PSEN1 Mutations Research Articles

Amyloid-β can activate JNK signalling via WNT5A-ROR2 to reduce synapse formation in Alzheimer's disease.

Wnt signalling is an essential signalling system in neurogenesis, with a crucial role in synaptic plasticity and neuronal survival, processes that are disrupted in Alzheimer's disease (AD). Within this network, the Wnt/β-catenin pathway has been studied for its neuroprotective role, and this is suppressed in AD. However, the involvement of the non-canonical Wnt-planar cell polarity (Wnt/PCP) pathway in AD remains to be determined. This study investigates the role of ROR2, a Wnt/PCP co-receptor, in synaptogenesis. We demonstrate that WNT5A-ROR2 signalling activates the JNK pathway, leading to synapse loss in mature neurons. This effect mirrors the synaptotoxic actions of Aβ1-42 and DKK1, which are elevated in AD. Notably, blocking ROR2 and JNK mitigates Aβ1-42 and DKK1-induced synapse loss, suggesting their dependence on ROR2. In induced pluripotent stem cell (iPSC)-derived cortical neurons carrying a PSEN1 mutation, known to increase the Aβ42/40 ratio, we observed increased WNT5A-ROR2 clustering and reduced numbers of synapses. Inhibiting ROR2 or JNK partially rescued synaptogenesis in these neurons. These findings suggest that, unlike the Wnt/β-catenin pathway, the Wnt/PCP-ROR2 signalling pathway can operate in a feedback loop with Aβ1-42 to enhance JNK signalling and contribute to synapse loss in AD.

Altered metabolic function induced by Aβ-oligomers and PSEN1 mutations in iPSC-derived astrocytes.

Altered energy metabolism in Alzheimer's disease (AD) is a major pathological hallmark implicated in the early stages of the disease process. Astrocytes play a central role in brain homeostasis and are implicated in multiple neurodegenerative diseases. Although numerous studies have investigated global changes in brain metabolism, redox status, gene expression and epigenetic markers in AD, the intricate interplay between different metabolic processes, particularly in astrocytes, remains poorly understood. Numerous studies have implicated amyloid-β and the amyloid-β precursor in the development and progression of AD. To determine the effects of amyloid-β peptides or the impact of amyloid-β precursor protein processing on astrocyte metabolism, we differentiated astrocytes from induced pluripotent stem cells derived from people with early onset familial AD and controls. This study demonstrates that familial AD-derived astrocytes exhibit significantly more changes in their metabolism including glucose uptake, glutamate uptake and lactate release, with increases in oxidative and glycolytic metabolism compared to acute amyloid-β exposure. In addition to changes in major metabolic pathways including glutamate, purine and arginine metabolism and the citric acid cycle, we demonstrate evidence of gliosis in familial AD astrocytes highlighting a potential pathological hallmark. This suggests that chronic alterations in metabolism may occur very early in the disease process and present significant risk factors for disease progression for patients with early onset AD. These findings may also reveal important drivers of disease in late onset dementia and highlights key targets for potential diagnostic features and therapeutic agents in the future.

Comorbidities in early-onset sporadic versus presenilin-1 mutation-associated Alzheimer disease dementia: Evidence for dependency on Alzheimer disease neuropathological changes.

Studying comorbidities in early onset Alzheimer disease (AD) may provide an advantageous perspective on their pathogenesis because aging factors may be largely inoperative for these subjects. We compared AD comorbidities between early-onset sporadic cases and American and Colombian cases with PSEN1 mutations. AD neuropathological changes (ADNC) were very severe in all groups but more severe in the PSEN1 groups. Lewy body disease and cerebral white matter rarefaction were the most common (up to 60%) of AD comorbidities, followed by arteriolosclerosis (up to 37%), and large-vessel atherosclerosis (up to 20%). Differences between the 3 groups included earlier age of onset in the American PSEN1 cases, shorter disease duration in sporadic cases, and more frequent large-vessel atherosclerosis and cerebral amyloid angiopathy in the Colombian PSEN1 cases. Logistic regression models adjusted for age and sex found the presence of a PSEN1 mutation, an apolipoprotein ε4 allele and TDP-43 pathology to predict an earlier age of onset; Hispanic ethnicity and multiracial subjects were predictive of severe CAA. Comorbidities are common in early onset AD and should be considered when planning clinical trials with such subjects. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.

Evaluating the Impact of Combined Clinical and Genetic Risk Factors on Dementia Onset

AbstractBackgroundIntegrating clinical and genetic risk factors for dementia in a precision medicine framework can play a crucial role in primary prevention. Here, we ascertained the proportion of individuals who are at heightened risk of developing dementia based on their family history, genetic, and clinical risk factors and evaluated how the additive burden of these risk indicators is associated with incident dementia.MethodWe analyzed longitudinal data from 3,395 diverse older adults, dementia‐free at baseline with follow‐up and whole genome sequencing, enrolled in the National Alzheimer’s Co‐coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative (Table 1). Our risk indicators comprised: 1) self‐reported first‐degree relative with cognitive impairment; 2) carriage of the APOE*e4 allele; 3) an AD polygenic risk score, incorporating 24 variants and normalized for genetic ancestry, ranking in the top 2% (AD‐PRS); 4) presence of dominantly inherited AD mutations in PSEN1, PSEN2, or APP; and 5) a score of ≥6 on a modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (mCAIDE), comprised of age, sex, education, obesity, hypertension, and hypercholesterolemia. We calculated the total risk burden as the sum of these indicators. Cox proportional hazard models were employed to estimate the risk of dementia progression associated with increasing risk burden.ResultsAmong participants, 55% had a family history of dementia, 36% were APOE*e4 carriers, 33% had high mCAIDE scores, 2.2% had extreme AD‐PRS, and none had ADAD mutations. Distribution of risk indicators was as follows: 20% had none, 41% one, 32% two, 7.5% three, and 0.2% four (Figure 1). Our analysis revealed a graded increase in dementia risk with more indicators: compared to those with none, individuals with one, two, three, or four indicators had 1.67, 3.14, 4.41, and 15.22 times increased dementia risk, respectively (Figure 2).ConclusionThe majority of our cohort exhibited at least one dementia risk indicator, with a higher risk burden markedly increasing dementia risk. These findings underscore the value of integrating genetic and clinical risk factors in predicting dementia, highlighting the potential of precision medicine in guiding preventive strategies for at‐risk individuals.

Technical and clinical validation of a novel plasma p‐tau217 assay: evaluation in real world population‐based and racially‐diverse cohorts

AbstractBackgroundPlasma phospho‐tau217 (p‐tau217) is a promising blood‐based biomarkers for Alzheimer's disease (AD). However, the accessibility of pTau217 tests for both research and clinical applications has been constrained. Previous studies focused on highly‐phenotyped cohorts that differ substantially from the wider population. To broaden the access to this highly precise biomarker for AD, we developed a novel blood‐based immunoassay for p‐tau217 at the University of Pittsburgh (Pitt‐p‐tau217). Following thorough analytical validation, we evaluated the clinical utility of the assay in four independent real‐world cohorts (n=503 total) reflective of the wider population.MethodsA two‐step ultra‐sensitive p‐tau217 immunoassay was developed on the Quanterix HDX Simoa platform. Analytical validation focused on dilution linearity, competitive binding, day‐to‐day stability, and spike recovery. Clinical validation was performed in four cohorts including: two population‐based, racially‐diverse cohorts in medically underserved communities (the MYHAT‐Neuroimaging and Human Connectome cohorts); and a cohort of neuropathologically‐confirmed familial AD participants carrying pathogenic PSEN1 mutations. The fourth cohort included older adults >65 years attending a memory clinic. Assay performance was compared with the commercially‐available ALZpath‐p‐tau217 assay.ResultsThe new plasma Pitt‐p‐tau217 assay demonstrated high between‐run stability, linearity of dilution, and substantial signal reduction when a p‐tau217‐positive antigen was allowed to competitively bind to the p‐tau217 target in plasma samples before assay measurement. Clinically, the assay differentiated amyloid‐beta (Aβ) PET‐positive and ‐negative cognitively unimpaired individuals with areas under the curve (AUCs) of 0.84‐0.87, equivalent to 0.87‐0.90 for ALZPath and correlations of 0.40‐0.73. According to centiloids (CL), the Pitt‐p‐tau217 assay showed stepwise higher values from Aβ‐negative (CL<15) to low‐burden Aβ (CL15‐25) and Aβ‐positive (CL>25). By tau‐PET status, Pitt‐p‐tau217 was elevated in tau‐PET‐positive versus negative (P<0.001) and separated the groups with the same AUC of 0.71 as ALZpath‐p‐tau217. Furthermore, Pitt‐p‐tau217 was 5.3‐fold and 3.3‐fold higher in neuropathologically‐confirmed PSEN1 mutation carriers and sporadic AD participants respectively versus controls, with correlation of 0.93 with ALZpath‐p‐tau217.ConclusionOur results indicate that the newly‐developed Pitt‐p‐tau217 assay, the first from an academic laboratory in North America, exhibits reliable and reproducible diagnostic accuracy for identifying individuals with biological evidence of AD. Demonstration of assay performance in inclusive cohorts suggests its suitability for use in the general population.

The genetic landscape of early and late-onset Alzheimer’s disease: A review

Abstract Alzheimer’s disease(AD) is a multifactorial neurodegenerative disorder characterized by the progressive loss of neurons and synaptic dysfunction, primarily affecting the cortex and hippocampus. The etiology of AD is complex, involving the continuous and intricate interaction between genetic and non-genetic environmental factors. Genetic predisposition plays a significant role, with approximately 60-80% of AD risk attributed to hereditary factors. Familial early-onset AD(EOAD), with autosomal-dominant mutations in APP, PSEN1, and PSEN2, represents about 1-5% of cases and typically manifests before age 65. Rare autosomal-recessive mutations, like A673V(APP gene), are also implicated. Late-onset AD(LOAD), more common, is influenced by a combination of genetic and environmental factors, with the APOE ε4 allele being a major risk factor. Protective factors, such as the APOE ε2 allele and rare mutations like Ala673Thr, can reduce AD risk. The interplay between genetic variants, environmental influences, and pathological processes underpins the disease’s progression. This study highlights the importance of understanding the genetic and non-genetic determinants of AD to advance personalized treatment and early detection strategies. Future research and personalized medicine approaches are essential for mitigating AD risks and improving management outcomes.

Alzheimer's Disease: Exploring the Landscape of Cognitive Decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD is marked by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD. Currently available treatments provide symptomatic relief but do not halt disease progression. Research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD. Advances in identification and validation of reliable biomarkers for AD hold great promise for enhancing early diagnosis, monitoring disease progression, and assessing treatment response in clinical practice in effort to alleviate the burden of this devastating disease. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in Alzheimer's disease. We examine the publication landscape in effort to provide insights into current knowledge advances and developments. We also review the most discussed and emerging concepts and assess the strategies to combat the disease. We explore the genetic risk factors, pharmacological targets, and comorbid diseases. Finally, we inspect clinical applications of products against AD with their development pipelines and efforts for drug repurposing. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding AD, to outline challenges, and to evaluate growth opportunities to further efforts in combating the disease.

Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aβ production in COS cells transfected with wild-type or mutant PSEN1. The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aβ42 in PSEN1 G266S-transfected cells significantly increased. Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Pathophysiologic abnormalities in transgenic mice carrying the Alzheimer disease PSEN1 Δ440 mutation.

Mutations in PSEN1 were first discovered as a cause of Alzheimer's disease (AD) in 1995, yet the mechanism(s) by which the mutations cause disease still remains unknown. The generation of novel mouse models assessing the effects of different mutations could aid in this endeavor. Here we report on transgenic mouse lines made with the Δ440 PSEN1 mutation that causes AD with parkinsonism:- two expressing the un-tagged human protein and two expressing a HA-tagged version. Detailed characterization of these lines showed that Line 305 in particular, which expresses the untagged protein, develops age-dependent memory deficits and pathologic features, many of which are consistent with features found in AD. Key behavioral and physiological alterations found in the novel 305 line included an age-dependent deficit in spontaneous alternations in the Y-maze, a decrease in exploration of the center of an open field box, a decrease in the latency to fall on a rotarod, a reduction in synaptic strength and pair-pulse facilitation by electrophysiology, and profound alterations to cerebral blood flow regulation. The pathologic alterations found in the line included, significant neuronal loss in the hippocampus and cortex, astrogliosis, and changes in several proteins involved in synaptic and mitochondrial function, Ca2+ regulation, and autophagy. Taken together, these findings suggest that the transgenic lines will be useful for the investigation of AD pathogenesis.

Gene-variant specific effects of plasma amyloid-β levels in Swedish autosomal dominant Alzheimer disease

BackgroundSeveral blood-based biomarkers offer the opportunity of in vivo detection of brain pathology and neurodegeneration in Alzheimer disease with high specificity and sensitivity, but the performance of amyloid-β (Aβ) measurements remains under evaluation. Autosomal dominant Alzheimer disease (ADAD) with mutations in PSEN1, PSEN2 and APP can be studied as a model for sporadic Alzheimer disease. However, clarifying the genetic effects on the Aβ-levels in different matrices such as cerebrospinal fluid or plasma is crucial for generalizability and utility of data. We aimed to explore plasma Aβ concentrations over the Alzheimer disease continuum in a longitudinal cohort of genetic Alzheimer disease.Methods92 plasma samples were collected from at-risk individuals (n = 47) in a Swedish cohort of ADAD, including 18 mutation carriers (13 APPswe (p.KM670/671NL) MC), 5 PSEN1 (p.H163Y) MC) and 29 non-carriers (NC) as the reference group. Concentrations of Aβ1–38, Aβ1–40 and Aβ1–42 were analyzed in plasma using immunoprecipitation coupled to tandem liquid chromatography mass spectrometry (IP-LC-MS/MS). Cross-sectional and repeated-measures data analyses were investigated family-wise, applying non-parametric tests as well as mixed-effects models.ResultsCross-sectional analysis at baseline showed more than a 3-fold increase in all plasma Aβ peptides in APPswe MC, regardless of clinical status, compared to controls (p < 0.01). PSEN1 (p.H163Y) presymptomatic MC had a decrease of plasma Aβ1–38 compared to controls (p < 0.05). There was no difference in Aβ1–42/1–40 ratio between APPswe MC (PMC and SMC), PSEN1 MC (PMC) and controls at baseline. Notably, both cross-sectional data and repeated-measures analysis suggested that APPswe MC have a stable Aβ1–42/1–40 ratio with increasing age, in contrast to the decrease seen with aging in both controls and PSEN1 (p.H163Y) MC.ConclusionThese data show very strong mutation-specific effects on Aβ profiles in blood, most likely due to a ubiquitous production outside of the CNS. Hence, analyses in an unselected clinical setting might unintentionally disclose genetic status. Furthermore, our findings suggest that the Aβ ratio might be a poor indicator of brain Aβ pathology in selected genetic cases. The very small sample size is a limitation that needs to be considered but reflects the scarcity of longitudinal in vivo data from genetic cohorts.

Positive amyloid and tau PET in an early-onset Alzheimer's disease with a rare PSEN1 (Arg278Gly) mutation.

Positive amyloid and tau PET in an early-onset Alzheimer's disease with a rare PSEN1 (Arg278Gly) mutation.

Strategies to promote contraception use by female volunteers in Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia trial.

Including women of childbearing age in a clinical trial makes it necessary to consider two factors from a bioethical perspective: first, the lack of knowledge about the potential teratogenic effects of an investigational product, and also, the principle of justice not to exclude any population from the benefits of research. The most common way to address this issue is by requiring volunteers to use contraceptives before, during, and a few weeks after the clinical trial. This work presents all the strategies used to promote contraception use and prevent pregnancy during the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia clinical trial. Two characteristics of this trial make it of special interest for closely monitoring contraception use. One is that the trial lasted more than 7 years, and the other is that participants could be carriers of the E280A PSEN1 mutation, leading to a mild cognitive impairment as early as their late 30s. An individual medical evaluation to select the contraception method that best fits the volunteer was carried out during the screening visit, remitting to the gynecologist when necessary. All non-surgical contraception methods were supplied by the sponsor. Staff were trained on contraception counseling, correctly dispensing contraceptive drugs to volunteers, and identifying, reporting, and following up on pregnancies. Two comprehensive educational campaigns on contraception use were performed, and the intervention included all volunteers. In addition, volunteers were asked on an annual survey to evaluate the dispensing procedure. Finally, the effectiveness of these strategies was retrospectively evaluated, comparing by extrapolation the number of pregnancies presented throughout the trial with the General Fertility Rate in Colombia. A total of 159 female volunteers were recruited. All strategies were implemented as planned, even during the COVID-19 contingency. Ten pregnancies occurred during the evaluation period (2015-2021). Two were planned; the rest were associated with a potential therapeutic failure or incorrect use of contraceptive methods for a contraceptive failure of 0.49% per year. Sixty percent of pregnancies led to an abortion, either miscarriage or therapeutic abortion. However, there was not enough data to associate the pregnancy outcome with the administration of the investigational product. Finally, we observed a lower fertility rate in women participating in the trial compared to the Colombian population. The lower rates of contraceptive failure and the decrease in the incidence of pregnancies in women participating in the trial compared to the Colombian population across the 7 years of evaluation suggest that the strategies used in API ADAD Colombia were adequate and effective in addressing contraception use.

Cortical neurodegeneration caused by Psen1 mutations is independent of Aβ

Mutations in the PSEN genes are the major cause of familial Alzheimer's disease, and presenilin (PS) is the catalytic subunit of γ-secretase, which cleaves type I transmembrane proteins, including the amyloid precursor protein (APP) to release Aβ peptides. While PS plays an essential role in the protection of neuronal survival, PSEN mutations also increase the ratio of Aβ42/Aβ40. Thus, it remains unresolved whether PSEN mutations cause AD via a loss of its essential function or increases of Aβ42/Aβ40. Here, we test whether the knockin (KI) allele of Psen1 L435F, the most severe FAD mutation located closest to the active site of γ-secretase, causes age-dependent cortical neurodegeneration independent of Aβ by crossing various Psen mutant mice to the App-null background. We report that removing Aβ completely through APP deficiency has no impact on the age-dependent neurodegeneration in Psen mutant mice, as shown by the absence of effects on the reduced cortical volume and decreases of cortical neurons at the ages of 12 and 18 mo. The L435F KI allele increases Aβ42/Aβ40 in the cerebral cortex while decreasing de novo production and steady-state levels of Aβ42 and Aβ40 in the presence of APP. Furthermore, APP deficiency does not alleviate elevated apoptotic cell death in the cerebral cortex of Psen mutant mice at the ages of 2, 12, and 18 mo, nor does it affect the progressive microgliosis in these mice. Our findings demonstrate that Psen1 mutations cause age-dependent neurodegeneration independent of Aβ, providing further support for a loss-of-function pathogenic mechanism underlying PSEN mutations.

Early blood immune molecular alterations in cynomolgus monkeys with a PSEN1 mutation causing familial Alzheimer's disease.

More robust non-human primate models of Alzheimer's disease (AD) will provide new opportunities to better understand the pathogenesis and progression of AD. We designed a CRISPR/Cas9 system to achieve precise genomic deletion of exon 9 in cynomolgus monkeys using two guide RNAs targeting the 3' and 5' intron sequences of PSEN1 exon 9. We performed biochemical, transcriptome, proteome, and biomarker analyses to characterize the cellular and molecular dysregulations of this non-human primate model. We observed early changes of AD-related pathological proteins (cerebrospinal fluid Aβ42 and phosphorylated tau) in PSEN1 mutant (ie, PSEN1-ΔE9) monkeys. Blood transcriptome and proteome profiling revealed early changes in inflammatory and immune molecules in juvenile PSEN1-ΔE9 cynomolgus monkeys. PSEN1 mutant cynomolgus monkeys recapitulate AD-related pathological protein changes, and reveal early alterations in blood immune signaling. Thus, this model might mimic AD-associated pathogenesis and has potential utility for developing early diagnostic and therapeutic interventions. A dual-guide CRISPR/Cas9 system successfully mimics AD PSEN1-ΔE9 mutation by genomic excision of exon 9. PSEN1 mutant cynomolgus monkey-derived fibroblasts exhibit disrupted PSEN1 endoproteolysis and increased Aβ secretion. Blood transcriptome and proteome profiling implicate early inflammatory and immune molecular dysregulation in juvenile PSEN1 mutant cynomolgus monkeys. Cerebrospinal fluid from juvenile PSEN1 mutant monkeys recapitulates early changes of AD-related pathological proteins (increased Aβ42 and phosphorylated tau).

Presenilin deficiency enhances tau phosphorylation and its secretion.

Alzheimer's disease (AD) is characterized by the accumulation of abnormally folded amyloid β-protein (Aβ) in the brain parenchyma and phosphorylated tau in neurons. Presenilin (PS, PSEN) 1 and PS2 are essential components of γ-secretase, which is responsible for the cleavage of amyloid precursor protein (APP) to generate Aβ. PSEN mutations are associated with tau aggregation in frontotemporal dementia, regardless of the presence or absence of Aβ pathology. However, the mechanism by which PS regulates tau aggregation is still unknown. Here, we found that tau phosphorylation and secretion were significantly increased in PS double-knock-out (PS1/2-/-) fibroblasts compared with wild-type fibroblasts. Tau-positive vesicles in the cytoplasm were significantly increased in PS1/2-/- fibroblasts. Active GSK-3β was increased in PS1/2-/- fibroblasts, and inhibiting GSK3β activity in PS1/2-/- fibroblasts resulted in decreased tau phosphorylation and secretion. Transfection of WT human PS1 and PS2 reduced the secretion of phosphorylated tau and active GSK-3β in PS1/2-/- fibroblasts. However, PS1D257A without γ-secretase activity did not decrease the secretion of phosphorylated tau. Furthermore, nicastrin deficiency also increased tau phosphorylation and secretion. These results suggest that deficient PS complex maturation may increase tau phosphorylation and secretion. Thus, our studies discover a new pathway by which PS regulates tau phosphorylation/secretion and pathology independent of Aβ and suggest that PS serves as a potential therapeutic target for treating neurodegenerative diseases involving tau aggregation.

Mutational Landscape of Alzheimer's Disease and Frontotemporal Dementia: Regional Variances in Northern, Central, and Southern Italy.

Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are the two major neurodegenerative diseases with distinct clinical and neuropathological profiles. The aim of this report is to conduct a population-based investigation in well-characterized APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 mutation carriers/pedigrees from the north, the center, and the south of Italy. We retrospectively analyzed the data of 467 Italian individuals. We identified 21 different GRN mutations, 20 PSEN1, 11 MAPT, 9 PSEN2, and 4 APP. Moreover, we observed geographical variability in mutation frequencies by looking at each cohort of participants, and we observed a significant difference in age at onset among the genetic groups. Our study provides evidence that age at onset is influenced by the genetic group. Further work in identifying both genetic and environmental factors that modify the phenotypes in all groups is needed. Our study reveals Italian regional differences among the most relevant AD/FTD causative genes and emphasizes how the collaborative studies in rare diseases can provide new insights to expand knowledge on genetic/epigenetic modulators of age at onset.

Presenilin-1 ΔE9 mutation associated sarcoplasmic reticulum leak alters [Ca2+]i distribution in human iPSC-derived cardiomyocytes

Mutations in ubiquitously expressed presenilin genes (PSENs) lead to early-onset familial Alzheimer's disease (FAD), but patients carrying the mutation also suffer from heart diseases. To elucidate the cardiac myocyte specific effects of PSEN ΔE9, we studied cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) from patients carrying AD-causing PSEN1 exon 9 deletion (PSEN1 ΔE9). When compared with their isogenic controls, PSEN1 ΔE9 cardiomyocytes showed increased sarcoplasmic reticulum (SR) Ca2+ leak that was resistant to blockage of ryanodine receptors (RyRs) by tetracaine or inositol-3-reseceptors (IP3Rs) by 2-ABP. The SR Ca2+ leak did not affect electrophysiological properties of the hiPSC-CMs, but according to experiments and in silico simulations the leak induces a diastolic buildup of [Ca2+] near the perinuclear SR and reduces the releasable Ca2+ during systole. This demonstrates that PSEN1 ΔE9 induced SR Ca2+ leak has specific effects in iPSC-CMs, reflecting their unique structural and calcium signaling features. The results shed light on the physiological and pathological mechanisms of PSEN1 in cardiac myocytes and explain the intricacies of comorbidity associated with AD-causing mutations in PSEN1.

The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations.

Familial Alzheimer's disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneity will enhance our understanding of the mechanisms of AD more widely. To determine the pathogenicity of the unclassified PSEN1 P436S mutation, we studied an expanded kindred of eight affected individuals, with magnetic resonance imaging (MRI) (two individuals), patient-derived induced pluripotent stem cell (iPSC) models (two donors), and post-mortem histology (one donor). An autosomal dominant pattern of inheritance of fAD was seen, with an average age at symptom onset of 46 years and atypical features. iPSC models and post-mortem tissue supported high production of amyloid beta 43 (Aβ43). PSEN1 peptide maturation was unimpaired. We confirm that the P436S mutation in PSEN1 causes atypical fAD. The location of the mutation in the critical PSEN1 proline-alanine-leucine-proline (PALP) motif may explain the early age at onset despite appropriate protein maturation. PSEN1 P436S mutations cause familial Alzheimer's disease. This mutation is associated with atypical clinical presentation. Induced pluripotent stem cells (iPSCs) and post-mortem studies support increased amyloid beta (Aβ43) production. Early age at onset highlights the importance of the PALP motif in PSEN1 function.

Familial Alzheimer's Disease Neurons Bearing Mutations in PSEN1 Display Increased Calcium Responses to AMPA as an Early Calcium Dysregulation Phenotype.

Familial Alzheimer's disease (FAD) can be caused by mutations in PSEN1 that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca2+) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess the early calcium and glutamate phenotypes of FAD by measuring the Ca2+ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA, and kainate compared to isogenic control and healthy lines. The data show that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca2+ responses to glutamate and AMPA, but not NMDA or kainate. Together, this suggests that PSEN1 mutations alter Ca2+ and glutamate signaling as an early phenotype of FAD.

Autosomal Dominant Alzheimer's Disease Mutations in Human Microglia Are Not Sufficient to Trigger Amyloid Pathology in WT Mice but Might Affect Pathology in 5XFAD Mice.

Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer's Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein (APP) or the presenilin (PSEN1/2) genes has not been addressed in microglia in vivo. We xenotransplanted human microglia derived from non-carriers and carriers of autosomal dominant AD (ADAD)-causing mutations in the brain of hCSF1 WT or 5XFAD mice. We observed that ADAD mutations in microglia are not sufficient to trigger amyloid pathology in WT mice. In 5XFAD mice, we observed a non-statistically significant increase in amyloid plaque volume and number of dystrophic neurites, coupled with a reduction in plaque-associated microglia in the brain of mice xenotransplanted with ADAD human microglia compared to mice xenotransplanted with non-ADAD microglia. In addition, we observed a non-statistically significant impairment in working and contextual memory in 5XFAD mice xenotransplanted with ADAD microglia compared to those xenotransplanted with non-ADAD-carrier microglia. We conclude that, although not sufficient to initiate amyloid pathology in the healthy brain, mutations in APP and PSEN1 in human microglia might cause mild changes in pathological and cognitive outcomes in 5XFAD mice in a manner consistent with increased AD risk.