Search

Background: Presenilin 1 (PSEN1) is one of the genes linked to the prevalence of early onset Alzheimer's disease. In mice, inactivation of Psen1 leads to developmental defects, including vertebral malformation and neural development. However, little is known about the role of PSEN1 during the development in other species. Objective: To investigate the role of PSEN1 in vertebral development and the pathogenic mechanism of neurodegeneration using a pig model. Methods: CRISPR/Cas9 system was used to generate pigs with different mutations flanking exon 9 of PSEN1, including those with a deleted exon 9 (Δexon9). Vertebral malformations in PSEN1 mutant pigs were examined by X-ray, micro-CT and micro-MRI. Neuronal cells from the brains of PSEN1 mutant pigs were analyzed by immunoflourescence, followed by image analysis including morphometric evaluation via image J and 3D reconstruction. Results: Pigs with a PSEN1 null mutation (Δexon9-12) died shortly after birth and had significant axial skeletal defects, whereas pigs carrying at least one Δexon9 allele developed normally and remained healthy. Effects of the null mutation on abnormal skeletal development were also observed in fetuses at day 40 of gestation. Abnormal distribution of astrocytes and microglia in the brain was detected in two PSEN1 mutant pigs examined compared to age-matched control pigs. The founder pigs were bred to establish and age PSEN1ΔE9/+ pigs to study their relevance to clinical Alzheimer's diseases. Conclusions: PSEN1 has a critical role for normal vertebral development and PSEN1 mutant pigs serves as novel resources to study Alzheimer's disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin‐1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre‐/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross‐sectionally evaluated regional Pittsburgh compound B‐positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging‐based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. Highlights: Mutation position influences Aβ burden, SVD, and dementia.PSEN1 pre‐200 group had stronger associations between Aβ burden and disease stage.PSEN1 post‐200 group had stronger associations between SVD markers and disease stage.PSEN1 post‐200 group had worse dementia score than pre‐200 in late disease stage.Diffusion tensor imaging‐based SVD markers mediated mutation position effects on dementia in the late stage. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Depressive symptoms are among early behavioral changes in Alzheimer's disease (AD); however, the relationship between neurodegeneration and depressive symptoms remains inconclusive. To better understand this relationship in preclinical AD, we examined hippocampal volume and depressive symptoms in cognitively unimpaired carriers of the presenilin‐1 (PSEN1) E280A mutation for autosomal dominant AD. METHODS: A total of 27 PSEN1 mutation carriers and 26 non‐carrier family members were included. Linear regression was used to test the relationship between hippocampal volume and 15‐item Geriatric Depression Scale. RESULTS: Carriers and non‐carriers did not differ in depressive symptoms or hippocampal volume. Within carriers, lower hippocampal volume was associated with greater depressive symptoms, which remained significant after adjusting for age and cognition. This relationship was not significant in non‐carriers. DISCUSSION: Hippocampal neurodegeneration may underlie depressive symptoms in preclinical autosomal dominant AD. These findings provide support for the utility of targeting depressive symptoms in AD prevention. Highlights: We compared unimpaired autosomal dominant Alzheimer's disease (AD) mutation carriers and non‐carriers.Carriers and non‐carriers did not differ in severity of depressive symptoms.In carriers, hippocampal volume was inversely associated with depressive symptoms.Depressive symptoms may be a useful target in AD prevention. [ABSTRACT FROM AUTHOR]

Using APP/PS1 mice that overproduce amyloid-β (Aβ) peptides, we investigated whether intranasal infection with a neurovirulent clinical strain of herpes simplex virus 1 (HSV-1) before Aβ deposition could accelerate or increase Alzheimer's disease-like pathology. After HSV-1 infection, APP/PS1 mice presented a similar disease as wild type animals based on body weight changes, clinical symptoms, and survival rates. The number and volume of Aβ plaques, the number of microglia, and the percentages of circulating monocyte subsets were similar in APP/PS1 mice infected or not with HSV-1. Thus, intranasal infection with HSV-1 does not alter Aβ pathology in this mouse model. [ABSTRACT FROM AUTHOR]

γ‐secretase processing of amyloid precursor protein (APP) has long been of interest in the pathological progression of Alzheimer's disease (AD) due to its role in the generation of amyloid‐β. The catalytic component of the enzyme is the presenilins of which there are two homologues, Presenilin‐1 (PS1) and Presenilin‐2 (PS2). The field has focussed on the PS1 form of this enzyme, as it is typically considered the more active at APP processing. However, much of this work has been completed without appropriate consideration of the specific levels of protein expression of PS1 and PS2. We propose that expression is an important factor in PS1‐ and PS2‐γ‐secretase activity, and that when this is considered, PS1 does not have greater activity than PS2. We developed and validated tools for quantitative assessment of PS1 and PS2 protein expression levels to enable the direct comparison of PS in exogenous and endogenous expression systems, in HEK‐293 PS1 and/or PS2 knockout cells. We show that exogenous expression of Myc‐PS1‐NTF is 5.5‐times higher than Myc‐PS2‐NTF. Quantitating endogenous PS protein levels, using a novel PS1/2 fusion standard we developed, showed similar results. When the marked difference in PS1 and PS2 protein levels is considered, we show that compared to PS1‐γ‐secretase, PS2‐γ‐secretase has equal or more activity on APP and Notch1. This study has implications for understanding the PS1‐ and PS2‐specific contributions to substrate processing, and their potential influence in AD pathogenesis. [ABSTRACT FROM AUTHOR]

BackgroundCigarette smoking is a known risk factor for Alzheimer's disease (AD). However, the association between neurodegeneration and other substances has not been fully determined. It is of vital importance to evaluate this relationship in populations at high risk of dementia. Since substance use possibly modifies the progression rate of cognitive decline, we studied this association in a unique and well-phenotyped cohort from the University of Antioquia: carriers of the PSEN1-E280A genetic variant.ObjectiveTo determine the association between substance use and cognitive decline in carriers of the PSEN1-E280A genetic variant.MethodsA retrospective cohort study was conducted with 94 carriers and 69 noncarriers recruited between January 2019 and April 2020. A psychiatrist interviewed the participants using the Consumption of Alcohol, Cigarettes and other Substances questionnaire. The participants were also submitted to cognitive evaluation. The relationship between cognitive decline and substance use was explored through a mixed effects regression model.ResultsThere was an association between cigarettes and better performance on tasks related to perceptual organization, verbal fluency, and memory in carriers. Alcohol had a positive or negative effect on memory according to the type of alcoholic beverage. Results on marijuana use were no conclusive. Coffee was associated with progressive improvements in executive function and verbal fluency.ConclusionCigarette and alcohol were associated with an improvement of some cognitive assessments, possibly by a survival bias. In addition, coffee was related to improvements in executive function and language; therefore, its short-term neuroprotective potential should be studied.

BackgroundMouse models have allowed for the direct interrogation of genetic effects on molecular, physiological, and behavioral brain phenotypes. However, it is unknown to what extent neurological or psychiatric traits may be human- or primate-specific and therefore which components can be faithfully recapitulated in mouse models.ResultsWe compare conservation of co-expression in 116 independent data sets derived from human, mouse, and non-human primate representing more than 15,000 total samples. We observe greater changes occurring on the human lineage than mouse, and substantial regional variation that highlights cerebral cortex as the most diverged region. Glia, notably microglia, astrocytes, and oligodendrocytes are the most divergent cell type, three times more on average than neurons. We show that cis-regulatory sequence divergence explains a significant fraction of co-expression divergence. Moreover, protein coding sequence constraint parallels co-expression conservation, such that genes with loss of function intolerance are enriched in neuronal, rather than glial modules. We identify dozens of human neuropsychiatric and neurodegenerative disease risk genes, such as COMT, PSEN-1, LRRK2, SHANK3, and SNCA, with highly divergent co-expression between mouse and human and show that 3D human brain organoids recapitulate in vivo co-expression modules representing several human cell types.ConclusionsWe identify robust co-expression modules reflecting whole-brain and regional patterns of gene expression. Compared with those that represent basic metabolic processes, cell-type-specific modules, most prominently glial modules, are the most divergent between species. These data and analyses serve as a foundational resource to guide human disease modeling and its interpretation.

Although pathogenic variants in PSEN1 leading to autosomal‐dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non‐carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre‐symptomatic and symptomatic phases of disease as compared to CY, using both cross‐sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ‐secretase and the generation of toxic β‐amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is one of the most common forms of dementia, is characterized by memory loss and cognitive impairment that affects more than 30 million people worldwide. The pathogenesis of Alzheimer's disease is primary driven by brain accumulation of the amyloid ß peptide generated from the amyloid-ß precursor protein (APP) via cleavages by ß- and -secretase. In this study, we propose an approach by molecular docking to select compounds as -secretase inhibitors for decreasing the APP generation. Methods: We selected potential -secretase inhibitors by molecular docking in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in presenilin-1 (PS-1), using a chemical library of over 500,000 compounds. Results: Eight compounds (AZ1 - AZ8) were selected by molecular docking to develop -secretase inhibitors for decreasing the APP generation. Conclusion: AZ1 - AZ8 compounds could be interacting in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in PS-1. These compounds could specifically interact in the binding pocket in PS-1 to prevent/decrease the APP generation, to develop a new drug against Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Introduction: Plasma‐measured tau phosphorylated at threonine 217 (p‐tau217) is a potential non‐invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p‐tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD. Methods: We analyzed baseline levels of plasma p‐tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.61 years later in non‐demented age‐ and education‐matched presenilin‐1 E280A carriers (n = 24) and non‐carrier (n = 20) family members. Results: Carriers had higher plasma p‐tau217 levels than non‐carriers. Baseline plasma p‐tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function. Discussion: Our findings suggest that plasma p‐tau217 predicts subsequent brain pathological burden and memory performance in presenilin‐1 E280A carriers. These results provide support for plasma p‐tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials. Highlights: Non‐demented presenilin‐1 E280A carriers have higher plasma tau phosphorylated at threonine 217 (p‐tau217) than do age‐matched non‐carriers.Higher baseline p‐tau217 is associated with greater future amyloid positron emission tomography (PET) pathology burden.Higher baseline p‐tau217 is associated with greater future tau PET pathology burden.Higher baseline p‐tau217 is associated with worse future memory performance. [ABSTRACT FROM AUTHOR]

Presenilin 1 (PSEN1) is a part of the gamma secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins and beta catenin. PSEN1 has been extensively studied in neurodegeneration, and more than 300 PSEN1 mutations have been discovered to date. In addition to the classical early onset Alzheimer's disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia (FTD), Parkinson's disease (PD), dementia with Lewy bodies (DLB) or spastic paraparesis (SP). For example, Leu113Pro, Leu226Phe, Met233Leu and an Arg352 duplication were discovered in patients with FTD, while Pro436Gln, Arg278Gln and Pro284Leu mutations were also reported in patients with motor dysfunctions. Interestingly, PSEN1 mutations may also impact non-neurodegenerative phenotypes, including PSEN1 Pro242fs, which could cause acne inversa, while Asp333Gly was reported in a family with dilated cardiomyopathy. The phenotypic diversity suggests that PSEN1 may be responsible for atypical disease phenotypes or types of disease other than AD. Taken together, neurodegenerative diseases such as AD, PD, DLB and FTD may share several common hallmarks (cognitive and motor impairment, associated with abnormal protein aggregates). These findings suggested that PSEN1 may interact with risk modifiers, which may result in alternative disease phenotypes such as DLB or FTD phenotypes, or through less-dominant amyloid pathways. Next-generation sequencing and/or biomarker analysis may be essential in clearly differentiating the possible disease phenotypes and pathways associated with non-AD phenotypes. [ABSTRACT FROM AUTHOR]

Abstract Background The mammalian target of rapamycin (mTOR) plays a critical role in controlling cellular homeostasis, and its dysregulation has been implicated in Alzheimer’s disease (AD). Presenilin-1 (PS1) mutations account for the most common causes of familial Alzheimer’s disease (FAD); however, whether PS1 mutation causes mTOR dysregulation in human neurons remains a key unresolved issue. Methods We generated heterozygotes and homozygotes of PS1 F105C knock-in mutation in human induced pluripotent stem cells (iPSCs) via CRISPR/Cas9/piggyback-based gene editing and differentiated them into human neurons. Secreted Aβ and tau accumulation were determined by ELISA assay, immunofluorescence staining, and western blotting analysis. mTOR signaling was evaluated by western blotting analysis, immunofluorescence staining, and co-immunoprecipitation. Autophagy/lysosome activities were determined by LC3-based assay, LysoTracker Red staining, and DQ-Red BSA staining. Results Through comparison among these isogenic neurons, PS1 F105C mutant neurons exhibited elevated Aβ and tau accumulation. In addition, we found that the response of mTORC1 to starvation decreases in PS1 F105C mutant neurons. The Akt/mTORC1/p70S6K signaling pathway remained active upon EBSS starvation, leading to the co-localization of the vast majority of mTOR with lysosomes. Consistently, PS1 F105C neurons displayed a significant decline in starvation-induced autophagy. Notably, Torin1, a mTOR inhibitor, could efficiently reduce prominent tau pathology that occurred in PS1 F105C neurons. Conclusion We demonstrate that Chinese PS1 F105C mutation causes dysregulation of mTORC1 signaling, contributing to tau accumulation in human neurons. This study on inherited FAD PS1 mutation provides unprecedented insights into our understanding of the molecular mechanisms of AD. It supports that pharmaceutical blocking of mTOR is a promising therapeutic strategy for the treatment of AD.

Alzheimer's disease (AD) is a progressive and irreversible brain disorder, which can occur either sporadically, due to a complex combination of environmental, genetic, and epigenetic factors, or because of rare genetic variants in specific genes (familial AD, or fAD). A key hallmark of AD is the accumulation of amyloid beta (Aβ) and Tau hyperphosphorylated tangles in the brain, but the underlying pathomechanisms and interdependencies remain poorly understood. Here, we identify and characterise gene expression changes related to two fAD mutations (A79V and L150P) in the Presenilin-1 (PSEN1) gene. We do this by comparing the transcriptomes of glutamatergic forebrain neurons derived from fAD-mutant human induced pluripotent stem cells (hiPSCs) and their individual isogenic controls generated via precision CRISPR/Cas9 genome editing. Our analysis of Poly(A) RNA-seq data detects 1111 differentially expressed coding and non-coding genes significantly altered in fAD. Functional characterisation and pathway analysis of these genes reveal profound expression changes in constituents of the extracellular matrix, important to maintain the morphology, structural integrity, and plasticity of neurons, and in genes involved in calcium homeostasis and mitochondrial oxidative stress. Furthermore, by analysing total RNA-seq data we reveal that 30 out of 31 differentially expressed circular RNA genes are significantly upregulated in the fAD lines, and that these may contribute to the observed protein-coding gene expression changes. The results presented in this study contribute to a better understanding of the cellular mechanisms impacted in AD neurons, ultimately leading to neuronal damage and death.

Background: Imbalance between the production and clearance of amyloid-β (Aβ) promotes the development of Alzheimer's disease (AD). Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, which is involved in the process of Aβ production. The profiles of autoantibodies are dysregulated in AD patients. Objective: This study aims to investigate the relative levels and clinical relevance of naturally occurring antibodies to PS1 (NAbs-PS1) in AD. Methods: A total of 55 subjects with AD (including both dementia and mild cognitive impairment due to AD), 28 subjects with cognitive impairment (including both dementia and mild cognitive impairment) not due to AD (non-AD CI), and 70 cognitively normal (CN) subjects were recruited. One-site ELISA was utilized to determine the relative levels of NAbs-PS1 in plasma. Results: AD subjects had lower plasma levels of NAbs-PS1 than CN and non-AD CI subjects. Plasma NAbs-PS1 were negatively associated with the brain Aβ load, as reflected by PET-PiB SUVR, and were positively associated with cognitive functions of participants. Plasma NAbs-PS1 discriminated AD patients from CN with an area under the curve (AUC) of 0.730, a sensitivity of 69.09%, and a specificity of 67.14%, and they discriminated AD patients from non-AD CI subjects with an AUC of 0.750, a specificity of 70.91%, and a sensitivity of 71.43%. Conclusion: This study found an aberrant immunological phenotype in AD patients. Further investigations are needed to determine the pathophysiological functions of NAbs-PS1 in AD. [ABSTRACT FROM AUTHOR]

Presenilin-1 (PSEN1) has been verified as an important causative factor for early onset Alzheimer's disease (EOAD). PSEN1 is a part of γ-secretase, and in addition to amyloid precursor protein (APP) cleavage, it can also affect other processes, such as Notch signaling, β-cadherin processing, and calcium metabolism. Several motifs and residues have been identified in PSEN1, which may play a significant role in γ-secretase mechanisms, such as the WNF, GxGD, and PALP motifs. More than 300 mutations have been described in PSEN1; however, the clinical phenotypes related to these mutations may be diverse. In addition to classical EOAD, patients with PSEN1 mutations regularly present with atypical phenotypic symptoms, such as spasticity, seizures, and visual impairment. In vivo and in vitro studies were performed to verify the effect of PSEN1 mutations on EOAD. The pathogenic nature of PSEN1 mutations can be categorized according to the ACMG-AMP guidelines; however, some mutations could not be categorized because they were detected only in a single case, and their presence could not be confirmed in family members. Genetic modifiers, therefore, may play a critical role in the age of disease onset and clinical phenotypes of PSEN1 mutations. This review introduces the role of PSEN1 in γ-secretase, the clinical phenotypes related to its mutations, and possible significant residues of the protein. [ABSTRACT FROM AUTHOR]

Objective To report 2 pedigrees of early⁃onset familial Alzheimer's disease (EOFAD) caused by PSEN1 gene mutation, review previous studies and summarize the PSEN1 gene mutation sites, clinical presentation and genotype characteristics of EOFAD in China. Methods and Results The clinical data of 2 pedigrees with EOFAD from Beijing Tiantan Hospital, Capital Medical University were collected. Genomic DNA from peripheral venous blood of the proband was screened. Search the reported Chinese cases of EOFAD caused by PSEN1 gene mutation. In the Case 1 family, there were 3 members with memory loss, including the proband, onset at the age of 45. His head MRI showed mild atrophy of the cerebral cortex and bilateral hippocampus. A c.488A＞G (p.His163Arg) pathogenic mutation in the exon 6 of PSEN1 gene was found, proving the diagnosis. In the Case 2 family, there were 6 members with memory and working competence loss, including the proband, onset at the age of 42. Head MRI showed whole cerebral cortical atrophy and bilateral hippocampal atrophy, obviously on the left side. A c.344A＞G (p.Tyr115Cys) pathogenic mutation in the exon 5 of PSEN1 gene was found, proving the diagnosis. A total of 40 cases (including this 2 cases) of EOFAD patients caused by PSEN1 gene mutation in China were enrolled. Thirty⁃eight pathogenic mutation sites were reported. The age of onset ranged from 21 to 62 years old, and the course of disease ranged from 4 to 10 years. About 87.50% (35/40) of the patients' onset manifestation was progressive memory loss and then rapidly with multiple cognitive domains involved. Some patients manifested with extrapyramidal symptoms, epilepsy or ear symptoms. Conclusions c.488A＞G and c.344A＞G mutations in the PSEN1 gene were identified to cause EOFAD, and c.344A＞G mutation is the first report in China. EOFAD occurs early and progresses rapidly, and sometimes the initial symptoms may be atypical. Therefore, gene detection plays an important role in the diagnosis of the disease.

Background: The mammalian target of rapamycin (mTOR) plays a critical role in controlling cellular homeostasis, and its dysregulation has been implicated in Alzheimer's disease (AD). Presenilin-1 (PS1) mutations account for the most common causes of familial Alzheimer's disease (FAD); however, whether PS1 mutation causes mTOR dysregulation in human neurons remains a key unresolved issue. Methods: We generated heterozygotes and homozygotes of PS1 F105C knock-in mutation in human induced pluripotent stem cells (iPSCs) via CRISPR/Cas9/piggyback-based gene editing and differentiated them into human neurons. Secreted Aβ and tau accumulation were determined by ELISA assay, immunofluorescence staining, and western blotting analysis. mTOR signaling was evaluated by western blotting analysis, immunofluorescence staining, and co-immunoprecipitation. Autophagy/lysosome activities were determined by LC3-based assay, LysoTracker Red staining, and DQ-Red BSA staining. Results: Through comparison among these isogenic neurons, PS1 F105C mutant neurons exhibited elevated Aβ and tau accumulation. In addition, we found that the response of mTORC1 to starvation decreases in PS1 F105C mutant neurons. The Akt/mTORC1/p70S6K signaling pathway remained active upon EBSS starvation, leading to the co-localization of the vast majority of mTOR with lysosomes. Consistently, PS1 F105C neurons displayed a significant decline in starvation-induced autophagy. Notably, Torin1, a mTOR inhibitor, could efficiently reduce prominent tau pathology that occurred in PS1 F105C neurons. Conclusion: We demonstrate that Chinese PS1 F105C mutation causes dysregulation of mTORC1 signaling, contributing to tau accumulation in human neurons. This study on inherited FAD PS1 mutation provides unprecedented insights into our understanding of the molecular mechanisms of AD. It supports that pharmaceutical blocking of mTOR is a promising therapeutic strategy for the treatment of AD. [ABSTRACT FROM AUTHOR]

Objective: Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer's disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world's largest ADAD kindred and sex differences in the relationship between SCD and memory performance. Methods: We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education. Results: Females in both groups had greater self-reported and study partner-reported SCD than males (all p < 0.001). In female mutation carriers, greater self-reported (p = 0.02) and study partner-reported SCD (p < 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported (p = 0.03), but not study partner-reported SCD (p = 0.11) was associated with worse verbal memory. Conclusions: Study partner-reported SCD may be a stronger indicator of memory decline in females versus males in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria. [ABSTRACT FROM AUTHOR]

Introduction. Amyloid plaques are one of the neuropathological markers of Alzheimer's disease, formed by peptide fragments that are deposited, derived from the protease cut of the enzyme γ-secretase, of which presenilin-1 is the subunit with the active site, it is possible to investigate at the evolutionary level what happens with this protein in a sample of hominids. Materials and methods. structural biology study is carried out to evaluate changes in the structure of the proteins modeled with the Phyre2 software and primary sequence alignments with Jalview from the hominids Pongo abelii, Pan troglodytes, Pan paniscus, Gorilla gorilla, Homo sapiens and two species used in biological tests as Macaca fascicularis, Macaca mulatta. Results. It was found that the primary sequences of isoform 467 presented very high percentages of identity with T-Coffee 2.0 of 99.57 % on average, within its primary sequence in the pairwise alignment and at the three-dimensional level, with the Needleman- Wunsch algorithm, slight changes were found in the structure at the loop level, but very conserved between species, which was also reflected in standard deviation values of the models of less than 5 Å. Conclusions. Finally, no significant changes were found at the structural level in the protein with protease function, so for the hominin sample there were no evolutionary changes, at least for this protein, and in perspective, the other components of the enzyme gamma-secretase remain to evaluate. [ABSTRACT FROM AUTHOR]

Presenilin 1 (PSEN1) is a part of the gamma secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins and beta catenin. PSEN1 has been extensively studied in neurodegeneration, and more than 300 PSEN1 mutations have been discovered to date. In addition to the classical early onset Alzheimer’s disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia (FTD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB) or spastic paraparesis (SP). For example, Leu113Pro, Leu226Phe, Met233Leu and an Arg352 duplication were discovered in patients with FTD, while Pro436Gln, Arg278Gln and Pro284Leu mutations were also reported in patients with motor dysfunctions. Interestingly, PSEN1 mutations may also impact non-neurodegenerative phenotypes, including PSEN1 Pro242fs, which could cause acne inversa, while Asp333Gly was reported in a family with dilated cardiomyopathy. The phenotypic diversity suggests that PSEN1 may be responsible for atypical disease phenotypes or types of disease other than AD. Taken together, neurodegenerative diseases such as AD, PD, DLB and FTD may share several common hallmarks (cognitive and motor impairment, associated with abnormal protein aggregates). These findings suggested that PSEN1 may interact with risk modifiers, which may result in alternative disease phenotypes such as DLB or FTD phenotypes, or through less-dominant amyloid pathways. Next-generation sequencing and/or biomarker analysis may be essential in clearly differentiating the possible disease phenotypes and pathways associated with non-AD phenotypes.

Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer's disease (AD) and in tumorigenesis. Interestingly, AD risk is inversely related to melanoma, suggesting that AD-related factors, such as PS-1, may affect melanomagenesis. PS-1 has been shown to reduce Wnt activity by promoting degradation of beta-catenin (β-catenin), an important Wnt signaling partner. Since Wnt is known to enhance progression of different cancers, including melanoma, we hypothesized that PS-1 could affect Wnt-associated melanoma aggressiveness. Western blot results showed that aggressive melanoma cells expressed significantly lower levels of both PS-1 and phosphorylated-β-catenin (P-β-catenin) than nonaggressive melanoma cells. Immunohistochemistry of human melanoma samples showed significantly reduced staining for PS-1 in advanced stage melanoma compared with early stage melanoma. Furthermore, γ-secretase inhibitor (GSI) treatment of aggressive melanoma cells was followed by significant increases in PS-1 and P-β-catenin levels, suggesting impaired Wnt signaling activity as PS-1 expression increased. Finally, a significant reduction in cell migration was associated with the higher levels of PS-1 and P-β-catenin in the GSI-treated aggressive melanoma cells. We demonstrate for the first time that PS-1 levels can be used to assess melanoma aggressiveness and suggest that by enhancing PS-1 expression, Wnt-dependent melanoma progression may be reduced [ABSTRACT FROM AUTHOR]

Mutations in the PSEN1 gene encoding presenilin-1 (PS1) protein are the most common cause of familial Alzheimer's disease. One of these, deletion of exon 9, results in the production of shortened PS1 protein (PS1ΔE9). Neuronal hyperexcitability and hyperactivation of L-type calcium channels were observed in cellular and animal models of familial Alzheimer's disease. However, the effect of PS1ΔE9 on L-type calcium channels has not been studied before. We demonstrate enhanced calcium entry through L-type calcium channels in hippocampal mouse neurons with exogenous expression of PS1ΔE9. Additionally, we show that the same effect of the exogenous PS1ΔE9 can be observed in cells with predominant expression of L-type calcium channels subunit Cav1.2. Further research is required to unravel molecular mechanisms underlying hyperactivation L-type calcium channels caused by PS1ΔE9 expression. [ABSTRACT FROM AUTHOR]

Impairment of the macroautophagy/autophagy-lysosomal pathway (ALP) can lead to amyloid plaque accumulation in Alzheimer disease (AD); however, the underlying mechanism remains unresolved. This study revealed a mechanism of ALP impairment mediated by gain-of-function of lysosomal TPCN2/TPC2 (two pore segment channel 2) and suggests a molecular target for AD intervention. Using mutant PSEN1/PS1 (presenilin 1)-expressing human neuroblastoma SH-SY5Y and familial AD fibroblasts collected from human patients, we showed lysosomal pH was increased in AD cells due to exaggerated TPCN2-mediated calcium (Ca2+) release which increases lysosomal pH and compromises ALP degradation. Genetic knockdown or pharmacological inhibition of the TPCN2 channel restored lysosomal Ca2+ homeostasis, acidity of the lysosome and ALP function. Furthermore, AD mice (5xFAD) that had received treatment with the TPCN2 inhibitor tetrandrine for 6 months or injection of AAV-shTpcn2 to knock down Tpcn2 showed reduction in amyloid plaques in cortical and hippocampal regions. These treatments also improved spine morphology and density and corrected cognitive deficits in 5xFAD mice assayed by immunohistochemistry, behavioral tests, and electrophysiological measurements, respectively. Taken together, these findings reveal a previously under-appreciated role of lysosomal TPCN2 in ALP impairment of AD. They also suggest targeting the lysosomal TPCN2 can serve as a therapeutic strategy for AD treatment in future drug development. Aβ: β-amyloid; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; ALP: autophagy-lysosomal pathway; APP: amyloid beta precursor protein; ATP6V1B1/V-ATPase V1b1: ATPase H+ transporting V1 subunit B1; AVs: autophagy vacuoles; BAF: bafilomycin A1; CFC: contextual/cued fear conditioning assay; CHX: Ca2+/H+ exchanger; CTF-β: carboxy-terminal fragment derived from β-secretase; CTSD: cathepsin D; fAD: familial Alzheimer disease; GFAP: glial fibrillary acidic protein; LAMP1: lysosomal associated membrane protein 1; LTP: long‐term potentiation; MCOLN1/TRPML1: mucolipin 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPT: microtubule associated protein tau; MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: prefrontal cortex; PSEN1: presenilin 1; SQSTM1/p62: sequestosome 1; TBS: theta burst stimulation; TEM: transmission electronic microscopy; TPCN2/TPC2: two pore segment channel 2; WT: wild-type; V-ATPase: vacuolar type H+-ATPase [ABSTRACT FROM AUTHOR]

Keywords: Presenilin-1; Alzheimer's disease; parkinsonism; motor fluctuations; levodopa-induced dyskinesia EN Presenilin-1 Alzheimer's disease parkinsonism motor fluctuations levodopa-induced dyskinesia 335 337 3 02/23/23 20230201 NES 230201 Pathogenic variants in the Presenilin 1 gene ( I PSEN1 i , OMIM#607822) represent the most frequent cause of Dominant Inherited Alzheimer's disease (DIAD),[1] with more than 200 pathogenic variants reported and associated with an age at onset before 50 years, with some cases reported even before 40.[2] Movement disorders, mainly myoclonus and parkinsonism, can occur in the early course of the disease and affect up to 30% of patients.[[2]] Furthermore, some of the cases with parkinsonism have been reported to be levodopa-responsive and to develop early motor fluctuations and dyskinesias.[4] However, I PSEN1 i variants are seldom considered in the assessment of patients with early-onset parkinsonism.[5] We describe the case of a patient with a mixed clinical phenotype of early-onset dementia and parkinsonism with motor complications due to a pathogenic variant in the I PSEN1 i gene. In summary, pathogenic variants in the I PSEN1 i gene might represent an underrecognized cause of early-onset dementia with parkinsonism that can present with marked motor fluctuations and dyskinesia. Alzheimer's disease, parkinsonism, motor fluctuations, levodopa-induced dyskinesia, Presenilin-1. [Extracted from the article]

Positron emission tomography (PET) with 18 F-Fluorodeoxyglucose ( 18 F-FDG) plays an outstanding role in the diagnostic work-up of dementia. Amyloid PET imaging is a complementary imaging technique for the early detection of Alzheimer disease (AD). β-amyloid precursor protein ( APP ), Presenilin-1 ( PSEN1 ) and Presenilin-2 ( PSEN2 ) are the 3 main causative genes responsible for autosomal dominant early-onset Alzheimer disease (EOAD). This is the first report of 18 F-Florbetapir amyloid imaging findings in a 35-year-old male patient with EOAD carrying the G378E mutation in PSEN1 gene. Brain computed tomography (CT) and magnetic resonance imaging scans showed remarkable cerebral atrophy with dilatation of the cerebrospinal fluid spaces; furthermore, a 18 F-Florbetapir PET/CT scan demonstrated also widespread remarkable accumulation of the amyloid tracer in the cerebral cortex, with reduction of the normal contrast between white and gray matter and flattening of the external cortical margins. Furthermore, PET/CT showed intense 18 F-florbetapir uptake in the striatum and in the thalamus bilaterally. Our case supports the usefulness of amyloid PET imaging in the diagnostic work-up of EOAD. [ABSTRACT FROM AUTHOR]

Objective To report 2 pedigrees of early - onset familial Alzheimer's disease (EOFAD) caused by PSEN1 gene mutation, review previous studies and summarize the PSEN1 gene mutation sites, clinical presentation and genotype characteristics of EOFAD in China. Methods and Results The clinical data of 2 pedigrees with EOFAD from Beijing Tiantan Hospital, Capital Medical University were collected. Genomic DNA from peripheral venous blood of the proband was screened. Search the reported Chinese cases of EOFAD caused by PSEN1 gene mutation. In the Case 1 family, there were 3 members with memory loss, including the proband, onset at the age of 45. His head MRI showed mild atrophy of the cerebral cortex and bilateral hippocampus. A c.488A > G (p.His163Arg) pathogenic mutation in the exon 6 of PSEN1 gene was found, proving the diagnosis. In the Case 2 family, there were 6 members with memory and working competence loss, including the proband, onset at the age of 42. Head MRI showed whole cerebral cortical atrophy and bilateral hippocampal atrophy, obviously on the left side. A c. 344A > G (p. Tyr115Cys) pathogenic mutation in the exon 5 of PSEN1 gene was found, proving the diagnosis. A total of 40 cases (including this 2 cases) of EOFAD patients caused by PSEN1 gene mutation in China were enrolled. Thirty-eight pathogenic mutation sites were reported. The age of onset ranged from 21 to 62 years old, and the course of disease ranged from 4 to 10 years. About 87.50% (35/40) of the patients' onset manifestation was progressive memory loss and then rapidly with multiple cognitive domains involved. Some patients manifested with extrapyramidal symptoms, epilepsy or ear symptoms. Conclusions c.488A > G and c.344A > G mutations in the PSEN1 gene were identified to cause EOFAD, and c.344A > G mutation is the first report in China. EOFAD occurs early and progresses rapidly, and sometimes the initial symptoms may be atypical. Therefore, gene detection plays an important role in the diagnosis of the disease. [ABSTRACT FROM AUTHOR]

Presenilin-1 (PSEN1) has been verified as an important causative factor for early onset Alzheimer’s disease (EOAD). PSEN1 is a part of γ-secretase, and in addition to amyloid precursor protein (APP) cleavage, it can also affect other processes, such as Notch signaling, β-cadherin processing, and calcium metabolism. Several motifs and residues have been identified in PSEN1, which may play a significant role in γ-secretase mechanisms, such as the WNF, GxGD, and PALP motifs. More than 300 mutations have been described in PSEN1; however, the clinical phenotypes related to these mutations may be diverse. In addition to classical EOAD, patients with PSEN1 mutations regularly present with atypical phenotypic symptoms, such as spasticity, seizures, and visual impairment. In vivo and in vitro studies were performed to verify the effect of PSEN1 mutations on EOAD. The pathogenic nature of PSEN1 mutations can be categorized according to the ACMG-AMP guidelines; however, some mutations could not be categorized because they were detected only in a single case, and their presence could not be confirmed in family members. Genetic modifiers, therefore, may play a critical role in the age of disease onset and clinical phenotypes of PSEN1 mutations. This review introduces the role of PSEN1 in γ-secretase, the clinical phenotypes related to its mutations, and possible significant residues of the protein.

Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer’s disease (AD) and in tumorigenesis. Interestingly, AD risk is inversely related to melanoma, suggesting that AD-related factors, such as PS-1, may affect melanomagenesis. PS-1 has been shown to reduce Wnt activity by promoting degradation of beta-catenin (β-catenin), an important Wnt signaling partner. Since Wnt is known to enhance progression of different cancers, including melanoma, we hypothesized that PS-1 could affect Wnt-associated melanoma aggressiveness. Western blot results showed that aggressive melanoma cells expressed significantly lower levels of both PS-1 and phosphorylated-β-catenin (P-β-catenin) than nonaggressive melanoma cells. Immunohistochemistry of human melanoma samples showed significantly reduced staining for PS-1 in advanced stage melanoma compared with early stage melanoma. Furthermore, γ-secretase inhibitor (GSI) treatment of aggressive melanoma cells was followed by significant increases in PS-1 and P-β-catenin levels, suggesting impaired Wnt signaling activity as PS-1 expression increased. Finally, a significant reduction in cell migration was associated with the higher levels of PS-1 and P-β-catenin in the GSI-treated aggressive melanoma cells. We demonstrate for the first time that PS-1 levels can be used to assess melanoma aggressiveness and suggest that by enhancing PS-1 expression, Wnt-dependent melanoma progression may be reduced

Objective: To discuss the influence of Sailuotong (, SLT) on the Neurovascular Unit (NVUs) of amyloid precursor protein (APP)/presenilin-1(PS1) mice and evaluate the role of gas supplementation in activating blood circulation during the progression of Alzheimer's disease (AD)., Methods: The mice were allocated into the following nine groups: (a) the C57 Black (C57BL) sham-operated group (control group), (b) ischaemic treatment in C57BL mice (the C57 ischaemic group), (c) the APP/PS1 sham surgery group (APP/PS1 model group), (d) ischaemic treatment in APP/PS1 mice (APP/PS1 ischaemic group), (e) C57BL mice treated with aspirin following ischaemic treatment (C57BL ischaemic + aspirin group), (f) C57BL mice treated with SLT following ischaemic treatment (C57BL ischaemic + SLT group), (g) APP/PS1 mice treated with SLT (APP/PS1 + SLT group), (h) APP/PS1 mice treated with donepezil hydrochloride following ischaemic treatment (APP/PS1 ischaemic + donepezil hydrochloride group) and (i) APP/PS1 mice treated with SLT following ischaemic treatment (APP/PS1 ischaemic + SLT group). The ischaemic model was established by operating on the bilateral common carotid arteries and creating a microembolism. The Morris water maze and step-down tests were used to detect the spatial behaviour and memory ability of mice. The hippocampus of each mouse was observed by haematoxylin and eosin (HE) and Congo red staining. The ultrastructure of NVUs in each group was observed by electron microscopy, and various biochemical indicators were detected by enzyme-linked immunosorbent assay (ELISA). The protein expression level was detected by Western blot. The mRNA expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR)., Results: The results of the Morris water maze and step-down tests showed that ischemia reduced learning and memory in the mice, which were restored by SLT. The results of HE staining showed that SLT restored the pathological changes of the NVUs. The Congo red staining results revealed that SLT also improved the scattered orange-red sediments in the upper cortex and hippocampus of the APP/PS1 and APP/PS1 ischaemic mice. Furthermore, SLT significantly reduced the content of Aβ, improved the vascular endothelium and repaired the mitochondrial structures. The ELISA detection, western blot detection and qRT-PCR showed that SLT significantly increased the vascular endothelial growth factor (VEGF), angiopoietin and basic fibroblast growth factor, as well as the levels of gene and protein expression of low-density lipoprotein receptor-related protein-1 (LRP-1) and VEGF in brain tissue., Conclusions: By increasing the expression of VEGF, SLT can promote vascular proliferation, up-regulate the expression of LRP-1, promote the clearance of Aβ and improve the cognitive impairment of APP/PS1 mice. These results confirm that SLT can improve AD by promoting vascular proliferation and Aβ clearance to protect the function of NVUs.

Introduction: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages., Methods: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition., Results: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating ® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures., Discussion: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials., Highlights: Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Proteostasis mechanisms mediated by macroautophagy/autophagy are altered in neurodegenerative diseases such as Alzheimer disease (AD) and their recovery/enhancement has been proposed as a therapeutic approach. From the two central nodes in the anabolism-catabolism balance, it is generally accepted that mechanistic target of rapamycin kinase complex 1 (MTORC1)&#95; activation leads to the inhibition of autophagy, whereas adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) has the opposite role. In AD, amyloid beta (Aβ) production disturbs the optimal neuronal/glial proteostasis. As astrocytes are essential for brain homeostasis, the purpose of this work was to analyze if the upregulation of autophagy in this cell type, either by MTORC1 inhibition or AMPK activation, could modulate the generation/degradation of β-amyloid. By using primary astrocytes from amyloid beta precursor protein (APP)/Presenilin 1 (PSEN1) mouse model of AD, we confirmed that MTORC1 inhibition reduced Aβ secretion through moderate autophagy induction. Surprisingly, pharmacologically increased activity of AMPK did not enhance autophagy but had different effects on Aβ secretion. Conversely, AMPK inhibition did not affect autophagy but reduced Aβ secretion. These puzzling data were confirmed through the overexpression of different mutant AMPK isoforms: while only the constitutively active AMPK increased autophagy, all versions augmented Aβ secretion. We conclude that AMPK has a significantly different role in primary astrocytes than in other reported cells, similar to our previous findings in neurons. Our data support that perhaps only a basal AMPK activity is needed to maintain autophagy whereas the increased activity, either physiologically or pharmacologically, has no direct effect on autophagy-dependent amyloidosis. These results shed light on the controversy about the therapeutic effect of AMPK activation on autophagy induction., (© 2023 Wiley Periodicals LLC.)