Presenilin-1 Gene Research Articles

Abundance of Aβ5-xlike immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer’s disease

BackgroundAccording to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer’s disease (AD) is the deposition of neurotoxic amyloid β-peptide (Aβ) within neurons. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that Aβx-42 isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and Aβx-42 species have been pointed as crucial players in AD etiology, the Aβ5-x isoforms have not received much attention.ResultsThe present study is the first to show immunohistochemical evidence of Aβ5-x in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe Aβ5-x peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of Aβ5-x distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular Aβ deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal Aβ5-x.ConclusionsDifferent degrees of Aβ5-x accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular Aβ5-x, these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher Aβ5-x–immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving Aβ5-x peptides and operating in a divergent way in the late and early onset forms of the disease.

An intronic rare mutation in Presenilin-1 (PSEN-1) gene may be involved in the developement of Alzheimer’s disease

Background The Presenilin-1 gene (PSEN-1) encodes a protein component of gamma-secretase complex which is involved in processing of amyloid precursor protein (APP). The PSEN-1 is involved in many cardinal mechanisms in several molecular pathway which when impaired leads to the manifestation of Alzheimer’s disease (AD). The aim of the study was to investigate the role of PSEN-1 gene in the developement of AD in Indian Bengali population.

An ancestral non-proteolytic role for presenilin proteins in multicellular development of the social amoeba Dictyostelium discoideum.

Mutations in either of two presenilin genes can cause familial Alzheimer's disease. Presenilins have both proteolysis-dependent functions, as components of the γ-secretase complex, and proteolysis-independent functions in signalling. In this study, we investigate a conserved function of human presenilins in the development of the simple model organism Dictyostelium discoideum. We show that the block in Dictyostelium development caused by the ablation of both Dictyostelium presenilins is rescued by the expression of human presenilin 1, restoring the terminal differentiation of multiple cell types. This developmental role is independent of proteolytic activity, because the mutation of both catalytic aspartates does not affect presenilin ability to rescue development, and the ablation of nicastrin, a γ-secretase component that is crucial for proteolytic activity, does not block development. The role of presenilins during Dictyostelium development is therefore independent of their proteolytic activity. However, presenilin loss in Dictyostelium results in elevated cyclic AMP (cAMP) levels and enhanced stimulation-induced calcium release, suggesting that presenilins regulate these intracellular signalling pathways. Our data suggest that presenilin proteins perform an ancient non-proteolytic role in regulating intracellular signalling and development, and that Dictyostelium is a useful model for analysing human presenilin function.

Disregulation of Calcium Homeostasis Connected with Familial Alzheimer's Disease

Familial Alzheimer's disease (FAD) caused by mutations in presenilin-1 (PS1) gene in approximately 50% of cases and in Amyloid precursor protein (APP) gene in 13 % cases. It was found that FAD genes mutants affect calcium homeostasis in hippocampal neurons by disrupting Ca2+ storage in the lumen of endoplasmic reticulum (ER). In our study we used electrophysiological recordings with a patch-clamp technique in whole-cell mode and calcium imaging with Fura-2AM to study calcium channels activity, ER calcium load and ER calcium leak. We observed different effects of FAD mutated genes expressions on activity of store-operated and L-type voltage-gated calcium channels in mouse hippocampal neurons, mouse neuroblastoma Neuro2a and human neuroblastoma SK-N-SH cell lines. We found that effects of FAD PS1 mutants on calcium channels were driven by misbalance in activity of ER calcium sensors STIM1 and STIM2. The different effects were connected with calcium sensors STIM1 or STIM2 impaired signal transduction from ER to calcium channels in plasmatic membrane (PM) under control of ER calcium levels. The impaired signal transduction was revealed in live confocal imaging experiments. The enzyme activity of PS1 was involved in regulation of store-operated calcium entry in two ways: the activity of channels was depended on PS1 endoproteolysis level and APP cleavage.This work was supported by the program of “Molecular and Cellular Biology” RAS, research grants from the Russian Basic Research Foundation, grant ERA.Net RUS, research grants from the OPTEC LLC and the President of Russia Scholarship.

A Rare Intronic Variation of Presenilin-1 (rs201992645) is Associated with Alzheimer’s Disease and Down Syndrome Birth

Background and objective: Presenilin-1 (PSEN-1) gene is a potent candidate that relates Alzheimer’s disease (AD) to Down syndrome (DS). Genetic variation of PSEN-1 could be a risk factor that predisposes individual for both AD and DS and may contribute the common etiology of both the disorders. Methods: We sequenced exon 8 of PSEN-1 with flanking introns in 136 DS patients with their parents, 96 AD patients, 173 age-matched controls. Results were analysed in-silico to anticipate the damaging effect at molecular level. Results: A rare polymorphism rs201992645 was identified within intron 8 and in silico analysis revealed the variation as ‘potentially damaging’ at the transcript splicing level. The genotypic frequencies of mutant heterozygotes were 0.031, 0.029 and 0.029 for AD, DS and mother of DS respectively. Conclusions: We have suggested that this variation may cause AD manifestation in mothers of DS patients and is the potential marker for predisposition testing of both disorders.

Chronic neurodegenerative consequences of traumatic brain injury

Traumatic brain injury (TBI) is a serious public health concern and a major cause of death and disability worldwide. Each year, an estimated 1.7 million Americans sustain TBI of which ~52,000 people die, ~275,000 people are hospitalized and 1,365,000 people are treated as emergency outpatients. Currently there are ~5.3 million Americans living with TBI. TBI is more of a disease process than of an event that is associated with immediate and long-term sensomotor, psychological and cognitive impairments. TBI is the best known established epigenetic risk factor for later development of neurodegenerative diseases and dementia. People sustaining TBI are ~4 times more likely to develop dementia at a later stage than people without TBI. Single brain injury is linked to later development of symptoms resembling Alzheimer's disease while repetitive brain injuries are linked to later development of chronic traumatic encephalopathy (CTE) and/or Dementia Pugilistica (DP). Furthermore, genetic background of ß-amyloid precursor protein (APP), Apolipoprotein E (ApoE), presenilin (PS) and neprilysin (NEP) genes is associated with exacerbation of neurodegenerative process after TBI. This review encompasses acute effects and chronic neurodegenerative consequences after TBI.

Alzheimer's disease and CADASIL are heritable, adult-onset dementias that both involve damaged small blood vessels.

This essay explores an alternative pathway to Alzheimer's dementia that focuses on damage to small blood vessels rather than late-stage toxic amyloid deposits as the primary pathogenic mechanism that leads to irreversible dementia. While the end-stage pathology of AD is well known, the pathogenic processes that lead to disease are often assumed to be due to toxic amyloid peptides that act on neurons, leading to neuronal dysfunction and eventually neuronal cell death. Speculations as to what initiates the pathogenic cascade have included toxic abeta peptide aggregates, oxidative damage, and inflammation, but none explain why neurons die. Recent high-resolution NMR studies of living patients show that lesions in white matter regions of the brain precede the appearance of amyloid deposits and are correlated with damaged small blood vessels. To appreciate the pathogenic potential of damaged small blood vessels in the brain, it is useful to consider the clinical course and the pathogenesis of CADASIL, a heritable arteriopathy that leads to damaged small blood vessels and irreversible dementia. CADASIL is strikingly similar to early onset AD in that it is caused by germ line mutations in NOTCH 3 that generate toxic protein aggregates similar to those attributed to mutant forms of the amyloid precursor protein and presenilin genes. Since NOTCH 3 mutants clearly damage small blood vessels of white matter regions of the brain that lead to dementia, we speculate that both forms of dementia may have a similar pathogenesis, which is to cause ischemic damage by blocking blood flow or by impeding the removal of toxic protein aggregates by retrograde vascular clearance mechanisms.

Investigation of Psen1&2 Genes in Early Onset Alzheimer’s Disease Patients

Investigation of Psen1&2 Genes in Early Onset Alzheimer’s Disease Patients

Is encephalopathic brain genetically more prone to dementia?

Encouraging progress in understanding the genetics of Alzheimer’s disease (AD) merely highlights the work that remains. AD and vascular dementia are two commonest dementias. Etiology of AD involves genetic factors in 25–40% [1]. Thus far, three fully penetrate genes’ mutations have been identified in patients younger than 60 years. First, this was assigned to the β amyloid precursor protein gene (APP) on chromosome 21and after that to the autosomal dominant gene defects of presenilin-1 (PS1) gene on chromosome 14. Presenilin-2 (PS2) gene on chromosome 1 was the last connected to earlyonset AD. Each of these mutations causes abnormal proteins to be formed. In 2012 for example, Kamboh identifies nine other genes/loci (CR1, BIN1, CLU, PICALM, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7) for late-onset Alzheimer’s disease (LOAD) using genome-wide association studies (GWASs) [2]. With identification of more of the genes involved in development of the disorder, and a greater understanding of their action, AD research holds the hope of reducing or potentially eliminating the burden of this overwhelming disease [1]. The single-gene mutations directly responsible for early-onset Alzheimer’s disease do not seem to be involved in late-onset Alzheimer’s. A specific gene causing the late-onset form of the disease has not been identified yet. However, one genetic risk factor does appear to increase a person’s risk of developing the disease. This is related to the apolipoprotein E (APOE) gene found on chromosome 19. APOE encodes for a protein that helps carry cholesterol and other types of fat in the bloodstream. APOE comes in several different forms, or alleles. Three forms – APOE e2, APOE e3, and APOE e4 – occur most frequently. APOE e4 is present in about 25 to 30 % of the population and in about 40 % of all people with lateonset AD. People who develop AD are more likely to have an APOE e4 allele than people who do not develop the disease. Testing for the E-4 allele cannot predict who will get the disease. Two national panels have raised their voice against the use of apoE-4 as a predictive test for AD. This could be justified even more, if one bears in mind that a great majority of people who carry E4 will not develop AD, respecting many people who do not. Cent. Eur. J. Med. • 8(6) • 2013 • 730-731 DOI: 10.2478/s11536-013-0229-7

An 1H-MRS framework predicts the onset of Alzheimer's disease symptoms in PSEN1 mutation carriers

BackgroundAlzheimer's disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy (1H-MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD. MethodsWe studied 75 subjects from the largest multigenerational pedigree in the world (∼5000 people) that segregates a unique form of early-onset Alzheimer's disease (EOAD) caused by a fully penetrant mutation in the Presenilin-1 gene (PSEN1 p.Glu280Ala [E280 A]). Forty-four subjects were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline (Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/Cr, and Glx/Cr, respectively) with two-dimensional 1H-MRS. Using advanced recursive partition analysis and random forest analysis, we built classificatory decision trees for both mutation carrier status and the presence of MCI-AD symptoms, fitting them to 1H-MRS data while controlling for age, educational level, and sex. ResultsWe found that (1) the combination of LPPGM Cho/Cr <0.165 and RPPGM Glx/Cr >1.54 fully excluded carriers; (2) LPPGM Cho/Cr >0.165, RPPGM Glx/Cr <1.54, and left parietal white mater NAA/Cr >1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of 77.4%; and (3) RPPGM NAA/Cr >1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%. ConclusionsBrain metabolites measured by 1H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence of AD caused by the PSEN1 p.Glu280Ala (E280 A) mutation.

Autosomal‐dominant Alzheimer's disease mutations at the same codon of amyloid precursor protein differentially alter Aβ production

Autosomal-dominant Alzheimer's disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studying the mechanisms underlying these mutations can provide insight into the pathways that lead to AD pathology. The majority of biochemical studies on APP mutations to-date have focused on comparing mechanisms between mutations at different codons. It has been assumed that amino acid position is a major determinant of protein dysfunction and clinical phenotype. However, the differential effect of mutations at the same codon has not been sufficiently addressed. In the present study we compared the effects of the aggressive ADAD-associated APP I716F mutation with I716V and I716T on APP processing in human neuroglioma and CHO-K1 cells. All APP I716 mutations increased the ratio of Aβ42/40 and changed the product line preference of γ-secretase towards Aβ38 production. In addition, the APP I716F mutation impaired the ε-cleavage and the fourth cleavage of γ-secretase and led to abnormal APP β-CTF accumulation at the plasma membrane. Taken together, these data indicate that APP mutations at the same codon can induce diverse abnormalities in APP processing, some resembling PSEN1 mutations. These differential effects could explain the clinical differences observed among ADAD patients bearing different APP mutations at the same position. The amyloid precursor protein (APP) I716F mutation is associated with autosomal dominant Alzheimer's disease with the youngest age-at-onset for the APP locus. Here, we describe that this mutation, when compared to two other familial Alzheimer's disease mutations at the same codon (I716V and I716T), interfered distinctly with γ-secretase cleavage. While all three mutations direct γ-secretase cleavage towards the 48→38 production line, the APP I716F mutation also impaired the ε-cleavage and the fourth cleavage of γ-secretase, resembling a PSEN1 mutation. These features may contribute to the aggressiveness of this mutation.

Human apolipoprotein E4 modulates the expression of Pin1, Sirtuin 1, and Presenilin 1 in brain regions of targeted replacement apoE mice

The apolipoprotein E4 (apoE4) allele is consistently associated with increased risk for Alzheimer’s disease (AD). We investigated the molecular mechanism of this susceptibility by analyzing the levels of genes involved in AD pathogenesis in transgenic mice expressing human apoE3 or apoE4 isoforms. mRNA and protein levels of Pin1, Sirtuin 1 (Sirt1), Presenilin 1 (PS1), and pro-Brain-derived Neurotrophic Factor (BDNF) were analyzed in brain regions affected by neuropathological changes in AD.Pin1 mRNA was significantly higher in the hippocampus of apoE4 mice than in apoE3 controls, whereas lower expression was detected in the entorhinal and parietal cortices. Reduced Pin1 levels may increase neurofibrillary degeneration and amyloidogenic processes, while compensatory mechanisms may take place in the hippocampus to balance spatial memory deficits. Sirt1 levels were significantly reduced in the frontal cortex of apoE4 mice. Sirt1 reduction may hinder its protective role against the formation of plaques and tangles and diminish its anti-inflammatory actions. Sirt1 decrease may also play a role in apoE4-associated memory impairments. Moreover, in apoE4 mice PS1 mRNA levels were lower in the frontal cortex. Lower PS1 expression may hamper γ-secretase function, thus affecting amyloid precursor protein processing. Pro-BDNF mRNA levels did not differ between apoE3 and apoE4 mice in any region analyzed.This study showed dysregulated expression of Pin1, Sirt1, and PS1 genes in different cerebral areas of apoE4 mice, suggesting that these changes may play a role in the mechanism of AD vulnerability.

The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ

BackgroundThe Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer’s disease. Here we report the special character of Arctic AD neuropathology in four deceased patients.ResultsAβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact.ConclusionsIn Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.

Degenerative alterations in noradrenergic neurons of the locus coeruleus in Alzheimer's disease.

Mice carrying mutant amyloid-β precursor protein and presenilin-1 genes (APP/PS1 double transgenic mice) have frequently been used in studies of Alzheimer's disease; however, such studies have focused mainly on hippocampal and cortical changes. The severity of Alzheimer's disease is known to correlate with the amount of amyloid-β protein deposition and the number of dead neurons in the locus coeruleus. In the present study, we assigned APP/PS1 double transgenic mice to two groups according to age: young mice (5–6 months old) and aged mice (16–17 months old). Age-matched wild-type mice were used as controls. Immunohistochemistry for tyrosine hydroxylase (a marker of catecholaminergic neurons in the locus coeruleus) revealed that APP/PS1 mice had 23% fewer cells in the locus coeruleus compared with aged wild-type mice. APP/PS1 mice also had increased numbers of cell bodies of neurons positive for tyrosine hydroxylase, but fewer tyrosine hydroxylase-positive fibers, which were also short, thick and broken. Quantitative analysis using unbiased stereology showed a significant age-related increase in the mean volume of tyrosine droxylase-positive neurons in aged APP/PS1 mice compared with young APP/PS1 mice. Moreover, the mean volume of tyrosine hydroxylase-positive neurons was positively correlated with the total volume of the locus coeruleus. These findings indicate that noradrenergic neurons and fibers in the locus coeruleus are predisposed to degenerative alterations in APP/PS1 double transgenic mice.

Enhanced motor performance and motor learning in 3xTg-AD mice in two tests: A longitudinal study

Background: Genetically engineered mouse models are critical tools to study the genetics and pathogenesis of Alzheimer’s disease (AD), and are widely used in preclinical research. The Jackson Laboratory AD resource provides a large set of strains expressing mutant forms of human APP, MAPT (tau), APOE, Baces, Presenilins, and other relevant genes, as well as information supporting their selection and usage. All strains are rederived to a high health status, and genetic quality control measures are used to verify the strain’s genetic background and the presence of the human allele. Here we describe our efforts to expand genetic quality control by using high throughput sequencing for transgene insertion site discovery. We are also expanding the resource to include in vitro tools for AD research. Here, we describe the development of novel ES cell lines from some of our most widely utilized AD strains.Methods: To identify transgene insertion sites, we are using high throughput sequencing of mate pair libraries and a novel analysis pipeline to identify transgene insertion sites. To develop novel ES cell lines, we are using well-established ES cell derivation techniques and have introduced a tau promoter driven GFP transgene to provide a marker for neuronal differentiation. Results: To date the transgenic integration events in the “5XFAD”, “APP/PS1”, and “3xTg-AD” strains have been defined and are currently being validated. In addition, we have now generated ES cell lines from “5XFAD”, “APP/PS1” and “J20” models and we are currently testing the capacity of these ES cells for neuronal differentiation.Conclusions:Many of the most widely cited mouse models are currently available through The Jackson Laboratory AD resource, and we continue to maintain the genetic integrity of these models and to expand the resource according to the needs of the AD research community. Our transgene insertion site data enable us to determine whether insertion sites disrupt genomic sequences that are physiologically relevant, and to develop simplified genotyping assays. The ES cells we are creating will provide in vitro tools for the study of neuronal phenotypes related to over-expression of human AD genes. Detailed strain, ES cell, and availability information can be found at http://research.jax.org/grs/alzheimers.html

Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers.

Alzheimer's disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-β (Aβ) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers. We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related noncarriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of Aβ isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer Pittsburgh compound B (PIB). CNS Aβ42 to Aβ40 production rates were 24% higher in mutation carriers compared to noncarriers, and this was independent of fibrillar amyloid deposits quantified by PET PIB imaging. The fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques, leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). Reversible exchange of Aβ42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF.

Presenilin Promotes Dietary Copper Uptake

Dietary copper is essential for multicellular organisms. Copper is redox active and required as a cofactor for enzymes such as the antioxidant Superoxide Dismutase 1 (SOD1). Copper dyshomeostasis has been implicated in Alzheimer’s disease. Mutations in the presenilin genes encoding PS1 and PS2 are major causes of early-onset familial Alzheimer’s disease. PS1 and PS2 are required for efficient copper uptake in mammalian systems. Here we demonstrate a conserved role for presenilin in dietary copper uptake in the fly Drosophila melanogaster. Ubiquitous RNA interference-mediated knockdown of the single Drosophila presenilin (PSN) gene is lethal. However, PSN knockdown in the midgut produces viable flies. These flies have reduced copper levels and are more tolerant to excess dietary copper. Expression of a copper-responsive EYFP construct was also lower in the midgut of these larvae, indicative of reduced dietary copper uptake. SOD activity was reduced by midgut PSN knockdown, and these flies were sensitive to the superoxide-inducing chemical paraquat. These data support presenilin being needed for dietary copper uptake in the gut and so impacting on SOD activity and tolerance to oxidative stress. These results are consistent with previous studies of mammalian presenilins, supporting a conserved role for these proteins in mediating copper uptake.

Familial dementia with frontotemporal features associated with M146V presenilin-1 mutation.

Most of the mutations in the presenilin-1 gene (PS-1) are associated with familial Alzheimer's disease (AD). However, certain examples can be associated with frontotemporal dementia (FTD). We performed a clinical evaluation of individuals belonging to a family with the FTD phenotype, and additional molecular studies and neuropathological assessment of the proband. The PS-1 M146V mutation was found in the 50-year-old subject (the proband) with family history of early-onset FTD. Neuropathological examination showed abundant amyloid plaques, widespread neurofibrillary pathology, Pick bodies in the hippocampus and cortex, cortical globose tangles and ubiquitin-positive nuclear inclusions in white matter oligodendrocytes. We report a kindred with clinical features of FTD, whose proband bore the PS-1 M146V mutation and showed diffuse Alzheimer's type pathology and Pick bodies on post-mortem neuropathological examination. As with other mutations within the same codon, this substitution may predispose to both diseases by affecting APP and/or tau processing.

Familial Alzheimer's disease-linked presenilin-1 mutation M146V affects store-operated calcium entry: Does gain look like loss?

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to neuron death and synapse loss in the hippocampus and cortex, with consequent cognitive disability and dementia. Mutations in the presenilin-1 (PS1) gene lead to familial Alzheimer's disease (FAD). Here, we report that the expression of FAD-linked PS1 M146V mutant affects store-operated calcium channel activity (Isoc) in human neuroblastoma SK-N-SH cells. Electrophysiological measurements and calcium imaging experiments have revealed the emergent role of calcium sensor STIM2 in the inhibition of calcium release-activated calcium channel activity (Icrac) and enhancement of intracellular Ca(2+) stores content due to PS1 M146V mutant expression. In general, the results of this study suggest that the pathological inhibition of one type of store-operated calcium channels caused by FAD PS1 mutant expression may be accounted for by preceding gain of spontaneous activity of store-operated calcium channels driven by STIM2.

Plasma Aβ: A Possible Missing Link Between Alzheimer Disease and Diabetes

Currently, there are more than 30 million dementia patients worldwide (1). More than half of dementia is caused by Alzheimer disease (AD), which consists of both familial and sporadic forms. Familial AD is caused by mutations in the amyloid precursor protein (APP) (2) and presenilin genes (3). Both mutations cause overproduction of amyloid-β (Aβ), particularly its longer form, Aβ42, which is more prone to aggregate. It should be noted that familial AD accounts for a small proportion of all AD cases. On the other hand, sporadic cases comprise more than 95% of AD, and emerging evidence suggests that diabetes is a nongenetic risk factor for sporadic AD (4). While diabetes increases AD 1.5–2-fold, the mechanism whereby diabetes enhances AD risk has not been elucidated. As 285 million people battle diabetes worldwide against the backdrop of an aging society (5), understanding the relationship between AD and diabetes is of extreme importance. Interestingly, several clinical reports have suggested that AD patients also have glucose intolerance, suggesting a bidirectional relationship between the two conditions (6,7). Supporting this idea are data from animal models such as APP + ob/ob mice showing that AD aggravates the diabetic phenotype (8,9). Although further evidence is still required to confirm this concept, it is intriguing to investigate the …