MicroRNA are a group of non-coding RNA which, through regulating expression of proteins at post-transcription level, plays an important role in modulating growth and development of nervous system, cell differentiation and functions. Altered expression of microRNA in the brain may influence development and advance of Alzheimer's disease from multiple perspectives. Research on microRNA will facilitate in depth understanding of the pathogenesis of Alzheimer's disease.
Alzheimer Disease ; genetics ; metabolism ; Animals ; Humans ; MicroRNAs ; genetics ; metabolism

Alzheimer Disease ; genetics ; metabolism ; therapy ; Humans ; tau Proteins ; genetics ; metabolism

Triggering receptor expressed on myeloid cells 2 (TREM2) is a membrane receptor on myeloid cells and plays an important role in the body's immune defense. Recently, TREM2 has received extensive attention from researchers, and its activity has been found in Alzheimer's disease, neuroinflammation, and traumatic brain injury. The appearance of TREM2 is usually accompanied by changes in apolipoprotein E (ApoE), and there has been a lot of research into their structure, as well as the interaction mode and signal pathways involved in them. As two molecules with broad and important roles in the human body, understanding their correlation may provide therapeutic targets for certain diseases. In this article, we reviewed several diseases in which TREM2 and ApoE are synergistically involved in the development. We further discussed the positive or negative effects of the TREM2-ApoE pathway on nervous system immunity and inflammation.
Humans ; Alzheimer Disease/metabolism* ; Apolipoproteins E/genetics* ; Microglia/metabolism* ; Myeloid Cells/metabolism* ; Signal Transduction ; Neuroinflammatory Diseases

Free radical hypothesis of aging emphasized that the age-related accumulation of free radicals results in cell injury. Alzheimer's disease (AD) is the most common form of neurodegenerative disease characterized by impaired cognition and memory of the elderly. Aging is a key risk factor in AD. Substantial evidence suggests that imbalance between free radical formation and clearance promotes AD pathogenesis. The brain overcomes oxidative stress by inducing expression of a set of genes called vitagenes. The protein products of vitagenes include heat shock proteins, heme oxygenases and thioredoxin systems, which serve as endogenous lifeguard of cells. This paper is a review of the expression and function of vitagenes in aging and AD brain, as well as relevant pharmacological study.
Aging ; genetics ; metabolism ; Alzheimer Disease ; genetics ; metabolism ; Brain ; metabolism ; Heat-Shock Proteins ; genetics ; metabolism ; Heme Oxygenase (Decyclizing) ; genetics ; metabolism ; Humans ; Oxidative Stress ; Thioredoxins ; genetics ; metabolism

This study investigated the mechanism of Danggui Shaoyao Powder(DSP) against mitophagy in rat model of Alzheimer's disease(AD) induced by streptozotocin(STZ) based on PTEN induced putative kinase 1(PINK1)-Parkin signaling pathway. The AD rat model was established by injecting STZ into the lateral ventricle, and the rats were divided into normal group, model group, DSP low-dose group(12 g·kg~(-1)·d~(-1)), DSP medium-dose group(24 g·kg~(-1)·d~(-1)), and DSP high-dose group(36 g·kg~(-1)·d~(-1)). Morris water maze test was used to detect the learning and memory function of the rats, and transmission electron microscopy and immunofluorescence were employed to detect mitophagy. The protein expression levels of PINK1, Parkin, LC3BⅠ/LC3BⅡ, and p62 were assayed by Western blot. Compared with the normal group, the model group showed a significant decrease in the learning and memory function(P<0.01), reduced protein expression of PINK1 and Parkin(P<0.05), increased protein expression of LC3BⅠ/LC3BⅡ and p62(P<0.05), and decreased occurrence of mitophagy(P<0.01). Compared with the model group, the DSP medium-and high-dose groups notably improved the learning and memory ability of AD rats, which mainly manifested as shortened escape latency, leng-thened time in target quadrants and elevated number of crossing the platform(P<0.05 or P<0.01), remarkably activated mitophagy(P<0.05), up-regulated the protein expression of PINK1 and Parkin, and down-regulated the protein expression of LC3BⅠ/LC3BⅡ and p62(P<0.05 or P<0.01). These results demonstrated that DSP might promote mitophagy mediated by PINK1-Parkin pathway to remove damaged mitochondria and improve mitochondrial function, thereby exerting a neuroprotective effect.
Rats ; Animals ; Mitophagy ; Alzheimer Disease/genetics* ; Powders ; Protein Kinases/metabolism* ; Ubiquitin-Protein Ligases/metabolism*

ObjectiveA comprehensive review of the network regulation of exosomes and microRNAs (miRNAs) in neurodegenerative diseases was done, centering on the mechanism of the formation of exosomes and miRNAs and the sorting mechanism of exosomal miRNAs, with the aim to provide a theoretical basis in the search of biomarkers and the treatment of neurodegenerative diseases.

Data SourcesThe comprehensive search used online literature databases including NCBI PubMed, Web of Science, Google Scholar, and Baidu Scholar.

Study SelectionThe study selection was based on the following keywords: exosomes, miRNAs, central nervous system (CNS), and neurodegenerative diseases. The time limit for literature retrieval was from the year 2000 to 2018, with language restriction in English. Relevant articles were carefully reviewed, with no exclusions applied to study design and publication type.

ResultsExosomes are the smallest nanoscale membranous microvesicles secreted by cells and contain important miRNAs, among other rich contents. In the CNS, exosomes can transport amyloid β-protein, α-synuclein, Huntington-associated protein 1, and superoxide dismutase I to other cells. These events relieve the abnormal accumulation of proteins and aggravating neurological diseases. In some neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, miRNAs are pathologically altered as an inexorable course, suggesting that miRNAs may contribute neurodegeneration. Exosomes and miRNAs form a network to regulate the homeostasis of the CNS, both synergistically and individually.

ConclusionThe network of exosomes and miRNAs that regulates CNS homeostasis is a promising biomarker for the diagnosis and treatment of neurodegenerative diseases.

Alzheimer Disease ; Amyloid beta-Peptides ; Exosomes ; Humans ; MicroRNAs ; Neurodegenerative Diseases ; genetics ; metabolism

This study is aimed at gaining insights into the brain site-specific proteomic senescence signature while comparing physiologically aged brains with aging-related dementia brains (for example, Alzheimer's disease (AD)). Our study of proteomic differences within the hippocampus (Hp), parietal cortex (pCx) and cerebellum (Cb) could provide conceptual insights into the molecular mechanisms involved in aging-related neurodegeneration. Using an isobaric tag for relative and absolute quantitation (iTRAQ)-based two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-LC-MS/MS) brain site-specific proteomic strategy, we identified 950 proteins in the Hp, pCx and Cb of AD brains. Of these proteins, 31 were significantly altered. Most of the differentially regulated proteins are involved in molecular transport, nervous system development, synaptic plasticity and apoptosis. Particularly, proteins such as Gelsolin (GSN), Tenascin-R (TNR) and AHNAK could potentially act as novel biomarkers of aging-related neurodegeneration. Importantly, our Ingenuity Pathway Analysis (IPA)-based network analysis further revealed ubiquitin C (UBC) as a pivotal protein to interact with diverse AD-associated pathophysiological molecular factors and suggests the reduced ubiquitin proteasome degradation system (UPS) as one of the causative factors of AD.
Aged, 80 and over ; Alzheimer Disease/*metabolism ; Brain/*metabolism ; Female ; Gelsolin/genetics/metabolism ; Humans ; Male ; Membrane Proteins/genetics/metabolism ; Neoplasm Proteins/genetics/metabolism ; Organ Specificity ; Proteome/genetics/*metabolism ; Tenascin/genetics/metabolism ; Ubiquitin C/genetics/metabolism

OBJECTIVETo detect the expression of miRNA-135a-5p, miRNA-135a-2-3p, miRNA-298-5p, miRNA-466b-3p and miR-669f-3p in the brain tissue of the APPswe/PS δE9 double transgenic mouse model of Alzheimer's disease using real-time PCR.

METHODSSix-month-old APPswe/PS δE9 double transgenic mice and wild-type C57 mice of the same species were examined for the expressions of miRNA-135a-5p, miRNA-135a-2-3p, miRNA-298-5p, miRNA-466b-3p and miR-669f-3p in the brain tissue using real-time PCR.

RESULTSThe relative expression levels of the 5 miRNAs in the transgenic versus the wild-type mice were 0.73∓0.27 vs 1.08∓0.58, 2.47∓6.15 vs 1.65∓0.67, 0.72∓0.14 vs 1.31∓0.73, 0.57∓0.34 vs 1.06∓0.35, and 0.63∓0.26 vs 1.02∓0.18, respectively, showing significance differences in the expressions of miRNA-135a-5p, miRNA-298-5p, miRNA-466b-3p, and miR-669f-3p between the two groups (P<0.05).

CONCLUSIONSmiRNA-135a-5p, miRNA-298-5p, miRNA-466b-3p and miR-669f-3p are expressed differentially in APPswe/PS δE9 double transgenic mice, suggesting their important roles in the pathogenesis of Alzheimer disease.

Alzheimer Disease ; genetics ; metabolism ; Animals ; Brain ; metabolism ; Disease Models, Animal ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; MicroRNAs ; genetics ; metabolism ; Real-Time Polymerase Chain Reaction ; methods

Alzheimer Disease ; metabolism ; Animals ; Brain ; metabolism ; Calcium-Binding Proteins ; biosynthesis ; chemistry ; genetics ; Gastrointestinal Tract ; metabolism ; Humans ; Islets of Langerhans ; metabolism ; Neoplasms ; metabolism ; RNA, Messenger ; metabolism ; Secretagogins ; Thyroid Gland ; metabolism

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease featuring progressive cognitive impairment. Although the etiology of late-onset AD remains unclear, the close association of AD with apolipoprotein E (APOE), a gene that mainly regulates lipid metabolism, has been firmly established and may shed light on the exploration of AD pathogenesis and therapy. However, various confounding factors interfere with the APOE-related AD risk, raising questions about our comprehension of the clinical findings concerning APOE. In this review, we summarize the most debated factors interacting with the APOE genotype and AD pathogenesis, depict the extent to which these factors relate to APOE-dependent AD risk, and discuss the possible underlying mechanisms.
Alzheimer Disease/pathology* ; Apolipoprotein E4/genetics* ; Apolipoproteins E/genetics* ; Genotype ; Humans ; Lipid Metabolism ; Neurodegenerative Diseases ; Risk Factors