PURPOSE: Presenilins are functionally important components of γ-secretase, which cleaves a number of transmembrane proteins. Manipulations of PSEN1 and PSEN2 have been separately studied in Alzheimer disease (AD) and cancer because both involve substrates of γ-secretase. However, numerous clinical studies have reported an inverse correlation between AD and cancer. Interestingly, AD is a neurodegenerative disorder, whereas cancer is characterized by the proliferation of malignant cells. However, this inverse correlation in the PSEN double-knockout (PSEN dKO) mouse model of AD has been not elucidated, although doing so would shed light onto the relationship between AD and cancer. METHODS: To investigate the inverse relationship of AD and cancer under conditions of PSEN loss, we used the hippocampus of 7-month-old and 18-month-old PSEN dKO mice for a microRNA (miRNA) microarray analysis, and explored the tumorsuppressive or oncogenic role of differentially-expressed miRNAs. RESULTS: The total number of miRNAs that showed changes in expression level was greater at 18 months of age than at 7 months. Most of the putative target genes of the differentially-expressed miRNAs involved Cancer pathways. CONCLUSIONS: Based on literature reviews, many of the miRNAs involved in Cancer pathways were found to be known tumorsuppressive miRNAs, and their target genes were known or putative oncogenes. In conclusion, the expression levels of known tumor-suppressive miRNAs increased at 7 and 18 months, in the PSEN dKO mouse model of AD, supporting the negative correlation between AD and cancer.
Alzheimer Disease* ; Animals ; Hippocampus ; Humans ; Infant ; Mice* ; Microarray Analysis ; MicroRNAs ; Neurodegenerative Diseases ; Oncogenes ; Presenilins

The purpose of this study is to investigate whether nicotinic acid (NA) and nicotinamide (NAM) reduce the Alzheimer disease (AD)-related gene expression in brain tissues of amyloid beta (Aβ)-injected mice. Male Crj:CD1 (ICR) mice were divided into 6 treatment groups; 1) control, 2) Aβ control, 3) Aβ + NA 20 mg/kg/day (NA20), 4) Aβ + NA40, 5) Aβ + NAM 200 mg/kg/day (NAM200), and 6) Aβ + NAM400. After 1-week acclimation period, the mice orally received NA or NAM once a day for a total of 7 successive days. On day 7, biotinylated Aβ42 was injected into mouse tail vein. At 5 hours after the injection, blood and tissues were collected. Aβ42 injection was confirmed by Western blot analysis of Aβ42 protein in brain tissue. NAM400 pre-treatment significantly reduced the gene expression of amyloid precursor protein and presenilin 1 in brain tissues. And, NAM200 and NAM400 pre-treatments significantly increased sirtuin 1 expression in brain tissues, which is accompanied by the decreased brain expression of nuclear factor kappa B by 2 doses of NAM. Increased expression of AD-related genes was attenuated by the NAM treatment, which suggests that NAM supplementation may be a potential preventive strategy against AD-related deleterious changes.
Acclimatization ; Aging ; Alzheimer Disease ; Amyloid* ; Animals ; Blotting, Western ; Brain* ; Gene Expression ; Humans ; Male ; Mice* ; NF-kappa B ; Niacin ; Niacinamide* ; Presenilin-1* ; Presenilins* ; Sirtuin 1 ; Tail ; Veins*

Alzheimer's disease (AD) is known to induce alterations of mitochondrial function such as elevation of oxidative stress and activation of apopotosis. The aim of this study was to investigate the effects of human Presenilin 2 mutant (hPS2m) overexpression on the γ-secretase complex in the mitochondrial fraction. To achieve this, alterations of γ-secretase complex expression and activity were detected in the mitochondrial fraction derived from brains of NSE/hPS2m Tg mice and Non-Tg mice. Herein, the following were observed: i) overexpression of the hPS2m gene significantly up-regulated the deposition of Aβ-42 peptides in the hippocampus and cortex of brain, ii) overexpression of hPS2m protein induced alterations of γ-secretase components such as main component protein and activator protein but not stabilization-related proteins, iii) changes in γ-secretase components induced by overexpression of hPS2m protein up-regulated γ-secretase activity in the mitochondrial fraction, and iv) elevation of γ-secretase activity induced production of Aβ-42 peptides in the mitochondrial fraction. Based on these observations, these results indicate that alteration of γ-secretase activity in cells upon overexpression of hPS2m is tightly linked to mitochondrial dysfunction under the specific physiological and pathological conditions of AD.
Alzheimer Disease ; Animals ; Brain* ; Hippocampus ; Humans ; Mice ; Mice, Transgenic* ; Mitochondria* ; Oxidative Stress ; Peptides ; Presenilin-2 ; Presenilins* ; Up-Regulation*

No abstract available.
Alzheimer Disease* ; Dementia ; Presenilins*

Alzheimer Disease ; drug therapy ; enzymology ; Amyloid Precursor Protein Secretases ; antagonists & inhibitors ; Animals ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Humans ; Medicine, Chinese Traditional ; methods ; Membrane Glycoproteins ; antagonists & inhibitors ; Molecular Targeted Therapy ; Phytotherapy ; methods ; Presenilins ; antagonists & inhibitors

Alzheimer's disease (AD), also called presenile dementia, is one of the most common neurodegenerative diseases in elderly people. The main pathological features of AD include senile plaques (SPs), neurofibrillary tangles (NFTs) and neuron loss. A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Class biomarkers of AD such as Abeta and phosphorylated tau have been widely used in clinical diagnosis of AD patients. Recently, novel technologies like proteomics, genomics, and imaging techniques have expanded the role of a biomarker from early diagnosis to monitoring the progression of diseases and evaluating the response to various treatments. In this article, we will review the progress of various biomarkers of AD.
Adipokines ; cerebrospinal fluid ; Alzheimer Disease ; cerebrospinal fluid ; diagnosis ; diagnostic imaging ; metabolism ; Amyloid beta-Peptides ; cerebrospinal fluid ; Biomarkers ; analysis ; Chitinase-3-Like Protein 1 ; Fluorodeoxyglucose F18 ; Humans ; Lectins ; cerebrospinal fluid ; Peptide Fragments ; cerebrospinal fluid ; Phosphorylation ; Positron-Emission Tomography ; Presenilins ; analysis ; alpha 1-Antitrypsin ; blood ; tau Proteins ; cerebrospinal fluid

Alzheimer's disease (AD) pathogenesis is characterized by senile plaques in the brain and evidence of oxidative damage. Oxidative stress may precede plaque formation in AD; however, the link between oxidative damage and plaque formation remains unknown. Presenilins are transmembrane proteins in which mutations lead to accelerated plaque formation and early-onset familial Alzheimer's disease. Presenilins physically interact with two antioxidant enzymes thiol-specific antioxidant (TSA) and proliferation-associated gene (PAG) of the peroxiredoxin family. The functional consequences of these interactions are unclear. In the current study we expressed a presenilin transgene in Drosophila wing and sensory organ precursors of the fly. This caused phenotypes typical of Notch signaling loss-of-function mutations. We found that while expression of TSA or PAG alone produced no phenotype, co-expression of TSA and PAG with presenilin led to an enhanced Notch loss-of-function phenotype. This phenotype was more severe and more penetrant than that caused by the expression of Psn alone. In order to determine whether these phenotypes were indeed affecting Notch signaling, this experiment was performed in a genetic background carrying an activated Notch (Abruptex) allele. The phenotypes were almost completely rescued by this activated Notch allele. These results link peroxiredoxins with the in vivo function of Presenilin, which ultimately connects two key pathogenetic mechanisms in AD, namely, antioxidant activity and plaque formation, and raises the possibility of a role for peroxiredoxin family members in Alzheimer's pathogenesis.
Amino Acid Sequence ; Animals ; Drosophila ; metabolism ; physiology ; Drosophila Proteins ; metabolism ; Molecular Sequence Data ; Peroxiredoxins ; chemistry ; genetics ; metabolism ; Presenilins ; chemistry ; metabolism ; Receptors, Notch ; metabolism ; Sequence Alignment ; Signal Transduction

DREAM (downstream regulatory element antagonistic modulator) is a calcium-binding protein that regulates dynorphin expression, promotes potassium channel surface expression, and enhances presenilin processing in an expression level-dependent manner. However, no molecular mechanism has yet explained how protein levels of DREAM are regulated. Here we identified group I mGluR (mGluR1/5) as a positive regulator of DREAM protein expression. Overexpression of mGluR1/5 increased the cellular level of DREAM. Up-regulation of DREAM resulted in increased DREAM protein in both the nucleus and cytoplasm, where the protein acts as a transcriptional repressor and a modulator of its interacting proteins, respectively. DHPG (3,5-dihydroxyphenylglycine), a group I mGluR agonist, also up-regulated DREAM expression in cortical neurons. These results suggest that group I mGluR is the first identified receptor that may regulate DREAM activity in neurons.
Calcium ; Cytoplasm ; Dynorphins ; Methoxyhydroxyphenylglycol ; Neurons ; Potassium Channels ; Presenilins ; Proteins ; Receptors, Metabotropic Glutamate ; Up-Regulation

Alzheimer's disease (AD) is an increasing epidemic threatening public health. Both men and women are susceptible to the disease although women are at a slightly higher risk. The prevalence of AD rises exponentially in elderly people from 1% at age of 65 to approximately 40%-50% by the age of 95. While the cause of the disease has not been fully understood, genetics plays a role in the onset of the disease. Mutations in three genes (APP, PSEN1, and PSEN2) have been found to cause AD and APOE4 allele increases the risk of the disease. As human genomic research progresses, more genes have been identified and linked with AD. Genetic screening tests for persons at high risk of AD are currently available and may help them as well as their families better prepare for a later life with AD.
Aged ; Aged, 80 and over ; Aging ; genetics ; metabolism ; Alzheimer Disease ; diagnosis ; epidemiology ; genetics ; Amyloid beta-Protein Precursor ; genetics ; metabolism ; Apolipoprotein E4 ; genetics ; Genetic Predisposition to Disease ; genetics ; Genetic Testing ; trends ; Humans ; Mutation ; genetics ; Presenilins ; genetics ; metabolism ; Risk Factors

Alzhelmer's disease (AD) is the most common cause of dementia that arises on a neuropathological background of amyloid plaques containing betaamylold (Abeta) derived from amyloid precursor protein (APP) and tau-rich neurofibrillary tangles. To date, the cause and progression of familial or sporadic AD have not been fully elucidated. About 10% of all cases of AD occur as autosomal dominant inherited forms of early-onset AD, which are caused by mutations in the genes encoding APP, presenilin-1 and presenilin-2. Proteolytic processing of APP by beta-gamma-secretase and caspase generates Abetaand carboxyl-terminal fragments of APP (APP-CTFs), which have been implicated in the pathogenesis of AD. The presenilins function as one of the gamma-secretases. Abetawhich is the main component of the amyloid plaques found, is known to exert neurotoxicity by accumulating free radicals, disturbing calcium homeostasis, evoking inflammatory response and activating signaling pathways. The CTFs have been found in AD patients' brain and reported to exhibit much greater neurotoxicity than Abeta. Furthermore CTFs are known to impair calcium homeostasis and learning and memory, triggering a strong inflammatory reaction through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction. Recently, it was reported that CTF translocated into the nucleus and in turn, affected transcription of genes including glycogen synthase kinase-3beta which results in the induction of tau-rich neurofibrillary tangles and subsequently cell death. One of the hallmarks of AD, neurofibrillary tangles (NFT), is formed by insoluble intracellular polymers of hyperphosphorylated tau that is believed to cause apoptosis by disrupting cytoskeletal and axonal transport. This review covers the processing of APP, toxic mechanisms of Abetaand CTFs of APP, presenilin and also tau in relation to the pathogenesis of AD.
Amyloid ; Apoptosis ; Axonal Transport ; Brain ; Calcium ; Cell Death ; Dementia* ; Free Radicals ; Gliosis ; Glycogen Synthase ; Homeostasis ; Learning ; Memory ; Neurofibrillary Tangles ; Plaque, Amyloid ; Polymers ; Presenilin-1 ; Presenilin-2 ; Presenilins