Cathepsin S, one of the lysosomal proteinases, has many important physiological functions in the nervous system, especially in process of extracellular matrix degradation and endocellular antigen presentation. Those functions are closely associated with the pathogenesis of various neurological diseases. It would be beneficial to elucidate the role of Cathepsin S in the pathogenesis of various neurological diseases.
Alzheimer Disease ; physiopathology ; Astrocytoma ; physiopathology ; Brain Neoplasms ; physiopathology ; Cathepsins ; physiology ; Humans ; Intracranial Arteriosclerosis ; physiopathology

Dementia is a comprehensive category of brain diseases that is great enough to affect a person's daily functioning. The most common type of dementia is Alzheimer's disease, which makes most of cases. New researches indicate that gastrointestinal tract microbiota are directly linked to dementia pathogenesis through triggering metabolic diseases and low-grade inflammation progress. A novel strategy is proposed for the management of these disorders and as an adjuvant for psychiatric treatment of dementia and other related diseases through modulation of the microbiota (e.g. with the use of probiotics).
Alzheimer Disease ; metabolism ; microbiology ; physiopathology ; therapy ; Gastrointestinal Microbiome ; Humans

In recent years, iron has been regarded as a common pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Friedreich's ataxia (FRDA). A number of genes involved in iron transport, storage and regulation have been found associated with initiation and progression of neurodegeneration. However, whether iron abnormalities represent a primary or secondary event still remains unknown. Due to the limitation in transgenic rodent model construction and transfection systems, the progress in unraveling the pathogenic role of different iron-related proteins in neurodegenerative diseases has been slow. Drosophila melanogaster, a simple organism which has a shorter lifespan and smaller genome with many conserved genes, and captures many features of human nervous system and neurodegeneration, may help speed up the progress. The characteristics that spatial- and temporal-specific transgenic Drosophila can be easily constructed and raised in large quantity with phenotype easily determined turn Drosophila into an excellent in vivo genetic system for screening iron-related modifiers in different neurodegenerative conditions and hence provide a better picture about the pathogenic contribution of different iron-related protein abnormalities. It is believed that identification of important iron-related genes that can largely stop or even reverse degenerative process in Drosophila models may lead to development of novel therapeutic strategies against neurodegenerative diseases.
Alzheimer Disease ; physiopathology ; Animals ; Disease Models, Animal ; Drosophila melanogaster ; Friedreich Ataxia ; physiopathology ; Humans ; Iron ; Neurodegenerative Diseases ; physiopathology ; Parkinson Disease ; physiopathology

Alzheimer's Disease (AD) is a chronic neurodegenerative disease that usually takes many years from preclinical phase to prodromal phase characterized by mild symptoms before the onset of dementia. Once diagnosed with AD, the brain is already severely damaged and the disease will process quickly to the most severe stages since there is no medications that reverse the neuronal injuries in the brain. Thus, simple, inexpensive, and widely available methods for detecting potential AD patients during their preclinical phases are urgently needed. In such case, olfactory testing may offer a chance for early diagnosis of AD. However, there are limitations in these olfactory tests due to the complexity of the brain areas it extends to and the frequently olfactory fatigue occurred in the behavioral olfactory tests. Great efforts have been done epidemiologically to investigate the correlation between olfactory functions and possibility of developing AD. Different patterns of olfactory dysfunction have been found in AD at early stages and even mild cognitive impairment (MIC), but the cause of the dysfunction remained unclear. Various kinds of AD animal models have been used in the field to clarify the existence of olfactory dysfunctions and thus study the underling mechanism of the dysfunction. In this review we discuss (1) the function of Tau physiologically and pathologically; (2) the genetic background and biological characteristics of the most commonly used Tau transgenic mice; (3) the structural and molecule basis of olfaction; (4) the possible relationship between Tau pathology and olfactory dysfunction. Finally, we suggest that the tau transgenic mouse models may be helpful in studying the possible mechanisms of the dysfunction.
Alzheimer Disease ; physiopathology ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Olfaction Disorders ; physiopathology ; tau Proteins

BACKGROUNDPrevious studies have shown that brain functional activity in the resting state is impaired in Alzheimer's disease (AD) patients. However, alterations in intrinsic brain activity patterns in mild cognitive impairment (MCI) patients are poorly understood. This study aimed to explore the differences in regional intrinsic activities throughout the whole brain between aMCI patients and controls.

METHODSIn the present study, resting-state functional magnetic resonance imaging (fMRI) was performed on 18 amnestic MCI (aMCI) patients, 18 mild AD patients and 20 healthy elderly subjects. And amplitude of low-frequency fluctuation (ALFF) method was used.

RESULTSCompared with healthy elderly subjects, aMCI patients showed decreased ALFF in the right hippocampus and parahippocampal cortex, left lateral temporal cortex, and right ventral medial prefrontal cortex (vMPFC) and increased ALFF in the left temporal-parietal junction (TPJ) and inferior parietal lobule (IPL). Mild AD patients showed decreased ALFF in the left TPJ, posterior IPL (pIPL), and dorsolateral prefrontal cortex compared with aMCI patients. Mild AD patients also had decreased ALFF in the right posterior cingulate cortex, right vMPFC and bilateral dorsal MPFC (dMPFC) compared with healthy elderly subjects.

CONCLUSIONSDecreased intrinsic activities in brain regions closely related to episodic memory were found in aMCI and AD patients. Increased TPJ and IPL activity may indicate compensatory mechanisms for loss of memory function in aMCI patients. These findings suggest that the fMRI based on ALFF analysis may provide a useful tool in the study of aMCI patients.

Aged ; Alzheimer Disease ; physiopathology ; Amnesia ; physiopathology ; Brain ; physiopathology ; Cognitive Dysfunction ; physiopathology ; Female ; Humans ; Magnetic Resonance Imaging ; Male

OBJECTIVETo study the relationship between the degrees of peripheral auditory dysfunction and clinical dementia rating (CDR) in the patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD).

METHODSPure-tone thresholds (PT), word recognition scores (WRS), acoustic immittance and auditory brain-stem responses (ABR) were done to evaluate the auditory function in 24 cases of the patients with MCI and in 31 cases of the patients with AD and in 50 subjects of the control group. Clinical dementia rating (CDR) questionnaire was used to define the dementia degree of the subjects.

RESULTSTwenty-four MCI patients and 31 AD patients were selected, with average age of 72.0 +/- 6. 5 and 73.1+/-7. 5 of whom 70.8% and 67.7% were female separately. There was no significant difference in PTT and WRS between the MCI and AD groups (P > 0.05). In order to ascertain the relationship between hearing level and degree of dementia, all subjects were divided into 4 groups according their hearing loss (PTA <25 dB:0, 25-30 dB:1, 31-35 dB:2, >35 dB:3) to compare their CDR scores (the control:0, MCI:0. 5, mild AD:1). The more the CDR scores have, the more hearing impairment after controlling the confounder factors (Kendalls tau b = - 0.285, P = 0.018). No significant difference was found between the two groups in audiometry reliability, acoustic immittance and ABR (P > 0.05).

CONCLUSIONThe positive relationship was founded the peripheral hearing impairment and the score of CDR questionnaire in less than 0.5 score of CDR groups and mild AD patients.

Aged ; Alzheimer Disease ; physiopathology ; Case-Control Studies ; Cognition Disorders ; physiopathology ; Female ; Hearing Loss ; Humans ; Male

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

Alzheimer's disease (AD) is the most common type of dementia and a neurodegenerative disease with progressive cognitive dysfunction as the main feature. How to identify the early changes of cognitive dysfunction and give appropriate treatments is of great significance to delay the onset of dementia. Some other researches have shown that AD is associated with abnormal changes of brain networks. To study human brain functional connectivity characteristics in AD, 16 channels electroencephalogram (EEG) were recorded under resting and eyes-closed condition in 15 AD patients and 15 subjects in the control group. The synchronization likelihood of the full-band and alpha-band (8-13 Hz) data were evaluated, which resulted in the synchronization likelihood coefficient matrices. Considering a threshold T, the matrices were converted into binary graphs. Then the graphs of two groups were measured by topological parameters including the clustering coefficient and global efficiency. The results showed that the global efficiency of the network in full-band EEG was significantly smaller in AD group for the values of T = 0.06 and T = 0.07, but there was no statistically significant difference in the clustering coefficients between the two groups for the values of T (0.05-0.07). However, the clustering coefficient and global efficiency were significantly lower in AD patients at alpha-band for the same threshold range than those of subjects in the control group. It suggests that there may be decreases of the brain connectivity strength in AD patients at alpha-band of the resting-state EEG. This study provides a support for quantifying functional brain state of AD from the brain network perspective.
Alzheimer Disease ; physiopathology ; Brain ; physiopathology ; Brain Mapping ; Case-Control Studies ; Cluster Analysis ; Cognition Disorders ; physiopathology ; Electroencephalography ; Humans ; Probability ; Rest

As an important neurotransmitter, adenosine displays its functions by acting on the adenosine receptors. Recent studies have shown that the distribution, expression and balance among subtypes of adenosine receptors are closely related with cognitive activities, and changes of adenosine receptors play key roles in neurodegenerative disorders including Alzheimer's disease. It has been pointed out that prolonged activation of adenosine receptors by high level adenosine may lead to the disturbance of balance among adenosine receptor subtypes. This imbalance mainly performed as increased expression of A2a receptor and decreased expression of A1 receptor, and enhancement of the excitatory signals mediated by A2a receptor and weakened inhibitory signals mediated by A1 receptor. Changes of these two subtypes of adenosine receptors may lead to a lot of disorders of neurological activities which developed into dysfunction of cognition to the end. These findings imply that the potential of maintaining the balance among adenosine receptors on the treatment of AD would facilitate both the revealing of the mechanism and the cure of AD.
Adenosine ; physiology ; Alzheimer Disease ; physiopathology ; Humans ; Neurotransmitter Agents ; physiology ; Receptors, Purinergic P1 ; classification ; physiology

Alzheimer's disease(AD)is a central nervous system disease characterized by progressive cognitive dysfunction and memory loss.Increasing evidences suggest that β amyloid(Aβ)plays a critical role and may be a upstream molecule in AD pathogenesis involving both genetic and environmental factors.Aβ accumulation and its related inflammation are considered early events preceding neurodegeneration and neuronal loss in AD brain.However,all strategies and compounds targeting Aβ deposition have failed in clinical trials,implying complexity of AD pathogenesis.This article reviews Aβ hypothesis and its related mechanisms,pathophysiological process,and therapeutics of AD.
Alzheimer Disease ; pathology ; prevention & control ; therapy ; Amyloid beta-Peptides ; Brain ; physiopathology ; Humans