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Pharmacological Reports : PR Jun 2016There are evidences for the influence of Alzheimer's proteins on postischemic brain injury. We present here an overview of the published evidence underpinning the... (Review)
Review
There are evidences for the influence of Alzheimer's proteins on postischemic brain injury. We present here an overview of the published evidence underpinning the relationships between β-amyloid peptide, hyperphosphorylated tau protein, presenilins, apolipoproteins, secretases and neuronal survival/death decisions after ischemia and development of postischemic dementia. The interactions of above molecules and their influence and contribution to final ischemic brain degeneration resulting in dementia of Alzheimer phenotype are reviewed. Generation and deposition of β-amyloid peptide and tau protein pathology are essential factors involved in Alzheimer's disease development as well as in postischemic brain dementia. Postischemic injuries demonstrate that ischemia may stimulate pathological amyloid precursor protein processing by upregulation of β- and γ-secretases and therefore are capable of establishing a vicious cycle. Functional postischemic brain recovery is always delayed and incomplete by an injury-related increase in the amount of the neurotoxic C-terminal of amyloid precursor protein and β-amyloid peptide. Finally, we present here the concept that Alzheimer's proteins can contribute to and/or precipitate postischemic brain neurodegeneration including dementia with Alzheimer's phenotype.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apolipoproteins; Brain Ischemia; Cell Survival; Humans; Phosphorylation; Presenilins; tau Proteins
PubMed: 26940197
DOI: 10.1016/j.pharep.2016.01.006 -
Molecular Neurobiology Mar 2018Presenilin 1 (PS1) is a catalytic component of the γ-secretase complex, responsible for the intramembraneous cleavage of more than 90 type I transmembrane proteins,... (Review)
Review
Presenilin 1 (PS1) is a catalytic component of the γ-secretase complex, responsible for the intramembraneous cleavage of more than 90 type I transmembrane proteins, including Alzheimer's disease (AD)-related amyloid precursor protein (APP). The γ-secretase-mediated cleavage of the APP C-terminal membrane stub leads to the production of various amyloid β (Aβ) species. The assembly of Aβ into neurotoxic oligomers, which causes synaptic dysfunction and neurodegeneration, is influenced by the relative ratio of the longer (Aβ42/43) to shorter Aβ (Aβ40) peptides. The ratio of Aβ42 to Aβ40 depends on the conformation and activity of the PS1/γ-secretase enzymatic complex. The latter exists in a dynamic equilibrium of the so called "closed" and "open" conformational states, as determined by the Förster resonance energy transfer (FRET)-based PS1 conformation assay. Here we review several factors that can allosterically influence conformational status of the enzyme, and hence the production of Aβ peptides. These include genetic variations in PS1, APP and other γ-secretase components, environmental stressors implicated in AD pathogenesis and pharmacological agents. Since "closed" PS1 conformation is the common outcome of many AD-related insults, the novel assays monitoring PS1 conformation in live/intact cells in vivo and in vitro might be utilized for diagnostic purposes and for validation of the potential therapeutic approaches.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Humans; Mutation; Presenilin-1; Protein Conformation
PubMed: 28332150
DOI: 10.1007/s12035-017-0487-5 -
Genetics in Medicine : Official Journal... May 2016The search for the genetic factors contributing to Alzheimer disease (AD) has evolved tremendously throughout the years. It started from the discovery of fully penetrant... (Review)
Review
The search for the genetic factors contributing to Alzheimer disease (AD) has evolved tremendously throughout the years. It started from the discovery of fully penetrant mutations in Amyloid precursor protein, Presenilin 1, and Presenilin 2 as a cause of autosomal dominant AD, the identification of the ɛ4 allele of Apolipoprotein E as a strong genetic risk factor for both early-onset and late-onset AD, and evolved to the more recent detection of at least 21 additional genetic risk loci for the genetically complex form of AD emerging from genome-wide association studies and massive parallel resequencing efforts. These advances in AD genetics are positioned in light of the current endeavor directing toward translational research and personalized treatment of AD. We discuss the current state of the art of AD genetics and address the implications and relevance of AD genetics in clinical diagnosis and risk prediction, distinguishing between monogenic and multifactorial AD. Furthermore, the potential and current limitations of molecular reclassification of AD to streamline clinical trials in drug development and biomarker studies are addressed.Genet Med 18 5, 421-430.
Topics: Alleles; Alzheimer Disease; Amyloid beta-Protein Precursor; Apolipoproteins E; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Mutation; Precision Medicine; Presenilin-1; Presenilin-2
PubMed: 26312828
DOI: 10.1038/gim.2015.117 -
Journal of Alzheimer's Disease : JAD 2018PRESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer's disease (fAD). However, the function of these genes and how they... (Review)
Review
PRESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer's disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2. As a core component of the γ-secretase complex, the PSEN2 protein is involved in many γ-secretase-related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD progression, indicating that PSEN2 plays a particular role in AD pathogenesis.
Topics: Alzheimer Disease; Animals; Disease Progression; Humans; Mutation; Presenilin-1; Presenilin-2; Signal Transduction
PubMed: 30412492
DOI: 10.3233/JAD-180656 -
International Journal of Molecular... Mar 2022Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer's disease (AD) have been sparse due to the...
Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer's disease (AD) have been sparse due to the concern about THC's psychotropic activity. The present study focused on demonstrating the beneficial effect of low-dose THC treatment in preclinical AD models. The effect of THC on amyloid-β (Aβ) production was examined in N2a/AβPPswe cells. An in vivo study was conducted in aged APP/PS1 transgenic mice that received an intraperitoneal injection of THC at 0.02 and 0.2 mg/kg every other day for three months. The in vitro study showed that THC inhibited Aβ aggregation within a safe dose range. Results of the radial arm water maze (RAWM) test demonstrated that treatment with 0.02 and 0.2 mg/kg of THC for three months significantly improved the spatial learning performance of aged APP/PS1 mice in a dose-dependent manner. Results of protein analyses revealed that low-dose THC treatment significantly decreased the expression of Aβ oligomers, phospho-tau and total tau, and increased the expression of Aβ monomers and phospho-GSK-3β (Ser9) in the THC-treated brain tissues. In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Dronabinol; Glycogen Synthase Kinase 3 beta; Maze Learning; Mice; Mice, Transgenic; Presenilin-1
PubMed: 35269905
DOI: 10.3390/ijms23052757 -
Glia Jan 2024Alzheimer's disease (AD) is among the most prevalent age-related neurodegenerative diseases. Endothelial cell (EC) senescence was discovered in the AD brain, but its...
Alzheimer's disease (AD) is among the most prevalent age-related neurodegenerative diseases. Endothelial cell (EC) senescence was discovered in the AD brain, but its function in AD pathogenesis was unidentified. Here we created an AD mouse model with EC senescence (APP/PS1;TERF2DN mice) by intercrossing APP/PS1 mice with Tie2 promoter-driven dominant negative telomeric repeat-binding factor 2 transgenic mice (TERF2DN-Tg mice). We evaluated cognitive functions and AD brain pathology in APP/PS1;TERF2DN mice. Surprisingly, compared with the control APP/PS1 mice, APP/PS1;TERF2DN mice demonstrated the attenuation of cognitive impairment and amyloid-β (Aβ) pathology, accompanied by the compaction of Aβ plaques with increased microglial coverage and reduced neurite dystrophy. Moreover, we evaluated whether EC senescence could affect microglial morphology and phagocytosis of Aβ. Compared with wild-type mice, microglia in TERF2DN-Tg mice display increased numbers of endpoints (a morphometric parameter to quantify the number of processes) and Aβ phagocytosis and related gene expression. Single-cell RNA-sequencing analysis showed that compared with APP/PS1 mouse microglia, APP/PS1;TERF2DN mouse microglia displayed a modest decline in disease-associated microglia, accompanied by an altered direction of biological process branching from antigen synthesis and arrangement to ribonucleoprotein complex biogenesis. Our outcomes indicate that EC senescence alters microglia toward a protective phenotype with a rise in phagocytic and barrier roles, and may offer a clue to create a novel preventive/therapeutic method to treat AD.
Topics: Mice; Animals; Alzheimer Disease; Amyloid beta-Protein Precursor; Presenilin-1; Mice, Inbred C57BL; Amyloid beta-Peptides; Mice, Transgenic; Cognitive Dysfunction; Microglia; Plaque, Amyloid; Disease Models, Animal
PubMed: 37610154
DOI: 10.1002/glia.24461 -
Seminars in Cell & Developmental Biology Sep 2020γ-Secretase cleavage is essential for many biological processes and its dysregulation is linked to disease, including cancer and Alzheimer's disease. Therefore,... (Review)
Review
γ-Secretase cleavage is essential for many biological processes and its dysregulation is linked to disease, including cancer and Alzheimer's disease. Therefore, understanding the regulation of its activity is of major importance to improve drug design and develop novel therapeutics. γ-Secretase belongs to the family of intramembrane cleaving proteases (i-CLiPs), which cleaves its substrates in a process termed regulated intramembrane proteolysis (RIP). During RIP, type-I transmembrane proteins are first cleaved within their ectodomain by a sheddase and then within their transmembrane domain by γ-secretase. γ-Secretase is composed of four integral membrane proteins that are all essential for its function: presenilin (PSEN), anterior pharynx defective 1 (APH1), nicastrin (NCT) and presenilin enhancer 2 (PEN-2). Given the presence of two PSEN homologues (PSEN1 & 2) and several APH1 isoforms, a heterogeneity exists in cellular γ-secretase complexes. It is becoming clear that each of these complexes has overlapping as well as distinct biological characteristics. This review summarizes our current knowledge on complex formation, trafficking, subcellular localization, interactors and the structure of γ-secretase, with a focus, when possible or known, on the contribution of PSEN1 and PSEN2 herein.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Cell Biology; Humans; Presenilins
PubMed: 32146031
DOI: 10.1016/j.semcdb.2020.02.005 -
International Journal of Molecular... Jan 2023In Alzheimer's disease (AD), the reduction in acetylcholinesterase (AChE) enzymatic activity is not paralleled with changes in its protein levels, suggesting the...
In Alzheimer's disease (AD), the reduction in acetylcholinesterase (AChE) enzymatic activity is not paralleled with changes in its protein levels, suggesting the presence of a considerable enzymatically inactive pool in the brain. In the present study, we validated previous findings, and, since inactive forms could result from post-translational modifications, we analyzed the glycosylation of AChE by lectin binding in brain samples from sporadic and familial AD (sAD and fAD). Most of the enzymatically active AChE was bound to lectins (Con A) and (LCA) that recognize terminal mannoses, whereas Western blot assays showed a very low percentage of AChE protein being recognized by the lectin. This indicates that active and inactive forms of AChE vary in their glycosylation pattern, particularly in the presence of terminal mannoses in active ones. Moreover, sAD subjects showed reduced binding to terminal mannoses compared to non-demented controls, while, for fAD patients that carry mutations in the PSEN1 gene, the binding was higher. The role of presenilin-1 (PS1) in modulating AChE glycosylation was then studied in a cellular model that overexpresses PS1 (CHO-PS1). In CHO-PS1 cells, binding to LCA indicates that AChE displays more terminal mannoses in oligosaccharides with a fucosylated core. Immunocytochemical assays also demonstrated increased presence of AChE in the trans-Golgi. Moreover, AChE enzymatic activity was higher in plasmatic membrane of CHO-PS1 cells. Thus, our results indicate that PS1 modulates trafficking and maturation of AChE in Golgi regions favoring the presence of active forms in the membrane.
Topics: Cricetinae; Animals; Humans; Acetylcholinesterase; Presenilin-1; Alzheimer Disease; Lectins; Brain; Cricetulus; Presenilin-2; Mutation
PubMed: 36674948
DOI: 10.3390/ijms24021437 -
Neurobiology of Disease May 2020Mutations in APP (amyloid precursor protein), PSEN1 (presenilin 1) or PSEN2 (presenilin 2) are the main cause of early-onset familial forms of Alzheimer's disease...
Mutations in APP (amyloid precursor protein), PSEN1 (presenilin 1) or PSEN2 (presenilin 2) are the main cause of early-onset familial forms of Alzheimer's disease (autosomal dominant AD or ADAD). These genes affect γ-secretase-dependent generation of Amyloid β (Aβ) peptides, the main constituent of amyloid plaques and one of the pathological hallmarks of AD. Evaluation of patients with ADAD includes assessment of family history, clinical presentation, biomarkers, neuropathology when available and DNA sequencing data. These analyses frequently uncover novel variants of unknown significance in ADAD genes. This presents a barrier to recruitment of such individuals into clinical trials, unless a biochemical test can demonstrate that a novel mutation results in altered APP processing in a manner consistent with pathogenicity. Here we describe generation and characterization of a novel presenilin 1 and 2 double knock-out in N2A mouse neuroblastoma cells using CRISPR/Cas9, which results in complete ablation of Aβ production, decreased Pen-2 expression and Nicastrin glycosylation. Because of the absence of background Aβ secretion from endogenous γ-secretases, these cells can be used for validation of PSEN1 and PSEN2 variant effects on production of Aβ or other γ-secretase substrates and for biochemical studies of γ-secretase function using novel variants. We examined several PSEN1 and PSEN2 mutations of known and unknown pathogenicity. Known mutants increased Aβ42/Aβ40 ratio with varying effect on Aβ40, Aβ42, total Aβ levels and Pen-2 expression, which aligns with previous work on these mutants. Our data on novel PSEN1 V142F, G206V and G206D mutations suggest that these mutations underlie the reported clinical observations in ADAD patients. We believe our novel cell line will be valuable for the scientific community for reliable validation of presenilin mutations and helpful in defining their pathogenicity to improve and facilitate evaluation of ADAD patients, particularly in the context of enrollment in clinical trials.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cell Line; Mice; Mutation; Patient Selection; Peptide Fragments; Plaque, Amyloid; Presenilin-1; Presenilin-2
PubMed: 32032730
DOI: 10.1016/j.nbd.2020.104785 -
Archives of Insect Biochemistry and... Oct 2018Aluminum (Al) is an important environmental metal factor that can be potentially associated with pathological changes leading to neurotoxicity. The silkworm, Bombyx...
Aluminum (Al) is an important environmental metal factor that can be potentially associated with pathological changes leading to neurotoxicity. The silkworm, Bombyx mori, is an important economic insect and has also been used as a model organism in various research areas. However, the toxicity of Al on silkworm physiology has not been reported. Here, we comprehensively investigate the toxic effects of Al on the silkworm, focusing on its effects on viability and development, superoxide dismutase (SOD) activity, and the expression of presenilin and cAMP response element-binding protein (CREB) in BmE cells and silkworm larvae. BmE cell viability decreased after treatment with aluminum chloride (AlCl ) in both dose- and time-dependent manners. When AlCl solution was injected into newly hatched fifth instar larvae, both larval weight gain and survival rate were significantly decreased in a manner correlating with AlCl dose and developmental stage. Furthermore, when BmE cells and silkworm larvae were exposed to AlCl , SOD activity decreased significantly relative to the control group, whereas presenilin expression increased more than twofold. Additionally, CREB and phosphorylated CREB (p-CREB) expression in the heads of fifth instar larvae decreased by 28.0% and 50.0%, respectively. These results indicate that Al inhibits the growth and development of silkworms in vitro and in vivo, altering SOD activity and the expressions of presenilin, CREB, and p-CREB. Our data suggest that B. mori can serve as a model animal for studying Al-induced neurotoxicity or neurodegeneration.
Topics: Aluminum; Aluminum Chloride; Aluminum Compounds; Animals; Body Weight; Bombyx; Cell Line; Cell Survival; Chlorides; Cyclic AMP Response Element-Binding Protein; Environmental Pollutants; Insect Proteins; Larva; Longevity; Neurotoxins; Presenilins; Superoxide Dismutase
PubMed: 29978503
DOI: 10.1002/arch.21480