency in finding the hidden-platform and markedly enhanced navigation near the maze-wall, and that such behavioral deficits were significantly reversed in Tg-APP/PS1 mice injected with Lenti-NIa. In the passive avoidance test, Tg-APP/PS1 mice exhibited a severe deficit in their contextual memory retention, which was reversed by NIa expression. In the marble burying test, Tg-APP/PS1 mice buried marbles fewer than non-transgenic mice, which was also significantly improved by NIa. After behavioral tests, it was verified that the Tg-APP/PS1 mice with Lenti-NIa injection had reduced Abeta levels and plaque deposition when compared to Tg-APP/PS1 mice. These results showed that the plant viral protease, NIa, not only reduces Abeta pathology, but also improves behavioral deficits.
Alzheimer Disease/*metabolism/pathology/physiopathology ; Amyloid beta-Peptides/*metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; Avoidance Learning ; Brain/*metabolism/pathology/physiopathology ; *Cognition ; Cognition Disorders ; Disease Models, Animal ; Endopeptidases/*genetics/metabolism ; Gene Expression ; Maze Learning ; Memory ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Plaque, Amyloid/metabolism/*pathology ; Presenilin-1/genetics ; Viral Proteins/*genetics/metabolism

S100beta is one kind of the calcium binding proteins. As growth factor of neuraxon, it is excreted by neuroglial cell, and distributing in nerve tissue extensively. Although S100beta has very important values neurophysiological, it also has neurotoxicity with excreting overmuch. Concentration of S100beta changes regularity in serum after the brain injury. In addition, it has a close relations with the degree of brain damage, which can be regarded as the neural new marker of biochemistry after brain damage. The advances of S100beta protein, in the research on neurophysiological values and its application for nerve tissue injury, disease were reviewed.
Alzheimer Disease/pathology* ; Biomarkers/blood* ; Brain Injuries/physiopathology* ; Cerebrovascular Disorders/pathology* ; Humans ; Nerve Growth Factors/blood* ; Neuroglia/metabolism* ; Postmortem Changes ; S100 Calcium Binding Protein beta Subunit ; S100 Proteins/blood* ; Severity of Illness Index ; Time Factors

OBJECTIVETo study the influence of beta-amyloid protein (Abeta) and cholesterol on the pathological changes of Alzheimer's disease (AD) and on the expression of nicotinic acetylcholine receptor (nAChR) subunits in the brains of rats.

METHODThe rats were treated by intracerebroventricular injection of Abeta1-42 and fed with a diet containing 5% cholesterol to establish animal model of AD. The pathological changes, learning and memory, and expression of nAChRs of rats were analyzed by Bieoschowsky staining, immunohistochemistry, water-labyrinth, Western blot, and RT-PCR.

RESULTSAbeta intracerebroventricular injection induced Abeta deposition in rat brains and high-cholesterol diet resulted in hypercholesterolemia in the animals. Injection of Abeta caused a reduction of learning and memory of rats and modifications of the expression of nAChRs. Cholesterol enhanced these effects of Abeta on neuropathology and expression of nAChRs.

CONCLUSIONSAbeta can induce marked neuropathological changes, influence the learning and study ability, and modify the expression of nAChRs. Cholesterol can enhance the neurotoxicity of Abeta.

Alzheimer Disease ; chemically induced ; metabolism ; pathology ; physiopathology ; Amyloid beta-Peptides ; metabolism ; Animals ; Cerebral Cortex ; metabolism ; pathology ; Cholesterol ; blood ; Drug Synergism ; Female ; Hypercholesterolemia ; blood ; Learning ; drug effects ; Male ; Peptide Fragments ; metabolism ; RNA, Messenger ; metabolism ; Random Allocation ; Rats ; Rats, Wistar ; Receptors, Nicotinic ; biosynthesis ; genetics

OBJECTIVESTo investigate the neuroprotective function of alpha7 nicotinic receptor (nAChR) and its roles in the pathogenesis of Alzheimer's disease (AD).

METHODSpecific RNA interference to alpha7 nAChR mRNA expression was performed by gene specific small interference RNA (siRNA). SH-SY5Y cells were transfected with the siRNA or treated with 20 micromol/L 3-[2, 4-dimethoxybenzylidene] anabaseine (DMXB), an alpha7 nAChR agonist. After 48 hrs culture, levels of alpha7 nAChR mRNA and protein were monitored by RT-PCR and Western blotting, respectively. In the second experiment, SH-SYSY cells treated with siRNA or DMXB were exposed to 1 micromol/L Abeta(25-35), followed by protein analysis of alpha-form of secreted beta-amyloid precursor peptide (alphaAPPs), and total APP was assayed by Western blotting. In addition, lipid peroxidation and MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] reduction were measured by spectrophotometry.

RESULTIn RNA interference group, as compared with controls, alpha7 nAChR mRNA and protein levels were decreased with inhibitory efficiency by 80% and 69%, respectively, along with a decrease in protein levels of alphaAPP and reduction of MTT. However the product of lipid peroxidation was increased. There was an enhanced gene inhibition of alpha7 nAChR by Abeta. While cells treated with DMXB, the alpha7 nAChR protein was increased by 23% as compared with that of the control, along with decrease of alphaAPP and ERK 1/2 at the protein level. The enhanced expression of alpha7 nAChR reduced the neurotoxic effects resulted from Abeta.

CONCLUSIONThe findings indicate that alpha7 nAChR may play a significant neuroprotective role by enhancing cleavage of APP, improving antioxidant defenses and limiting the toxicity of Abeta, which has been implied in the pathogenesis of AD.

Acetylcholine ; pharmacology ; Alzheimer Disease ; pathology ; physiopathology ; Amyloid beta-Peptides ; metabolism ; toxicity ; Amyloid beta-Protein Precursor ; pharmacology ; Cells, Cultured ; Humans ; Lipid Peroxidation ; Neurons ; drug effects ; pathology ; Neuroprotective Agents ; pharmacology ; Nicotinic Agonists ; pharmacology ; Protease Nexins ; RNA Interference ; RNA, Messenger ; drug effects ; metabolism ; RNA, Small Interfering ; pharmacology ; Receptors, Cell Surface ; Receptors, Nicotinic ; metabolism ; physiology ; alpha7 Nicotinic Acetylcholine Receptor