Mutations In Presenilin Genes Research Articles

Towards A Cell Biology of Alzheimer’s Disease

In many neurodegenerative disorders, including Alzheimer's Disease (AD), the dysfunction of multiple cell types causes neuronal cell death, but the precise cellular processes involved remain incompletely understood for any neurodegenerative disease. Strikingly, synapses are often affected early during pathogenesis, probably because presynaptic terminals are distant outstations of neurons that are the most vulnerable part of a neuron. In AD, multiple mutations in APP and presenilin genes cause rare familial cases, while the ApoE4 variant of the ApoE gene represents the strongest genetic risk factor for sporadic AD in the general population. APP and presenilin gene mutations are thought to induce AD pathogenesis by overproducing pathogenic Abeta variants, and ApoE4 is thought to influence Abeta clearance, but how Abeta might incite AD pathogenesis and how ApoE4 might predispose to AD pathogenesis remains incompletely understood. Moreover, compelling evidence implicates microglial and possibly astrocytic dysfunction in AD pathogenesis. In my lab, we have taken a cell-biological approach to these questions with a focus on synapses because of their prominent role in AD, recognizing that synapse impairments in AD may also be secondary to microglial dysfunction. We have examined how pathogenic APP mutations, chronic impairments of presenilin function, or ApoE4 may act on synapses, using human neurons trans-differentiated from ES and iPS cells as a model. In my presentation, I will discuss the current status of this project which is far from providing a definitive account of AD pathogenesis but may offer a basis for understanding the most basic processes underlying such pathogenesis.

Generation of a human induced pluripotent stem cell (iPSC) line from skin fibroblasts of a patient carrying an E363Q mutation in PSEN1 gene

Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by cognitive decline even leading to incapacity, which prevalence estimates that about 5% of AD cases are caused by mutations in genes such as Presenilin-1 (PSEN1). Here we report the generation and characterization of an iPSC line derived from a patient carrying an E363Q mutation in PSEN1 gene. The iPSC line we generated presented a typical morphology, normal karyotype, free from Sendai viral vectors and exogenous factors, expressed endogenous pluripotency marker genes and proteins, which could form embryoid bodies in vitro and form teratoma in vivo as well, demonstrating its pluripotency.

Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder which leads to mental deterioration due to aberrant accretion of misfolded proteins in the brain. According to mitochondrial cascade hypothesis, mitochondrial dysfunction is majorly involved in the pathogenesis of AD. Many drugs targeting mitochondria to treat and prevent AD are in different phases of clinical trials for the evaluation of safety and efficacy as mitochondria are involved in various cellular and neuronal functions. Mitochondrial dynamics is regulated by fission and fusion processes mediated by dynamin-related protein (Drp1). Inner membrane fusion takes place by OPA1 and outer membrane fusion is facilitated by mitofusin1 and mitofusin2 (Mfn1/2). Excessive calcium release also impairs mitochondrial functions; to overcome this, calcium channel blockers like nilvadipine are used. Another process acting as a regulator of mitochondrial function is mitophagy which is involved in the removal of damaged and non-functional mitochondria however this process is also altered in AD due to mutations in Presenilin1 (PS1) and Amyloid Precursor Protein (APP) gene. Mitochondrial dynamics is altered in AD which led to the discovery of various fission protein (like Drp1) inhibitors and drugs that promote fusion. Modulations in AMPK, SIRT1 and Akt pathways can also come out to be better therapeutic strategies as these pathways regulate functions of mitochondria. Oxidative phosphorylation is major generator of Reactive Oxygen Species (ROS) leading to mitochondrial damage; therefore reduction in production of ROS by using antioxidants like MitoQ, Curcumin and Vitamin Eis quiteeffective.

In-Frame and Frameshift Mutations in Zebrafish Presenilin 2 Affect Different Cellular Functions in Young Adult Brains.

Background:Mutations in PRESENILIN 2 (PSEN2) cause early onset familial Alzheimer’s disease (EOfAD) but their mode of action remains elusive. One consistent observation for all PRESENILIN gene mutations causing EOfAD is that a transcript is produced with a reading frame terminated by the normal stop codon—the “reading frame preservation rule”. Mutations that do not obey this rule do not cause the disease. The reasons for this are debated.Objective:To predict cellular functions affected by heterozygosity for a frameshift, or a reading frame-preserving mutation in zebrafish psen2 using bioinformatic techniques.Methods:A frameshift mutation (psen2N140fs) and a reading frame-preserving (in-frame) mutation (psen2T141 _ L142delinsMISLISV) were previously isolated during genome editing directed at the N140 codon of zebrafish psen2 (equivalent to N141 of human PSEN2). We mated a pair of fish heterozygous for each mutation to generate a family of siblings including wild type and heterozygous mutant genotypes. Transcriptomes from young adult (6 months) brains of these genotypes were analyzed.Results:The in-frame mutation uniquely caused subtle, but statistically significant, changes to expression of genes involved in oxidative phosphorylation, long-term potentiation and the cell cycle. The frameshift mutation uniquely affected genes involved in Notch and MAPK signaling, extracellular matrix receptor interactions and focal adhesion. Both mutations affected ribosomal protein gene expression but in opposite directions.Conclusion:A frameshift and an in-frame mutation at the same position in zebrafish psen2 cause discrete effects. Changes in oxidative phosphorylation, long-term potentiation and the cell cycle may promote EOfAD pathogenesis in humans.

Gene mutations associated with early onset familial Alzheimer's disease in China: An overview and current status.

BackgroundMutations of three causative genes, namely presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP), have been identified as the major causes of early‐onset familial Alzheimer's disease (EOFAD). The prevalence of causative gene mutations in patients with EOFAD has been reported in previous studies worldwide but remains unclear in China. The patients with these known mutations always show considerable clinical phenotypic variability. However, to date, there have been no detailed descriptions of the clinical phenotypes associated with these Chinese EOFAD mutations. Thus, the aim of this study was to describe all of the known mutations in three EOFAD causative genes and genotype–phenotype correlations in Chinese patients with EOFAD.MethodWe systematically searched the PubMed, MEDLINE, CNKI, VIP, and WAN‐FANG databases to find Chinese EOFAD mutations in reports from inception through May 2020.ResultWe identified 31 studies reporting mutations of three causative genes in China. 10 mutations in APP gene, 27 mutations in PSEN1 gene and six mutations in PSEN2 were discovered in Chinese EOFAD. This review summarized all these probably pathogenic mutations as well as its clinical features. To the best of our knowledge, this is the first systemic review of causative gene mutations in patients with EOFAD in China.ConclusionThe analysis of the genetic and clinical phenotype correlations in this review supports the idea that the clinical phenotype might be influenced by specific genetic defects. It also suggests genetic testing and genotype–phenotype correlations are important for the accurate diagnosis and for understanding disease‐associated pathways and might also improve disease therapy and prevention.

Concurrent Alzheimer disease and primary lateral sclerosis associated with presenilin-1 gene mutation in a 30-year-old man (1176)

Concurrent Alzheimer disease and primary lateral sclerosis associated with presenilin-1 gene mutation in a 30-year-old man (1176)

Effects of gene mutation and disease progression on representative neural circuits in familial Alzheimer\u2019s disease

BackgroundAlthough structural and functional changes of the striatum and hippocampus are present in familial Alzheimer’s disease, little is known about the effects of specific gene mutation or disease progression on their related neural circuits. This study was to evaluate the effects of known pathogenic gene mutation and disease progression on the striatum- and hippocampus-related neural circuits, including frontostriatal and hippocampus-posterior cingulate cortex (PCC) pathways.MethodsA total of 102 healthy mutation non-carriers, 40 presymptomatic mutation carriers (PMC), and 30 symptomatic mutation carriers (SMC) of amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 gene, with T1 structural MRI, diffusion tensor imaging, and resting-state functional MRI were included. Representative neural circuits and their key nodes were obtained, including bilateral caudate-rostral middle frontal gyrus (rMFG), putamen-rMFG, and hippocampus-PCC. Volumes, diffusion indices, and functional connectivity of circuits were compared between groups and correlated with neuropsychological and clinical measures.ResultsIn PMC, APP gene mutation carriers showed impaired diffusion indices of caudate-rMFG and putamen-rMFG circuits; PS1 gene mutation carriers showed increased fiber numbers of putamen-rMFG circuit. SMC showed increased diffusivity of the left hippocampus-PCC circuit and volume reduction of all regions as compared with PMC. Imaging measures especially axial diffusivity of the representative circuits were correlated with neuropsychological measures.ConclusionsAPP and PS1 gene mutations affect frontostriatal circuits in a different manner in familial Alzheimer’s disease; disease progression primarily affects the structure of hippocampus-PCC circuit. The structural connectivity of both frontostriatal and hippocampus-PCC circuits is associated with general cognitive function. Such findings may provide further information about the imaging biomarkers for early identification and prognosis of familial Alzheimer’s disease, and pave the way for early diagnosis, gene- or circuit-targeted treatment, and even prevention.

Mental Disorders in Young Adults from Families with the Presenilin-1 Gene Mutation E280A in the Preclinical Stage of Alzheimer's Disease.

Background:There are forms of Alzheimer’s disease (AD) that have an autosomal dominant inheritance pattern; one of them is caused by the E280A mutation in the gene that codes for Presenilin-1 (PSEN1). Studying families of people with this mutation allows the evaluation of characteristics of the subjects before cognitive decline begins.Objective:To determine whether having the mutation E280A in PSEN1 increases the risk of presenting mental disorders in adults under 30 years old who are in the preclinical stage of AD and may be eligible for primary prevention studies of AD.Methods:A psychiatric evaluation was made to 120 people belonging to families with a history of early onset AD. Of these, 62 carried the E280A mutation in PSEN1. The occurrence of mental disorders between carriers and non-carriers of the mutation was compared.Results:No statistically significant differences were found in the frequency of any mental disorder between the group of carriers and non-carriers of the mutation (Hazard Ratio: 0.80, 95% CI 0.49 to 1.31); nor were differences observed when evaluating specific disorders.Conclusion:The E280A mutation does not increase the risk of mental disorders before the age of 30 in the relatives of people affected by familial AD. Studies with larger sample sizes are required to assess the risk of low incidence mental disorders.

WITHDRAWN: Mental Disorders in Young Adults from Families with the Presenilin-1 Gene Mutation E280A in the Preclinical Stage of Alzheimer's Disease.

Ahead of Print article withdrawn by publisher.

Decrease in p3-Alcβ37 and p3-Alcβ40, products of Alcadein β generated by γ-secretase cleavages, in aged monkeys and patients with Alzheimer's disease

IntroductionNeuronal p3-Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α- and γ-secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3-Alcβ is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets. MethodsWe developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF). ResultsIn monkeys, CSF p3-Alcβ decreases with age, and the aging is also accompanied by decreased brain expression of Alcβ. In humans, CSF p3-Alcβ levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcβ level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcβ37 while increasing the production of Aβ42. DiscussionAging decreases the generation of p3-Alcβ, and further significant decrease of p3-Alcβ caused by aberrant γ-secretase activity may accelerate pathogenesis in AD.

The zebrafish orthologue of familial Alzheimer's disease gene PRESENILIN 2 is required for normal adult melanotic skin pigmentation.

Alzheimer’s disease is the most common form of age-related dementia. At least 15 mutations in the human gene PRESENILIN 2 (PSEN2) have been found to cause familial Alzheimer’s disease (fAD). Zebrafish possess an orthologous gene, psen2, and present opportunities for investigation of PRESENILIN function related to Alzheimer’s disease. The most prevalent and best characterized fAD mutation in PSEN2 is N141I. The equivalent codon in zebrafish psen2 is N140. We used genome editing technology in zebrafish to target generation of mutations to the N140 codon. We isolated two mutations: psen2N140fs, (hereafter “N140fs”), causing truncation of the coding sequence, and psen2T141_L142delinsMISLISV, (hereafter “T141_L142delinsMISLISV”), that deletes the two codons immediately downstream of N140 and replaces them with seven codons coding for amino acid residues MISLISV. Thus, like almost every fAD mutation in the PRESENILIN genes, this latter mutation does not truncate the gene’s open reading frame. Both mutations are homozygous viable although N140fs transcripts are subject to nonsense-mediated decay and lack any possibility of coding for an active γ-secretase enzyme. N140fs homozygous larvae initially show grossly normal melanotic skin pigmentation but subsequently lose this as they grow while retaining pigmentation in the retinal pigmented epithelium. T141_L142delinsMISLISV homozygotes retain faint skin melanotic pigmentation as adults, most likely indicating that the protein encoded by this allele retains weak γ-secretase activity. Null mutations in the human PRESENILIN genes do not cause Alzheimer’s disease so these two mutations may be useful for future investigation of the differential effects of null and fAD-like PRESENILIN mutations on brain aging.

A Three-Factor Structure of Cognitive Functioning Among Unimpaired Carriers and Non-Carriers of Autosomal-Dominant Alzheimer's Disease.

There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset. The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

Presenilins as Drug Targets for Alzheimer's Disease-Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development.

A major cause underlying familial Alzheimer’s disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta (Aβ). Consequently, presenilins have been the target of numerous and varied research efforts to develop therapeutic strategies for AD. The presenilin 1 gene harbors the largest number of AD-causing mutations resulting in the late onset familial form of AD. As a result, the majority of efforts for drug development focused on PS1 and Aβ. Soon after the discovery of the major involvement of PS1 and PS2 in γ-secretase activity, it became clear that neuronal signaling, particularly calcium ion (Ca2+) signaling, is regulated by presenilins and impacted by mutations in presenilin genes. Intracellular Ca2+ signaling not only controls the activity of neurons, but also gene expression patterns, structural functionality of the cytoskeleton, synaptic connectivity and viability. Here, we will briefly review the role of presenilins in γ-secretase activity, then focus on the regulation of Ca2+ signaling, oxidative stress, and cellular viability by presenilins within the context of AD and discuss the relevance of presenilins in AD drug development efforts.

Presenilin-1 Targeted Morpholino Induces Cognitive Deficits, Increased Brain Aβ1-42 and Decreased Synaptic Marker PSD-95 in Zebrafish Larvae.

Presenilins are transmembrane proteases required for the proteolytic cleavage of Notch and also act as the catalytic core of the γ-secretase complex, which is responsible for the final cleavage of the amyloid precursor protein into Amyloid-β (Aβ) peptides of varying lengths. Presenilin-1 gene (psen1) mutations are the main cause of early-onset autosomal-dominant Familial Alzheimer Disease. Elucidating the roles of Presenilin-1 and other hallmark proteins involved in Alzheimer's disease is crucial for understanding the disease etiology and underlying molecular mechanisms. In our study, we used a morpholino antisense nucleotide that targets exon 8 splicing site of psen1 resulting in a dominant negative protein previously validated to investigate behavioral and molecular effects in 5days post fertilization (dpf) zebrafish larvae. Morphants showed specific cognitive deficits in two optomotor tasks and morphological phenotypes similar to those induced by suppression of Notch signaling pathway. They also had increased mRNA levels of neurog1 at 5dpf, confirming the potential interaction of Presenilin-1 and Notch in our model. We also evaluated levels of apoptotic markers including p53, PAR-4, Caspase-8 and bax-alpha and found only bax-a decreased at 5dpf. Western Blot analysis showed an increase in Aβ1-42 and a decrease in the selective post-synaptic marker PSD-95 at 5dpf. Our data demonstrates that psen1 splicing interference induces phenotypes that resemble early-stage AD, including cognitive deficit, Aβ1-42 accumulation and synaptic reduction, reinforcing the potential contribution of zebrafish larvae to studies of human brain diseases.

Influence of low frequency PSEN1 variants on familial Alzheimer's disease risk in Brazil.

About 30-70% of familial Alzheimer's disease (AD) cases are related to mutations in presenilin-1 gene (PSEN1). Although the role of mutations and common variants in AD had been extensively investigated, the contribution of rare or low frequency PSEN1 variants on AD risk remains unclear. In the current study, we performed a mutational screening of PSEN1 coding exons and flanking intronic sequences among 53 index cases with familial history of AD from Rio de Janeiro (Brazil). Two missense variants (rs63750592; rs17125721), one rare and a low frequency variant, and two intronic variants (rs3025786; rs165932) were identified. In silico tools were used to predict the functional impact of the variants, revealing no changes in protein functionality by exonic variants. Otherwise, all variants were predicted to alter splicing signals. Prediction results, together with previous reports, suggest a correlation between rs17125721 and AD. So, a subsequent case-control study to evaluate the role of rs1712572 on AD risk was performed in an additional sample of 120 AD sporadic cases and in 149 elderly healthy controls by TaqMan Genotyping Assay. Our data indicates a risk association for rs17125721 in familial AD cases (OR=6.0; IC95%=1.06-33.79; p=0.042). In addition, we tested the multiplicative interaction between allele ε4 of the apolipoprotein E (APOE) and rs17125721 and no statistical association was found. Taken together, our findings provide new insight about the genetic relevance of low frequency PSEN1 variants for familial AD development.

The Alzheimer Conundrum: Entanglements of Dementia and Aging by Margaret Lock

Reviewed by: The Alzheimer Conundrum: Entanglements of Dementia and Aging by Margaret Lock Stephen Katz Margaret Lock. The Alzheimer Conundrum: Entanglements of Dementia and Aging. Princeton, N.J.: Princeton University Press, 2013. x + 310 pp. Ill. $24.95 (978-0-6911-6847-0). The Alzheimer Conundrum is a provocative account of why Alzheimer’s disease (AD) is such a puzzling mix of scientific hypotheses, research agendas, pharmaceutical interests, funding objectives, and theories of aging. Indeed, the idea that AD is a singular disease is called into question given the uncertainty of its causes, diagnoses, treatments, prevention, and possible cure. Hence the book’s frequent use of “entanglement” to characterize the relationships between aging brains, bodies, individuals, and populations within the AD community is apposite. Author Margaret Lock asks us to rethink AD in three bold ways. First, we should focus more on how social and environmental factors, particularly poverty and social inequality, affect cognitive health. Second, care must be a research priority so that the investments poured into high-tech screening and treatment are shared with funding public health programs that improve the lives of older people. Third, the cruel depictions of AD and dementia encapsulated by popular metaphors of being “robbed” of personhood should be contested and AD included, rather than isolated, as part of our collective humanity. For people diagnosed with AD or the risk of it, their world is infused with the intense stigma, shame, isolation, and burden usually reserved for our most troublesome citizens. The Alzheimer Conundrum elaborates these issues in nine main chapters that organize the growing interdisciplinary literature stemming from genetics, epidemiology, neuropathology and gerontology, along with the results of eighty interviews with experts in the dementia field and Lock’s qualitative work with subjects from the REVEAL survey (Risk Evaluation and Education of Alzheimer’s Disease Study). The book’s twenty-nine pages of endnotes add a wealth of additional sources and ideas. A main theme of the book is that since the death in 1906 of Auguste Deter, considered the first AD patient, the mystery of AD has been about matching [End Page 760] hypotheses to evidence. The current hypothesis is that amyloid buildup is correlated with neurodegeneration; hence identifying amyloid deposits is a key component of prevention strategy, especially biomarker testing. As well, since the APOE gene has been associated with inherited AD, genetic screening is another aspect of prevention strategy. On the evidence side, however, the standard medical model is confounded by cases of people with amyloid buildup and neurodegeneration in their brains, yet who exhibit no symptoms of AD or dementia. There are also people who have tested positive for proven risk of AD or who have been diagnosed with a predementia stage such as mild cognitive impairment, but do not progress to develop AD. Lock reminds us that ethical questions are a profound issue in AD research because of the ways in which samples and trials are created and participants are treated. Given the fear and anxiety that come with any diagnosis of AD or its risks, we need to ask how people should be informed and what kinds of follow-up surveillance are reasonable. The gathering of good AD data also requires long-term commitments of public trust even if effective treatment is not available. A fascinating case reviewed in the book is the so-called paisa mutation (presenilin-1 gene mutation) among a group of people in Medellín, Colombia, where AD is widespread in younger and older cohorts. The population has become an ideal genetic laboratory for Eric Reiman and his team from the Banner Alzheimer’s Institute (Phoenix, Ariz.), who are pursuing on-site research, but it is also an example of further ethical dilemmas that can arise when North American big science imposes upon poor Third World communities. In the end, The Alzheimer Conundrum is a timely critique of the disease model and its cultural consequences. The book’s appeal is that it takes readers beyond scientific fields to consider social, historical, and cross-cultural dimensions of AD that broaden conceptual debates about mind and body, nature and nurture, and normal and pathological. One quibble is that several of the thinkers upon whom...

Corticobasal Syndrome in a Family with Early-Onset Alzheimer's Disease Linked to a Presenilin-1 Gene Mutation.

Alzheimer's disease (AD) is the second-most frequent cause underlying corticobasal syndrome (CBS). However, a reliable diagnosis using clinical, neuropsychological, or neuroimaging approaches has not yet been achieved. Clinical, neuropsychological, imaging, and neuropathology studies were undertaken in a large Spanish family with early-onset familial AD (EOFAD) carrying a Met233Leu mutation linked to presenilin-1 gene (PSEN-1). Two of three examined members of this family presented with the usual amnestic pattern. At the age of 47years, a third family member, in whom pathology was later confirmed, developed prominent CBS combined with severe neuropsychiatric and behavioral disturbances resembling those often found in EOFAD. Although CBS in EOFAD appears to be rare, demonstration of a linkage to PSEN-1 gene mutations may permit invivo diagnosis.

Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset Alzheimer's disease

A minority of Alzheimer disease (AD) patients begin presenting symptoms before the age of 65 years. A familial aggregation is often found in this group of early-onset AD, and, in a subset of families, the pattern of inheritance is consistent with autosomal dominant inheritance. Fully penetrant variants in amyloid precursor protein, presenilin 1 (PSEN1), and presenilin 2 are the only causative mutations reported for autosomal dominant AD. This study is to explore the PSEN1 gene mutation in a Tunisian familial Alzheimer's disease. The patient in this family showed a novel missense mutation in exon 4 of the PSEN1 gene (complementary DNA 248T>C), altering isoleucine to threonine at 83 position. Because the change occurred in conserved domains of this gene, and cosegregated with affected family member, we suggested that this change may have a mutagenic and probably pathogenic effect.

Dual memory task impairment in E280A presenilin-1 mutation carriers.

Patients with sporadic Alzheimer's disease (AD) are impaired in their ability to perform two tasks concurrently compared to healthy younger and older adults, despite being able to successfully perform the tasks on their own reasonably well. Dual task impairments have also been found in those individuals with an E280A presenilin-1 genetic mutation but who do not yet meet the criteria for AD. The aim of the current study is to determine whether this dual task deficit is specific to the given combination of tasks performed simultaneously or whether it reflects a general deficit in the ability to coordinate two tasks. Thirty-one carriers of the gene mutation who did not meet the criteria for AD and 38 non-carriers were asked to perform two memory tasks simultaneously. The familial AD carriers showed significant dual task decrements compared to those family members without the gene mutation. The findings support the notion that a deficit in the mechanism responsible for coordinating the performance of two tasks may be a clinical marker for the early detection of AD due to the E280A presenilin-1 gene mutation.

Possible Role of STIM1 Sensor Signal in Memory Loss Connected with Familial Alzheimer's Disease

Familial Alzheimer's disease (FAD) which leads to memory impairments is caused by mutations in presenilin-1 (PS1) gene in approximately 40% of cases. PS1 is well known as a component of the gamma-secretase enzyme which cleaves APP to A-beta. To become a catalytic part of enzyme PS1 undergoes an endoproteolysis. It was shown that mutations in PS1 gene disrupt endoproteolysis increasing uncleaved protein level in brain tissue of FAD patients. In our study we found effects of FAD PS1 mutants (PS1DE9, PS1 D247A) on activity of store-operated calcium (SOC) channels in mice hippocampal neurons and Neuro2a cell line. Increased uncleaved PS1 levels led to SOC channels hyperactivities detected with direct single-cell electrophysiological measurements and calcium imaging experiments with fura2-AM. The effects were caused by impaired signal transduction from ER to SOC channels in plasmatic membrane. The impaired intracellular signal transduction by STIM1 sensor was revealed in live confocal imaging experiments and proved with STIM1 knock-down. Moreover, a feeding of Drosophila melanogaster transgenes expressing human mutated PS1 in cholinergic nervous system with pharmacological inhibitor of STIM sensor signal transduction 2APB led to rescue of the memory loss detected by courtship based assay with aged animals. Therefore hyperactive STIM1 signal transduction leads to increased SOC channels activity which could be the reason for memory loss in FAD.This work was supported by the program of “Molecular and Cellular Biology” RAS, research grants from the Russian Basic Research Foundation, Russian Scientific Fund and the President of Russia Scholarship.