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Since the mid-1990s, scientists have been generating mouse models of Alzheimer's disease to elucidate key mechanisms underlying the onset and progression of the disease and aid in developing potential therapeutic approaches. The first successful mouse model of Alzheimer's disease was reported in 1995 with the generation of the PDAPP mice, which were obtained by the overexpression of gene coding for the amyloid precursor protein (APP). Since then, scientists have used different approaches to develop other APP overexpression mice, mice overexpressing tau, or a combination of them. More recently, Saito and colleagues generated a mouse model by knocking in mutations associated with familial Alzheimer's disease into the APP gene. In this review, we will describe the most used animal models and provide a practical guide for the disease's age of onset and progression. We believe that this guide will be valuable for the planning and experimental design of studies utilizing these mouse models. [ABSTRACT FROM AUTHOR]

A significant proportion of brains with Alzheimer's disease pathology are obtained from patients that were cognitively normal, suggesting that differences within the brains of these individuals made them resilient to the disease. Here, we describe recent approaches that specifically increase synaptic resilience, as loss of synapses is considered to be the first change in the brains of Alzheimer's patients. We start by discussing studies showing benefit from increased expression of neurotrophic factors and protective genes. Methods that effectively make dendritic spines stronger, specifically by acting through actin network proteins, scaffolding proteins and inhibition of phosphatases are described next. Importantly, the therapeutic strategies presented in this review tackle Alzheimer's disease not by targeting plaques and tangles, but instead by making synapses resilient to the pathology associated with Alzheimer's disease, which has tremendous potential.

Amyloid-β (Aβ) accumulation caused by an imbalance of the production and clearance of Aβ in the brain is associated with the development of Alzheimer's disease (ad). Apolipoprotein E (ApoE) (the strongest genetic risk factor) enhances Aβ clearance, preventing Aβ deposition. Sirtuin 2 (Sirt2) is an NAD+-dependent histone deacetylase and its inhibition has been reported to ameliorate memory impairment in ad -like model mice. However, the role of Sirt2 in ApoE secretion is unknown. Here, we found that inhibition of Sirt2 activity in primary cultured astrocytes and BV2 cells decreased ApoE secretion, resulting in the accumulation of intracellular ApoE and inhibiting extracellular Aβ degradation. However, the reduction of Sirt2 protein level by Sirt2 siRNA decreased ApoE protein level, which ultimately reduces ApoE secretion. In addition, the knockdown of Sirt2 in the HEK293-APP cells also decreased levels of intracellular ApoE leading to reduction of its secretion, which is accompanied by increased Aβ levels without altering APP and APP processing enzymes. Our findings provide a novel role of Sirt2 in ApoE secretion. [ABSTRACT FROM AUTHOR]

The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) framework for classifying variants uses six evidence categories related to the splicing potential of variants: PVS1, PS3, PP3, BS3, BP4, and BP7. However, the lack of guidance on how to apply such codes has contributed to variation in the specifications developed by different Clinical Genome Resource (ClinGen) Variant Curation Expert Panels. The ClinGen Sequence Variant Interpretation Splicing Subgroup was established to refine recommendations for applying ACMG/AMP codes relating to splicing data and computational predictions. We utilized empirically derived splicing evidence to (1) determine the evidence weighting of splicing-related data and appropriate criteria code selection for general use, (2) outline a process for integrating splicing-related considerations when developing a gene-specific PVS1 decision tree, and (3) exemplify methodology to calibrate splice prediction tools. We propose repurposing the PVS1_Strength code to capture splicing assay data that provide experimental evidence for variants resulting in RNA transcript(s) with loss of function. Conversely, BP7 may be used to capture RNA results demonstrating no splicing impact for intronic and synonymous variants. We propose that the PS3/BS3 codes are applied only for well-established assays that measure functional impact not directly captured by RNA-splicing assays. We recommend the application of PS1 based on similarity of predicted RNA-splicing effects for a variant under assessment in comparison with a known pathogenic variant. The recommendations and approaches for consideration and evaluation of RNA-assay evidence described aim to help standardize variant pathogenicity classification processes when interpreting splicing-based evidence. [Display omitted] The ClinGen SVI Splicing Subgroup provides recommendations for the application of existing splicing-related ACMG/AMP codes and re-purposing of other codes to capture splicing-related evidence. This study outlines a process for developing a gene-specific PVS1 decision tree and provides methodology to calibrate bioinformatic splice prediction tools. [ABSTRACT FROM AUTHOR]

To understand the impact of genome sequence variation (the genotype) responsible for biological diversity and human health (the phenotype) including cystic fibrosis and Alzheimer's disease, we developed a Gaussian-process-based machine learning (ML) approach, variation spatial profiling (VSP). VSP uses a sparse collection of known variants found in the population that perturb the protein fold to define unknown variant function based on the emergent general principle of spatial covariance (SCV). SCV quantitatively captures the role of proximity in genotype-to-phenotype spatial-temporal relationships. Phenotype landscapes generated through SCV provide a platform that can be used to describe the functional properties that drive sequence-to-function-to-structure design of the polypeptide fold at atomic resolution. We provide proof of principle that SCV can enable the use of population-based genomic platforms to define the origins and mechanism of action of genotype-to-phenotype transformations contributing to the health and disease of an individual.

Presenilin-1 (PS1) protein is the catalytic subunit of the gamma-secretase, and participates in the processing of beta-amyloid precursor protein (APP) to produce Abeta peptide and Notch 1 receptor to release Notch intracellular domain (NICD) in the cytoplasm. NICD migrates to the nucleus and causes Notch signaling by increasing the expression of the Hes1 gene. The mammalian target of rapamycin (mTOR) controls cellular homeostasis, and its activity is inhibited by rapamycin. The buildup of Abeta increases the mTOR signaling, whereas decreasing mTOR signaling reduces Abeta levels suggesting an interrelationship between mTOR signaling and Abeta. Administration of rapamycin in 3XTg-AD mouse model of Alzheimer’s disease (AD) rescues cognitive deficits and ameliorates Abeta and Tau pathology. We have dissected the mechanisms by which rapamycin inhibits PS1 expression and Notch1 signaling. Our results demonstrated that rapamycin efficiently suppressed phosphorylation of mTOR (p-mTOR), and decreased expression of PS1-mRNA as well as p-p70S6K1, 4EBP1, PS1, NICD, and Hes1 protein levels. Therefore, rapamycin decreased PS1 protein levels and Notch 1 processing by inhibiting PS1 transcription.

Presenilin-1 (PS1) is the catalytic subunit of gamma-secretase. PS1 cleaves beta-amyloid precursor protein (APP) to produce Abeta peptide and Notch 1 receptor to release Notch intracellular domain (NICD) in the cytoplasm. We have previously shown that rapamycin inhibits p-mTOR to repress PS1 transcription and Notch 1-signaling. But the exact mechanism by which rapamycin inhibits PS1 transcription is not known. We have also published that inhibition of basal activity of c-jun-NH2-terminal kinase (JNK) with JNK-specific inhibitor SP600125 represses PS1 transcription by reducing p-JNK and via p53 dependent mechanism. We now report that rapamycin inhibits the phosphorylation of both mTOR (p-mTOR) and JNK (p-JNK). It appears that rapamycin represses PS1 transcription by inhibiting the expression of p-JNK in SK-N-SH cells under non-stressed condition. Consequently, one of the mechanisms of inhibition of PS1 transcription by rapamycin is similar to the mechanism of repression of PS1 transcription by JNK-specific inhibitor SP600125. We also report that JNK-inhibitor SP6000125 decreases both p-JNK and p-mTOR protein levels. These results suggest that JNK and mTOR may potentially activate each other by mutual phosphorylation.

Objective: Cancer-associated fibroblasts (CAFs) were associated with tumor progression in the tumor microenvironment (TME). However, their immunosuppressive roles in protecting cancer cells from the attack by cytotoxic T lymphocytes (CTLs) are not fully clear. In this study, we investigated whether and how CAFs regulate tumor-infiltrating lymphocytes as well as their role in tumor immunosuppression.Methods: Eighty-three cases of ovarian cancer and 10 controls were analyzed for CAFs and CD8+ tumor-infiltrating lymphocytes by gene array and immunohistochemistry. We evaluated presenilin 1 (PS1) expression in CAFs, CTL penetration, tumor burden, dendritic cell function, and migration of tumor-infiltrating lymphocytes and their function in vivo and in vitro after silencing PS1. In addition, the pathway via which PS1 affects the TME was also evaluated.Results: PS1 was highly expressed in CAFs, and its silencing significantly promoted CD8+ CTL proliferation and penetration in multiple ovarian models (p < 0.05), resulting in tumor regression and growth inhibition. Interleukin (IL)-1β was identified as a major immune inhibitor in the TME, and it was significantly decreased after PS1 silencing (p < 0.05), which was regulated by the WNT/β-catenin pathway. It was also showed that high expression of IL-1β in CAFs inhibits CTL penetration significantly (p < 0.05).Conclusion: Highly expressed PS1 in CAFs plays a crucial role in regulating tumor-infiltrating lymphocyte populations in the TME via the WNT/β-catenin pathway. Targeting PS1 may retrieve functional CTLs in the TME and improve the efficacy of current immunotherapies.

Huntington's disease (HD) is a relentlessly progressive neurodegenerative disease featured by the over-expanded polyglutamine (polyQ)-induced protein aggregation. Using Caenorhabditis elegans (C. elegans) as a model system, we show that water soluble polysaccharide extracted from the herb Peganum harmala L. (PS1) not only reduces polyQ aggregation but also alleviates the associated neurotoxicity. Genetic and pharmacologic analysis suggested that PS1 treatment acts though proteasome-mediated protein degradation pathway to inhibit polyQ aggregation. Notably, the efficacy of PS1 is aroused specifically by co-incubation with live Escherichia coli OP50, which is the sole food source for worms. Further UPLC-Q-TOF/MS analysis determined the bioactivity of polyQ inhibition, which is composed of several oligosaccharides, including stachyoses, verbascoses, trisaccharides and tetrasaccharides composed of galacturonic acids. Together, our study revealed a potential drug target for further HD treatment and pinpointed the possibility that the secreted metabolites produced from bacteria treated with various compounds may provide direct beneficial effect to human bodies. [ABSTRACT FROM AUTHOR]

Objective: Cancer-associated fibroblasts (CAFs) were associated with tumor progression in the tumor microenvironment (TME). However, their immunosuppressive roles in protecting cancer cells from the attack by cytotoxic T lymphocytes (CTLs) are not fully clear. In this study, we investigated whether and how CAFs regulate tumor-infiltrating lymphocytes as well as their role in tumor immunosuppression. Methods: Eighty-three cases of ovarian cancer and 10 controls were analyzed for CAFs and CD8+ tumor-infiltrating lymphocytes by gene array and immunohistochemistry. We evaluated presenilin 1 (PS1) expression in CAFs, CTL penetration, tumor burden, dendritic cell function, and migration of tumor-infiltrating lymphocytes and their function in vivo and in vitro after silencing PS1. In addition, the pathway via which PS1 affects the TME was also evaluated. Results: PS1 was highly expressed in CAFs, and its silencing significantly promoted CD8+ CTL proliferation and penetration in multiple ovarian models (p < 0.05), resulting in tumor regression and growth inhibition. Interleukin (IL)-1β was identified as a major immune inhibitor in the TME, and it was significantly decreased after PS1 silencing (p < 0.05), which was regulated by the WNT/β-catenin pathway. It was also showed that high expression of IL-1β in CAFs inhibits CTL penetration significantly (p < 0.05). Conclusion: Highly expressed PS1 in CAFs plays a crucial role in regulating tumor-infiltrating lymphocyte populations in the TME via the WNT/β-catenin pathway. Targeting PS1 may retrieve functional CTLs in the TME and improve the efficacy of current immunotherapies. [ABSTRACT FROM AUTHOR]

We investigated early phenotypes caused by familial Alzheimer’s disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor. Our data suggest that accumulation of β-CTFs of APP, but not Aβ, slow vesicle formation from an endocytic recycling compartment marked by the transcytotic GTPase Rab11. We confirm previous results that endocytosis is affected in AD and extend these to uncover a neuron-specific defect. Decreased lipoprotein endocytosis and transcytosis to the axon suggest that a neuron-specific impairment in endocytic axonal delivery of lipoproteins and other key materials might compromise synaptic maintenance in fAD.

Neurofibrillary degeneration in transgenic models of tauopathies has been observed to be enhanced when these models are crossed with transgenic models developing an Aβ pathology. The mechanisms leading to this enhanced tau pathology are not well understood. We have performed a detailed analysis of tau misprocessing in a new transgenic mouse model combining APP, PS1 and tau mutations (5xFAD × Tg30 mice) by comparison with littermates expressing only a FTD mutant tau (Tg30 mice). These 5xFAD × Tg30 mice showed a more severe deficient motor phenotype than Tg30 mice and developed with age a dramatically accelerated NFT load in the brain compared to Tg30 mice. Insoluble tau in 5xFAD × Tg30 mice compared to insoluble tau in Tg30 mice showed increased phosphorylation, enhanced misfolding and truncation changes mimicking more closely the post-translational changes characteristic of PHF-tau in Alzheimer's disease. Endogenous wild-type mouse tau was recruited at much higher levels in insoluble tau in 5xFAD × Tg30 than in Tg30 mice. Extracellular amyloid load, Aβ40 and Aβ42, β-CTFs and β-CTF phosphorylation levels were lower in 5xFAD × Tg30 mice than in 5xFAD mice. Despite this reduction of Aβ, a significant hippocampal neuronal loss was observed in 5xFAD × Tg30 but not in 5xFAD mice indicating its closer association with increased tau pathology. This 5xFAD × Tg30 model thus mimics more faithfully tau pathology and neuronal loss observed in AD and suggests that additional post-translational changes in tau and self-recruitment of endogenous tau drive the enhanced tau pathology developing in the presence of Aβ pathology.

U1 small nuclear RNA (snRNA) is selectively enriched in 100% of familial Alzheimer's disease (AD) resulting from presenilin1 (PS1) and amyloid precursor protein (APP) mutations. However, it remains unknown what gene or protein cause the U1 snRNA overexpression and then resulted in AD. Using SH-SY5Y cells, we discovered that PS1 induced the overexpression of U1 snRNA, which increased the production of Aβ. Moreover, the U1 snRNA overexpression induced the upregulation of apoe and clu transcripts. In addition, the levels of phosphorylation of tau protein at Thr212 were significantly elevated in U1 snRNA overexpression cells. Immunofluorescence using antibodies reactive with the phosphorylation of tau at Thr212 site demonstrated the hyperphosphorylated tau localization with α-tubulin, the main component of cytoskeleton. Importantly, the increased levels of Bax, Bcl2, and Bax/Bcl2 ratio showed that the overexpression of U1 snRNA could cause cell apoptosis. Conclusively, these findings suggest that PS1 considerably increases the level of U1snRNA accompanied with the adverse change of Aβ level, AD-related tau cytoskeletal pathology, and cell apoptosis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the efficacy and molecular mechanisms of SB239063 on cognitive deficits and Aβ generation in APPswe/PSldE9 mice. Methods: Six-month-old male APPswe PSldE9 mice and their wild-type littemiates were randomized into SB239063-treatedgroups and control groups respectively. The treated groups received SB239063 (dissolved in 3% DMSO at a dose of 15mgkg) once per day by intraperitoneal injection, whereas the control groups received an equal volume of 3% DMSO once per day by intraperitoneal injection. Six weeks after the treatments, the spatial learning and memory ability of all mice were evaluated by the Morris water maze test, the levels of soluble Ap were detected with enzyme-linked immunosorbent assay (ELISA) kits, the expression of crucial enzymes in the production of Ap were tested with western blot method. Results: Compared with the vehicle-treated APPswe PSldE9 mice, the escape latency in reaching the hidden-platform were significantly decreased (P<0.01). while the percentage of time spend in the target quadrant (P<0.01) and the frequency of crossing the platform (P<0.01) were potently increased in SB239063-treated APPswePSldE9 mice (P<0.01). Meanwhile, the levels of soluble Api-42 (P<0.05). Api-40 (P<0.05) and Ap oligomers (P<0.01) were dramatically decreased in SB239063-treated APPswe PSldE9 mice versus the control group. In addition, the expression of p-p3SMAPK. BACE1 and PS1 in APPswe PSldE9 mice were markedly reduced by SB239063 treatment (P<0.01). Conclusion: SB239063 can reverse cognitive impairments and Ap toxicity by decreasing the expression of BACE1 and PS1 which may result from inhibition of p-p3SMAPK. Our findings provide that SB239063 may be a promising therapeutic strategy for the treatment of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder that nowadays affects more than 40 million people worldwide and it is predicted to exponentially increase in the coming decades. Because no curative treatment exists, research on the pathophysiology of the disease, as well as the testing of new drugs, are mandatory. For these purposes, animal models constitute a valuable, although perfectible tool. This review takes a tour through several aspects of mouse models of AD, such as the generation of transgenic models, the relevance of the promoter driving the expression of the transgenes, and the concrete transgenes used to simulate AD pathophysiology. Then, transgenic mouse lines harboring mutated human genes at several loci such as APP, PSEN1, APOEɛ4, and ob (leptin) are reviewed. Therefore, not only the accumulation of the Aβ peptide is emulated but also cholesterol and insulin metabolism. Further novel information about the disease will allow for the development of more accurate animal models, which in turn will undoubtedly be helpful for bringing preclinical research closer to clinical trials in humans. [ABSTRACT FROM AUTHOR]

Summary We investigated early phenotypes caused by familial Alzheimer’s disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor. Our data suggest that accumulation of β-CTFs of APP, but not Aβ, slow vesicle formation from an endocytic recycling compartment marked by the transcytotic GTPase Rab11. We confirm previous results that endocytosis is affected in AD and extend these to uncover a neuron-specific defect. Decreased lipoprotein endocytosis and transcytosis to the axon suggest that a neuron-specific impairment in endocytic axonal delivery of lipoproteins and other key materials might compromise synaptic maintenance in fAD. [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~ 25% of cases were found to carry a pathogenic mutation or risk variant in APP , GBA or PSEN1 , highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA , 10% of cases carried a risk variant or mutation in PSEN1 , and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients ( p -value < 0.001). Our results conclusively show that mutations in GBA , PSEN1 , and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia. [ABSTRACT FROM AUTHOR]

Purpose: Alzheimer's disease (AD) is a highly prevalent type of dementia. The epigenetic mechanism of gene methylation provides a putative link between nutrition, one-carbon metabolism, and disease progression because folate deficiency may cause hypomethylation of promoter regions in AD-relevant genes. We hypothesized that folic acid supplementation may protect neuron cells from amyloid β (Aβ) oligomer-induced toxicity by modulating DNA methylation of APP and PS1 in AD models. Methods: Primary hippocampal neuronal cells and hippocampal HT-22 cells were incubated for 24 h with a combination of folic acid and either Aβ oligomers or vehicle and were then incubated for 72 h with various concentrations of folic acid. AD transgenic mice were fed either folate-deficient or control diets and gavaged daily with various doses of folic acid (0 or 600 μg/kg). DNA methyltransferase (DNMT) activity, cell viability, methylation potential of cells, APP and PS1 expression, and the methylation of the respective promoters were determined. Results: Aβ oligomers lowered DNMT activity, increased PS1 and APP expression, and decreased cell viability. Folic acid dose-dependently stimulated methylation potential and DNMT activity, altered PS1 and APP promoter methylation, decreased PS1 and APP expression, and partially preserved cell viability. Folic acid increased PS1 and APP promoter methylation in AD transgenic mice. Conclusion: These results suggest a mechanism by which folic acid may prevent Aβ oligomer-induced neuronal toxicity. [ABSTRACT FROM AUTHOR]

There is no molecular explanation for the many presenilin 1 (PSEN1) mutations causing Alzheimer's disease, but both gain of function relating to amyloid production and loss of isolated PSEN1 function have been implied. We report here the first detailed dynamic all-atom model of mature PSEN1 from molecular dynamics in an explicit membrane with particular account of the as yet unexplored loop dynamics. We find that mature PSEN1 contains multiple distinct conformational states whereas non-mature PSEN1 is a typical one-state protein. We confirm a previously suggested gating mechanism, and find that the 106–131 loop acts as a “hinge” for the TM2 and TM6 “doors”. More importantly, we identify an unplugging mechanism of the Exon 9 loop associated only with mature PSEN1. Proper opening of both the “gate” and “plug” in the membrane produces channel-like morphologies and access to the catalytic aspartates. Dynamically, these features seem linked. The long-range sensitivity of this gate–plug system to subtle conformational changes can explain why so many PSEN1 mutants cause disease. Reduced access and imprecise substrate cleavage associated with impaired gate–plug dynamics is directly illustrated by the effect of maturation in our work and could explain the overall reduction in Aβ levels upon PSEN1 mutation and the increase in the Aβ 42/40 ratio. Yet, our PSEN1-only dynamics are particularly insightful in revealing PSEN1-only dynamics relating to e.g. its role as membrane channel. Thus, our identified gate–plug mechanism is relevant for designing PSEN1 modulating therapies for treatment of Alzheimer's disease within both the amyloid/γ-secretase hypothesis and within the PSEN1 loss of function paradigm. [ABSTRACT FROM AUTHOR]

Chemoradiation therapy is an important component of the curative treatment for oesophageal carcinomas. These therapeutic effects are prevented in patients according to radioresistance and multi-drug resistance, and the cause of such resistance remains unclear. In this study, we identified the role of miR-193a-3p in modulating the radioresistance and chemoresistance of oesophageal cancer cells. We found that KYSE150 and KYSE410 cells could be characterized as relatively radiation-sensitive and radiation-resistant cells, respectively. Similarly, KYSE150 and KYSE410 cells were found to be chemosensitive and chemoresistant, respectively. Over-expression of miR-193a-3p increased the radioresistance and chemoresistance of oesophageal squamous cell carcinoma (ESCC) cells. In contrast, the down-regulation of miR-193a-3p decreased the radioresistance and chemoresistance of ESCC cells. In addition, miR-193a-3p inducing DNA damage has also been demonstrated through measuring the level of gamma-H2AX associated with miR-193a-3p. Moreover, a small interfering RNA(siRNA)-induced repression of the PSEN1 gene had an effect similar to that of miR-193a-3p up-regulation. The above processes also inhibited oesophageal cancer cells apoptosis. These findings suggest that miR-193a-3p contributes to the radiation and chemotherapy resistance of oesophageal carcinoma by down-regulating PSEN1. Thus, miR-193a-3p and PSEN1 might be potential biomarkers for chemoradiation resistant cancers. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. The disease, clinically characterized by a progressive decline in intellectual functions, becomes increasingly distressing for the patient and for his/her caregivers, since it is also associated with psychosis, depresion, agitation, anxiety and loss of personality. The two neuropathological hallmarks of AD are senile plaques and neurofibrillary tangles. Following diagnosis, the course of AD varies considerably from a few years to over 20 years, with a mean survival of 2-8 years according to age of onset. A positive family history, previous head injury depression, atherosclerosis low education level are found to be risk factors for AD besides age, which is the most effective risk factor. AD usually onsets after age of 65 years and its prevalence increases with age. Late-onset AD occurs after the age of 65 and 70% of those cases are sporadic; 60 % of early-onset AD, occuring before 65 years are familial. In a small number of pedigrees, AD segregates with a fully penetrant autosomal dominant trait, which indicates that AD has a genetic ethiology. To date, three genes are identified that when mutated cause early-onset AD: β-amyloid precursor protein gene (APP), Presenilin 1 gene (PS1) and Presenilin 2 gene (PS2). Together these mutations, which are by themselves sufficient to cause early-onset AD, account for 2-10% of the whole AD population. The mutations located in the coding region of these genes, increase the production of Aβ42, thereby leading to an increased Aβ deposition, which is the major component of the senile plaques. Apolipoprotein E (APOE) gene is an other indication for the genetic ethiology of AD. ApoE4 allele has been shown to be a risk factor for sporadic and familial AD in multiple populations. To date more than 100 genes, including the promoter regions of PS1, PS2 and APOE, have been considered to contribute to sporadic AD pathology; however the majority of these studies showed contradictory results. The linkage and association analysis data provide evidence for the high complexity of the disease, rather than shedding light on the disease mechanism. Full genome screens revealed many different loci on different chromosomes, but only some of them yielded positive results in independent studies, which may be promising for the discovery of new AD genes. Although there is enough of evidence that Aβ is central to AD pathogenesis, there are many complex secondary events that all contribute to the final outcome of neurodegeneration. Ultimately, the disease process in man has to be prevented through the appropriate use of therapeutic drugs. In this regard Aβ is leading the way as a target for therapeutic agents in an attempt to reduce its production, inhibit aggregation and neurotoxicity. When in future advanced treatment options become available for the early prevention of AD, individuals at risk can make use of predictive DNA testing; the DNA test has to be performed according to strictly approved international guidelines, which asure the confidentiality of the test results.

Presenilin 1 (PS1) and presenilin 2 play a critical role in the γ-secretase processing of amyloid precursor protein (APP) and Notch1. Here, we investigate maturation and intracellular trafficking of APP and other membrane proteins in cells expressing an experimental PS1 deletion mutant (ΔM1,2). Stable expression of ΔM1,2 impairs γ-secretase processing of Notch1 and delays Aβ secretion. Kinetic studies show enhanced O-glycosylation and sialylation of holo-APP and marked accumulation of APP COOH-terminal fragments (CTFs). Surface biotinylation, live staining, and trafficking studies show increased surface accumulation of holo-APP and CTFs in ΔM1,2 cells resulting from enhanced surface delivery of newly synthesized APP. Expression of a loss-of-function PS1 mutant (D385A) or incubation of cells with γ-secretase inhibitors also increases surface levels of holo-APP and CTFs. In contrast to APP, glycosylation and surface accumulation of another type I membrane protein, nicastrin, are markedly reduced in ΔM1,2 cells. Finally, expression of ΔM1,2 results in the increased assembly and surface expression of nicotinic acetylcholine receptors, illustrating that PS1's influence on protein trafficking extends beyond APP and other type I membrane protein substrates of γ-secretase. Collectively, our findings provide evidence that PS1 regulates the glycosylation and intracellular trafficking of APP and select membrane proteins.

Sleep disturbances are common in Alzheimer’s disease (AD) and now assumed to contribute to disease onset and progression. Here, we investigated whether activity, sleep/wake pattern, and electroencephalogram (EEG) profiles are altered in the knock-in PLB1 Triple mouse model from 5 to 21 months of age. PLB1 Triple mice displayed a progressive increase in wakefulness and non-rapid eye movement sleep fragmentation from 9 months onward, whereas PLB1 WT wild type controls showed such deterioration only at 21 months. Impaired habituation to spatial novelty was also detected in PLB1 Triple mice. Hippocampal power spectra of transgenic mice revealed progressive, vigilance stage-, brain region-, and age-specific changes. Age had an impact on EEG spectra in both cohorts but led to accelerated genotype-dependent differences, ultimately affecting all bands at 21 months. Overall, although PLB1 Triple animals display only subtle amyloid and tau pathologies, robust sleep-wake and EEG abnormalities emerged. We hypothesize that such endophenotypes are sensitive, noninvasive, and reliable biomarker to identify onset and progression of AD. [ABSTRACT FROM AUTHOR]

To research the efffect of Electro-acupuncture on the PS1 protein expression in the hippocampus of mice SAMP8, and discuss the mechanism of the EA treatment on AD. Methods: Twenty 8-month-old SAMP8 mice were randomly divided into model group and EA group, with ten SAMR1 mice as the normal control group. All the groups feed in normal environment. Model group and normal group should be caught and bounded once when the EA group is being treated. "Baihui", "Yintang", "Renzhong" were selected as the EA treat points for EA group 20 min a day for 15 days. The current frequency is 2 Hz and current strength is appropriate when the head of mice is quivering. The learning-memorize ability of mice was assessed by Morris water maze when the treatment finished. Immunohistochemistral method was used to observe the PS1 protein expression in the hippocampus of mice. The contents of PS1 protein in hippocampus was tested by Western Blotting. Results: The Morris water maze test showed the escape latency of model group increased, the number of platform-site crossover and the swimming duration in platform quadrant of model group were reduced compared with the control group（P<0.05，P<0.01）; the escape latency of EA group reduced, while the crossing time and dwell time in the target quadrant increased compared with the model group(P<0.05). The Immunohistochemistral result showed that the PS1 protein in the hippocampus of EA group obviously decreased compared with the model group（P<0.01）. The Western Blotting result showed the contents of PS1 protein in the model group were higher than that in the control group（P<0.01）, while the EA group could reduce its expression（P<0.01). Conclusions: EA therapy can improve the learning-memorize ability of the SAMP8 mice and decrease the protein contents of A茁and PS1 in hippocampus. The EA treatment might be a promising method to AD patients. [ABSTRACT FROM AUTHOR]

We collected blood DNA from 120 late-onset Alzheimer’s disease (AD) patients and 115 healthy matched controls and analysed the methylation levels of genes involved in amyloid-beta peptide production ( PSEN1 and BACE1 ), in DNA methylation ( DNMT1 , DNMT3A and DNMT3B ), and in one-carbon metabolism ( MTHFR ), searching for correlation with age and gender, with biomarkers of one-carbon metabolism (plasma homocysteine, and serum folate and vitamin B12 levels), and with disease status (being healthy or having AD). We also evaluated the contribution of the APOE ϵ4 allele, the major late-onset AD genetic risk factor, to the studied gene methylation levels. All the genes showed low mean methylation levels (<5%) in both AD and control DNA, no difference between groups, and no correlation with the studied biomarkers, except for MTHFR that showed methylation levels ranging from 5% to 75%, and correlation with circulating biomarkers of one-carbon metabolism. However, mean MTHFR methylation levels were similar between groups (31.1% in AD and 30.7% in controls, P = 0.58). Overall, present data suggest that none of the studied regions is differently methylated in blood DNA between AD and control subjects. [ABSTRACT FROM AUTHOR]

Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid β-peptide (Aβ). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aβ produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aβ. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aβ. We also briefly outline how the emerging knowledge about the pathways involved in Aβ generation and clearance can be potentially targeted therapeutically. This article is part of Special Issue entitled "Neuronal Protein". [ABSTRACT FROM AUTHOR]

Chemoresistance prevents the curative cancer therapy, our understanding of which remains inadequate. Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the γ-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer. [ABSTRACT FROM AUTHOR]

Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein ( APP ), presenilin 1 ( PSEN1 ), and presenilin 2 ( PSEN2 ) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1 , and PSEN2 , in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD). [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by progressive memory loss accompanied by synaptic and neuronal degeneration. Although research has shown that substantial neurodegeneration occurs even during the early stages of AD, the detailed mechanisms of AD pathogenesis are largely unknown because of difficulties in diagnosis and limitations of the analytical methods. The 5XFAD mouse model harbors five early-onset familial AD (FAD) mutations and displays substantial amyloid plaques and neurodegeneration. Here, we use quantitative mass spectrometry to identify proteome-wide changes in the 5XFAD mouse hippocampus during the early stages of AD pathology. A subset of the results was validated with immunoblotting. We found that the 5XFAD mice display higher expression of ApoE, ApoJ (clusterin), and nicastrin, three important proteins in AD that are known to participate in amyloid-β processing and clearance, as well as the neurological damage/glial marker protein GFAP and other proteins. A large subset of the proteins that were up- or downregulated in 5XFAD brains have been implicated in neurological disorders and cardiovascular disease, suggesting an association between cardiovascular disease and AD. Common upstream regulator analysis of upregulated proteins suggested that the XBP1, NRF2, and p53 transcriptional pathways were activated, as was IGF-1R signaling. Protein interactome analysis revealed an interconnected network of regulated proteins, with two major sub-networks centered on AβPP processing membrane complexes and mitochondrial proteins. Together with a recent study on the transcriptome of 5XFAD mice, our study allows a comprehensive understanding of the molecular events occurring in 5XFAD mice during the early stages of AD pathology. [ABSTRACT FROM AUTHOR]

Abstract: Familial Alzheimer''s disease (AD) due to PSEN1 mutations provides an opportunity to examine AD biomarkers in persons in whom the diagnosis is certain. We describe a 55 year-old woman with clinically probable AD and a novel PSEN1 mutation who underwent genetic, clinical, biochemical and magnetic resonance and nuclear imaging assessments. We also describe neuropathological findings in her similarly affected brother. Neuropsychological testing confirmed deficits in memory, visuospatial and language function. CSF t-tau and p-tau181 were markedly elevated and Aβ42 levels reduced. FDG-PET revealed hypometabolism in the left parietotemporal cortex. FDDNP-PET showed increased binding of tracer in medial temporal and parietal lobes and in the head of the caudate and anterior putamen bilaterally. Neuropathological examination of her brother showed the typical findings of AD and the striatum demonstrated amyloid pathology and marked neurofibrillary pathology beyond that typically seen in late-onset AD. A novel S212Y substitution in PSEN1 was present in the index patient and her affected brother but not in an older unaffected sister. An in vitro assay in which the S212Y mutation was introduced in cell culture confirmed that it was associated with increased production of Aβ42. We describe biochemical, imaging, and neuropathological changes in a pedigree with a novel PSEN1 mutation. This allows us to validate the pathogenicity of this mutation and the indices used to assess AD. [Copyright &y& Elsevier]

Presenilin-1 (PSEN1) is a primary component of the γ-secretase complex, and total levels of its holoprotein and endoproteolytic fragments are tightly regulated. We examined the effects of several types of endoplasmic reticulum (ER) stress on quantitative changes in the levels of PSEN1 mRNA, holoprotein, and fragments. The ER stress-inducing chemical compounds tunicamycin, brefeldin-A, thapsigargin, and staurosporine were added to the culture media of various human cell lines. Tunicamycin treatment caused a doubling of PSEN1 holoprotein production in HEK293 cells and an increase in holoprotein production to approximately 180% in GOTO human neuroblastoma and KNS-42 human glioma cell lines, without changing the amounts of PSEN1 N- or C-terminal fragments. The elevated holoprotein level in HEK293 cells was accompanied by an increase in PSEN1 mRNA expression. HEK293 cells that stably overexpressed PSEN1 holoprotein showed increased resistance to ER stress induced by tunicamycin, but they did not show resistance to ER stress caused by thapsigargin, a specific inhibitor of sarco ER calcium-ATPase (SERCA). In wild-type HEK293 cells under ER stress induced by tunicamycin, an increased amount of SERCA interacted with PSEN1 holoprotein. PSEN1 production varied among cell types and circumstances. The results suggested that the holoprotein forms a complex with the SERCA channel and participates in the regulation of intracellular calcium homeostasis. These findings provide support for the calcium hypothesis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract: Caloric restriction (CR) mitigates neurological damage arising from aging and a variety of other sources, including neuropathology in young adult mice that express single and double transgenic (tg) mutations associated with Alzheimer disease (AD). To evaluate the potential of CR to protect against relatively heavy AD-type pathology, middle-aged (13–14-month-old) mice that co-express two mutations related to familial AD, amyloid precursor protein (APP) and presenilin 1 (PS1), were fed balanced diets with 40% fewer calories than ad libitum-fed controls. Following 18 weeks of treatment, mice were killed and brains were processed for quantification of total volume of amyloid-beta (Aβ) in the hippocampal formation and the overlying neocortex. Computerized stereology confirmed that CR reduced the total Aβ volume by about one-third compared to that in age-matched controls. Thus, CR appears to attenuate the accumulation of AD-type neuropathology in two cortical brain regions of middle-aged dtg APP/PS1 mice. These findings support the view that CR could be a potentially effective, non-pharmacology strategy for reducing relatively heavy Aβ deposition in older adult dtg APP/PS1 mice, and possibly afford similar protection against the onset and progression of AD in older adult humans. [Copyright &y& Elsevier]

Abstract: The lifecycle of intracellular pathogens, especially viruses, is intimately tied to the macromolecular synthetic processes of their host cell. In the case of positive-stranded RNA viruses, the ability to translate and, thus, replicate their infecting genome is dependent upon hijacking host proteins. To identify proteins that participate in West Nile virus (WNV) replication, we tested the ability of siRNAs designed to knock-down the expression of a large subset of human genes to interfere with replication of WNV replicons. Here we report that multiple siRNAs for proteasome subunits interfered with WNV genome amplification. Specificity of the interference was shown by demonstrating that silencing proteasome subunits did not interfere with Venezuelan equine encephalitis virus replicons. Drugs that blocked proteasome activity were potent inhibitors of WNV genome amplification even if cells were treated 12 h after infection, indicating that the proteasome is required at a post-entry stage(s) of the WNV infection cycle. [Copyright &y& Elsevier]

Abstract: Amyloid deposits are one of the hallmarks of Alzheimer''s disease. Recent studies, in transgenic mice modeling Alzheimer''s disease showed that, using in vivo, contrast agent-free, MRI, thalamic amyloid plaques are more easily detected than other plaques of the brain. Our study evaluated the characteristics of these thalamic plaques in a large population of APP/PS1, PS1 and C57BL/6 mice. Thalamic spots were detected in all mice but with different frequency and magnitude. Hence, the prevalence and size of the lesions were higher in APP/PS1 mice. However, even in APP/PS1 mice, thalamic spots did not occur in all the old animals. In APP/PS1 mice, spots detection was related to high iron and calcium load within amyloid plaques and thus reflects the ability of such plaque to capture large amounts of minerals. Interestingly, calcium and iron was also detected in extra-thalamic plaques but with a lower intensity. Hypointense lesions in the thalamus were not associated with the iron load in the tissue surrounding the plaques, nor with micro-hemorrhages, inflammation, or a neurodegenerative context. [Copyright &y& Elsevier]

Abstract: Wild-type and single-transgenic (APP, PS1) and double-transgenic (APP+PS1) mice were studied at three different (3-, 12-, and 18-month-old) age periods. Transgenic mice had reflex eyelid responses like those of controls, but only 3-month-old mice were able to fully acquire conditioned eyeblinks, using a trace paradigm, whilst 12-month-old wild-type and transgenic mice presented intermediate values, and 18-month-old wild-type and transgenic mice were unable to acquire this type of associative learning. 18-month-old wild-type and transgenic mice presented a normal synaptic activation of CA1 pyramidal cells by the stimulation of Schaffer collaterals, but they did not show any activity-dependent potentiation of the CA3–CA1 synapse across conditioning sessions, as was shown by 3-month-old wild-type mice. Moreover, 18-month-old wild-type and transgenic mice presented a noticeable deficit in long-term potentiation evoked in vivo at the hippocampal CA3–CA1 synapse. The 18-month-old wild-type and transgenic mice also presented a significant deficit in prepulse inhibition as compared with 3-month-old controls. Except for results collected by prepulse inhibition, the above-mentioned deficits were not related with the presence of amyloid β deposits. Thus, learning and memory deficits observed in aged wild-type and transgenic mice are not directly related to the genetic manipulations or to the presence of amyloid plaques. [Copyright &y& Elsevier]

Alzheimer’s disease (AD) is characterized by an accumulation in the brain of amyloid β peptides (Aβ). The production of Aβ requires two sequential cleavages induced by β- and γ-secretases on the β-amyloid precursor protein (APP). Altered activity of these secretases is involved in the pathogenesis of AD. The expression and activity of β-secretase (BACE1) is augmented in the brain in late-onset sporadic AD. Mutant presenilin 1 (PS1), the major genetic defect of early-onset familial AD (FAD), alters the activity of γ-secretase, leading to increased production of Aβ42. Here we review the role of oxidative stress as a molecular link between the β- and the γ-secretase activities, and provide a mechanistic explanation of the pathogenesis of sporadic late-onset AD. We also discuss evidence for a role of the same mechanism in the pathogenesis of familial AD carrying PS1 mutations. [ABSTRACT FROM AUTHOR]

Intracellular Ca2+ signaling involves Ca2+ liberation through both inositol triphosphate and ryanodine receptors (IP3R and RyR). However, little is known of the functional interactions between these Ca2+ sources in either neuronal physiology, or during Ca2+ disruptions associated with Alzheimer's disease (AD). By the use of whole-cell recordings and 2-photon Ca2+ imaging in cortical slices we distinguished between IP3R- and RyR-mediated Ca2+ components in nontransgenic (non-Tg) and AD mouse models and demonstrate powerful signaling interactions between these channels. Ca2+-induced Ca2+ release (CICR) through RyR contributed modestly to Ca2+ signals evoked by photoreleased IP3 in cortical neurons from non-Tg mice. In contrast, the exaggerated signals in 3×Tg-AD and PS1KI mice resulted primarily from enhanced CICR through RyR, rather than through IP3R, and were associated with increased RyR expression levels. Moreover, membrane hyperpolarizations evoked by IP3 in neurons from AD mouse models were even greater than expected simply from the exaggerated Ca2+ signals, pointing to an increased coupling efficiency between cytosolic [Ca2+] and K+ channel regulation. Our results highlight the critical roles of RyR-mediated Ca2+ signaling in both neuronal physiology and pathophysiology, and point to presenilin-linked disruptions in RyR signaling as an important genetic factor in AD. [ABSTRACT FROM AUTHOR]

Abstract: A recent epidemiological study suggested that higher caffeine intake over decades reduces the risk of Alzheimer’s disease (AD). The present study sought to determine any long-term protective effects of dietary caffeine intake in a controlled longitudinal study involving AD transgenic mice. Caffeine (an adenosine receptor antagonist) was added to the drinking water of amyloid precursor protein, Swedish mutation (APPsw) transgenic (Tg) mice between 4 and 9 months of age, with behavioral testing done during the final 6 weeks of treatment. The average daily intake of caffeine per mouse (1.5 mg) was the human equivalent of 500 mg caffeine, the amount typically found in five cups of coffee per day. Across multiple cognitive tasks of spatial learning/reference memory, working memory, and recognition/identification, Tg mice given caffeine performed significantly better than Tg control mice and similar to non-transgenic controls. In both behaviorally-tested and aged Tg mice, long-term caffeine administration resulted in lower hippocampal β-amyloid (Aβ) levels. Expression of both Presenilin 1 (PS1) and β-secretase (BACE) was reduced in caffeine-treated Tg mice, indicating decreased Aβ production as a likely mechanism of caffeine’s cognitive protection. The ability of caffeine to reduce Aβ production was confirmed in SweAPP N2a neuronal cultures, wherein concentration-dependent decreases in both Aβ1–40 and Aβ1–42 were observed. Although adenosine A1 or A2A receptor densities in cortex or hippocampus were not affected by caffeine treatment, brain adenosine levels in Tg mice were restored back to normal by dietary caffeine and could be involved in the cognitive protection provided by caffeine. Our data demonstrate that moderate daily intake of caffeine may delay or reduce the risk of AD. [Copyright &y& Elsevier]

Abstract: Regional cerebral atrophy was evaluated in APP/PS1 mice harboring mutated transgenes linked to familial Alzheimer''s disease, using complementary methods. In vivo high resolution MRI was selected for measurements of brain atrophy and associated cerebrospinal fluid dilation; histological analysis was performed to reveal localized atrophies and to evaluate amyloid burden. Young APP/PS1 mice examined at a pre-amyloid stage (10 weeks) showed disruption in development (reduced intracranial and brain volumes). Comparison of young and old (24 months) mice, indicated that both APP/PS1 and control brains endure growth during adulthood. Aged APP/PS1 animals showed a moderate although significant global brain atrophy and a dilation of CSF space in posterior brain regions. The locus of this atrophy was identified in the midbrain area and not, as expected, at isocortical/hippocampal levels. Atrophy was also detected in fiber tracts. The severity of brain atrophy in old APP/PS1 mice was not correlated with the extent of cerebral amyloidosis. The relevance of current transgenic mouse models for the study of brain atrophy related to Alzheimer''s disease is discussed. [Copyright &y& Elsevier]

Abstract: T1 and T2 magnetic resonance relaxation times have the potential to provide biomarkers of amyloid-β deposition that could be helpful to the development of new therapies for Alzheimer''s disease. Here, we measured T1 and T2 times as well as plaques and iron loads in APP/PS1 mice, which model brain amyloidosis, and control PS1 mice. Iron was mostly associated with amyloid deposits in APP/PS1 animals, while it was diffuse in the PS1 mice. T1 was negatively correlated with age in most structures in APP/PS1 animals. This may be related to the age-associated myelin loss described in APP/PS1 mice rather than to amyloid deposition. T2 in the subiculum of adult APP/PS1 animals was lower than in PS1 mice, which may be related to the very high amyloid and iron loads in this region. T2 in the subiculum could thus serve as an early marker of the amyloid pathology. [Copyright &y& Elsevier]

&#x03B3-secretase depends on presence of presenilins (PS), Nct, Aph-I, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-β precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PSI or P52 genes shift APP cleavage from production of amyloid-β (Aβ) 40 peptide to greater production of Aβ42. Although studies in PSI/PS2-deficient embryonic cells define overlapping activities for these proteins. in vivo complementation of PSI-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PSI transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little Aβ40 or Aβ42 production. and FAD PS2 alleles support robust production of only Aβ42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a "gained" competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against &#x03B3-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct &#x03B3-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates. [ABSTRACT FROM AUTHOR]

Plastocyanin (Pc) is a copper-containing protein, which functions as an electron carrier between the cytochrome b6f and photosystem 1 (PS1) complexes in the photosynthetic electron transfer (ET) chain. The ET is mediated by His87 situated in the hydrophobic surface in the north region of Pc. Also situated in this region is Leu12, which mutated to other amino acids severely disturbs the ET from cytochrome f and to PS1, indicating the importance of the hydrophobic surface. The crystal structure of the Pc double mutant G8D/L12E has been determined to 2.0 A˚ resolution, with a crystallographic R-factor of 18.3% (Rfree=23.2%). A comparison with the wild-type structure reveals that structural differences are limited to the sites of the mutations. In particular, there is a small but significant change in the hydrophobic surface close to His87. Evidently, this leads to a mismatch in the reactive complex with the redox partners. For PS1 this results in a 20 times weaker binding and an eightfold slower ET as determined by kinetic measurements. The mutations that have been introduced do not affect the optical absorption spectrum. However, there is a small change in the EPR spectrum, which can be related to changes in the copper coordination geometry. [Copyright &y& Elsevier]

The prolongation of life and the rapidly increasing incidence of Alzheimer’s disease have brought to the foreground the need for greater understanding of the etiology of the disease and the means to prevent or at least slow down the process. Out of this need the transgenic mouse and the production of synthetic amyloid peptides have been developed in an attempt to create experimental models of Alzheimer’s disease that will help our understanding of the cellular and molecular mechanisms by which the pathology leads to memory dysfunction and to test potential therapeutic strategies. Despite 10 or so years of reasonably intensive research with these models, both fall short of producing a viable and faithful model of the complete pathology of Alzheimer’s disease and the behavioral consequences are far from modelling the progressive decline in cognitive function. Here we review the advantages and the caveats associated with the two models in terms of the pathology, the associated memory dysfunction, and the effect on synaptic plasticity. Given the more recent advances that have been made in the understanding of the neurobiological changes that occur with the disease and with the consideration of other environmental effects, which have been clearly shown to have an impact on the progression of the disease in humans, we emphasis the advantage of pharmacological or environmental in transgenic mice or rodents injected with synthetic peptides that may prove to be more fruitful in our understanding of the memory deficits associated with the disease. [ABSTRACT FROM AUTHOR]

Understanding mechanisms involved in the production of Aβ has long been the central focus of cell biologists engaged in molecular AD research. The discovery of two genes that encode homologous polytopic membrane proteins termed Presenilins (PS), has lead to several exciting recent findings on the proteolytic processes responsible for generating the COOH-terminus of Aβ. What we now know is that PS proteins play an important role in Aβ production and are considered one of the therapeutic targets. Here I have reviewed the vast literature on the biology of PS, especially focusing on PS endoproteolysis and the accumulation of stable PS derivatives that are likely the functional units. [ABSTRACT FROM AUTHOR]

The article presents a case study a 36-year-old female with progressive behavioral disturbances, dementia, involuntary movements and a family history of early-onset dementia accompanied by involuntary movements who was presented to an outpatient clinic in Krakow, Poland in March 2011. He was diagnosed with early-onset Alzheimer's disease as a result of mutation in exon 12 of the presenilin I (PSEN-I) gene.

• FoxO1 reduces Aβ level by inhibiting the amyloid pathway mediated by BACE1 and PS1. • FoxO1 reduces tau phosphorylation by regulating the activities of GSK-3β and ERK. • FoxO1 plays a critical role in AD-like pathology and that FoxO1 is a novel target for AD treatment. Forkhead box O1 (FoxO1), a key molecule in the regulation of cell growth, differentiation and metabolism, is an important transcription factor. However, the effect of FoxO1 on Alzheimer's disease (AD) needs further investigation. In this study, we aimed to explore the function and mechanism of FoxO1 in amyloid-β (Aβ) production and tau phosphorylation in AD. First, compared with the age matched wild-type (WT) mice, we showed that FoxO1 protein levels were reduced in the cortices but nearly unchanged in the hippocampi of 6-month-old APPswe/PSEN1dE9 transgenic mice expressing Swedish APP and Presenilin1 delta exon 9 mutations (APP/PS1 mice). Then, we found that overexpression of FoxO1 significantly attenuated Aβ production through inhibiting the amyloidogenic processing of β-amyloid precursor protein (APP), mediated by the key enzymes BACE1 and PS1, in N2a/APPsw cells. Furthermore, in FoxO1-overexpressing HEK293/Tau cells, the decreased levels of tau phosphorylation at selective sites (S262 and T231) were accompanied by increasing the expression of p-GSK-3β (S9), and reducing p-ERK. In contrast, the total tau (Tau-5), non-phosphorylated tau (Tau-1), p-Tau (S404), CDK5 and PP2A levels remained unchanged. These findings indicate that FoxO1 is related to AD and suggest FoxO1 as a therapeutic target for AD that reduces the levels of both Aβ expression and tau phosphorylation. [ABSTRACT FROM AUTHOR]