scholarly journals Genetic analyses of SERPINA5 in Alzheimer’s disease

2021 ◽  
Author(s):  
Billie J. Matchett ◽  
Sarah J. Lincoln ◽  
Matt Baker ◽  
Nikoleta Tamvaka ◽  
Janisse Cabrera-Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Duration ◽  
Age Of Onset ◽  
Positive Family History ◽  
Neuronal Loss ◽  
Missense Variant ◽  
Brain Regions ◽  
Allelic Frequency ◽  
Genomic Databases

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Our previous studies have shown that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in AD, and that the SERPINA5 protein binds to tau and co-localizes within neurofibrillary tangles. To determine if genetic variants in the SERPINA5 gene may be contributing to this phenotype, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. We observed one individual with a rare missense variant (rs140138746) in the SERPINA5 gene, resulting in an amino acid change (p.E228Q). We screened a further 1170 neuropathologically diagnosed AD cases and identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.002141 within our AD validation cohort, which was comparable to online genomic databases. Although not significant, SERPINA5 p.E228Q variant carriers were found to be younger at age of onset and age of death than non-carriers. SERPINA5 p.E228Q variant carriers had a longer disease duration than non-carriers, which approached significance. To further elucidate possible neuropathologic contributions of the SERPINA5 p.E228Q variant, we carried out descriptive neuropathologic burden analysis on a variant carrier that was matched to a non-carrier for age, sex, disease duration, Braak tangle stage, TDP-43 positive status, and who possessed an APOE ε4 risk allele. Interestingly, SERPINA5 burden was lower in the SERPINA5 p.E228Q carrier than the non-carrier in 9 corticolimbic brain regions studied, which exaggerated the tau:SERPINA5 immunohistochemical ratio. The SERPINA5 p.E228Q carrier was observed to have more severe neuronal loss in several brain regions compared to the non-carrier. Together, we cautiously interpret these findings to suggest that the SERPINA5 p.E228Q variant may stall tangle maturity and slow AD disease progression, thus prolonging disease duration in these individuals.

scholarly journals Exome-wide age-of-onset analysis reveals exonic variants in ERN1, TACR3 and SPPL2C associated with Alzheimer’s disease

2020 ◽  
Author(s):  
Liang He ◽  
Yury Loika ◽  
Yongjin Park ◽  
David A. Bennett ◽  
Manolis Kellis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variants ◽  
Age Of Onset ◽  
Missense Variant ◽  
Brain Regions ◽  
Posterior Cingulate Cortex ◽  
Minor Allele ◽  
Eqtl Analysis ◽  
Apoe Ε4

AbstractDespite recent discovery in GWAS of genomic variants associated with Alzheimer’s disease (AD), its underlying biological mechanisms are still elusive. Discovery of novel AD-associated genetic variants, particularly in coding regions and from APOE ε4 non-carriers, is critical for understanding the pathology of AD. In this study, we carried out an exome-wide association analysis of age-of-onset of AD with ~20,000 subjects and placed more emphasis on APOE ε4 non-carriers. Using Cox mixed-effects models, we find that age-of-onset shows a stronger genetic signal than AD case-control status, capturing many known variants with stronger significance, and also revealing new variants. We identified two novel rare variants, rs56201815, a synonymous variant in ERN1, from the analysis of APOE ε4 non-carriers, and a missense variant rs144292455 in TACR3. In addition, we detected rs12373123, a common missense variant in SPPL2C in the MAPT region in APOE ε4 non-carriers. In an attempt to unravel their regulatory and biological functions, we found that the minor allele of rs56201815 was associated with lower average FDG uptake across five brain regions in ADNI. Our eQTL analyses based on 6198 gene expression samples from ROSMAP and GTEx revealed that the minor allele of rs56201815 was associated with elevated expression of ERN1, a key gene triggering unfolded protein response (UPR), in multiple brain regions, including posterior cingulate cortex and nucleus accumbens. Our cell-type-specific eQTL analysis of based on ~80,000 single nuclei in the prefrontal cortex revealed that the protective minor allele of rs12373123 significantly increased expression of GRN in microglia, and was associated with MAPT expression in astrocytes. These findings provide novel evidence supporting the hypothesis of the potential involvement of the UPR to ER stress in the pathological pathway of AD, and also give more insights into underlying regulatory mechanisms behind the pleiotropic effects of rs12373123 in multiple degenerative diseases including AD and Parkinson’s disease.

scholarly journals Exome-wide age-of-onset analysis reveals exonic variants in ERN1 and SPPL2C associated with Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liang He ◽  
◽  
Yury Loika ◽  
Yongjin Park ◽  
David A. Bennett ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age Of Onset ◽  
Association Studies ◽  
Missense Variant ◽  
Brain Regions ◽  
Posterior Cingulate Cortex ◽  
Minor Allele ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies

AbstractDespite recent discoveries in genome-wide association studies (GWAS) of genomic variants associated with Alzheimer’s disease (AD), its underlying biological mechanisms are still elusive. The discovery of novel AD-associated genetic variants, particularly in coding regions and from APOEε4 non-carriers, is critical for understanding the pathology of AD. In this study, we carried out an exome-wide association analysis of age-of-onset of AD with ~20,000 subjects and placed more emphasis on APOEε4 non-carriers. Using Cox mixed-effects models, we find that age-of-onset shows a stronger genetic signal than AD case-control status, capturing many known variants with stronger significance, and also revealing new variants. We identified two novel variants, rs56201815, a rare synonymous variant in ERN1, and rs12373123, a common missense variant in SPPL2C in the MAPT region in APOEε4 non-carriers. Besides, a rare missense variant rs144292455 in TACR3 showed the consistent direction of effect sizes across all studies with a suggestive significant level. In an attempt to unravel their regulatory and biological functions, we found that the minor allele of rs56201815 was associated with lower average FDG uptake across five brain regions in ADNI. Our eQTL analyses based on 6198 gene expression samples from ROSMAP and GTEx revealed that the minor allele of rs56201815 was potentially associated with elevated expression of ERN1, a key gene triggering unfolded protein response (UPR), in multiple brain regions, including the posterior cingulate cortex and nucleus accumbens. Our cell-type-specific eQTL analysis using ~80,000 single nuclei in the prefrontal cortex revealed that the protective minor allele of rs12373123 significantly increased the expression of GRN in microglia, and was associated with MAPT expression in astrocytes. These findings provide novel evidence supporting the hypothesis of the potential involvement of the UPR to ER stress in the pathological pathway of AD, and also give more insights into underlying regulatory mechanisms behind the pleiotropic effects of rs12373123 in multiple degenerative diseases including AD and Parkinson’s disease.

scholarly journals Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Boris Guennewig ◽  
Julia Lim ◽  
Lee Marshall ◽  
Andrew N. McCorkindale ◽  
Patrick J. Paasila ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Sequencing ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Post Mortem ◽  
Tau Pathology ◽  
Membrane Spanning ◽  
Immune Related Genes ◽  
Vesicle Secretion

AbstractTau pathology in Alzheimer’s disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The ‘early’ AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

scholarly journals Ceramide and Related-Sphingolipid Levels Are Not Altered in Disease-Associated Brain Regions of APPSLand APPSL/PS1M146LMouse Models of Alzheimer's Disease: Relationship with the Lack of Neurodegeneration?

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Laurence Barrier ◽  
Bernard Fauconneau ◽  
Anastasia Noël ◽  
Sabrina Ingrand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Neuronal Death ◽  
Time Course ◽  
Neuronal Loss ◽  
Brain Regions ◽  
App Processing ◽  
Ceramide Accumulation ◽  
The Brain

There is evidence linking sphingolipid abnormalities, APP processing, and neuronal death in Alzheimer's disease (AD). We previously reported a strong elevation of ceramide levels in the brain of the APPSL/PS1Ki mouse model of AD, preceding the neuronal death. To extend these findings, we analyzed ceramide and related-sphingolipid contents in brain from two other mouse models (i.e., APPSLand APPSL/PS1M146L) in which the time-course of pathology is closer to that seen in most currently available models. Conversely to our previous work, ceramides did not accumulate in disease-associated brain regions (cortex and hippocampus) from both models. However, the APPSL/PS1Ki model is unique for its drastic neuronal loss coinciding with strong accumulation of neurotoxic Aβisoforms, not observed in other animal models of AD. Since there are neither neuronal loss nor toxic Aβspecies accumulation in APPSLmice, we hypothesized that it might explain the lack of ceramide accumulation, at least in this model.

scholarly journals Spatiotemporal activation of the C/EBPβ/δ-secretase axis regulates the pathogenesis of Alzheimer’s disease

2018 ◽  
Vol 115 (52) ◽  
pp. E12427-E12434 ◽  
Author(s):  
Hualong Wang ◽  
Xia Liu ◽  
Shengdi Chen ◽  
Keqiang Ye
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Dependent Manner ◽  
Chronic Neuroinflammation ◽  
Factor C ◽  
The Brain ◽  
Ad Mouse Model

Alzheimer’s disease (AD) neuropathological hallmarks include senile plaques with aggregated amyloid beta as a major component, neurofibrillary tangles (NFT) containing truncated and hyperphosphorylated Tau, extensive neuronal loss, and chronic neuroinflammation. However, the key molecular mechanism that dominates the pathogenesis of AD remains elusive for AD. Here we show that the C/EBPβ/δ-secretase axis is activated in an age-dependent manner in different brain regions of the 3×Tg AD mouse model, elevating δ-secretase–truncated APP and Tau proteolytic truncates and promoting senile plaques and NFT formation in the brain, associated with gradual neuronal loss and chronic neuroinflammation. Depletion of inflammatory cytokine-regulated transcription factor C/EBPβ from 3×Tg mice represses APP, Tau, and δ-secretase expression, which subsequently inhibits APP and Tau cleavage, leading to mitigation of AD pathologies. Knockout of δ-secretase from 3×Tg mice strongly blunts AD pathogenesis. Consequently, inactivation of the C/EBPβ/δ-secretase axis ameliorates cognitive dysfunctions in 3×Tg mice by blocking APP and Tau expression and their pathological fragmentation. Thus, our findings support the notion that C/EBPβ/δ-secretase axis plays a crucial role in AD pathogenesis.

scholarly journals Cortical developmental abnormalities in logopenic variant primary progressive aphasia with dyslexia

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Zachary A Miller ◽  
Salvatore Spina ◽  
Mikhail Pakvasa ◽  
Lynne Rosenberg ◽  
Christa Watson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age Of Onset ◽  
Primary Progressive Aphasia ◽  
Later Life ◽  
Brain Regions ◽  
Developmental Abnormalities ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Underlying Pathology

Abstract An increased prevalence of dyslexia has been observed in individuals diagnosed with primary progressive aphasia, most notably the logopenic variant primary progressive aphasia. The underlying pathology most commonly associated with logopenic variant primary progressive aphasia is Alzheimer’s disease. In this clinical case report series, we describe the neuropathological findings of three patients with logopenic variant primary progressive aphasia and developmental dyslexia, each demonstrating a pattern of cerebrocortical microdysgenesis, reminiscent of findings first reported in dyslexic individuals, alongside expected Alzheimer’s disease pathology. Neurodevelopmental and most severe Alzheimer’s disease pathological changes overlapped within perisylvian brain regions, areas associated with phonological deficits in both logopenic variant primary progressive aphasia and dyslexia. These three cases with pathological findings support the hypothesis that early-life neurodevelopmental changes might influence later-life susceptibility to neurodegenerative disease and could contribute to non-amnestic, early age-of-onset presentations of Alzheimer’s disease. Larger studies investigating neurobiological vulnerability across the lifespan are needed.

scholarly journals PLCG2 as a Risk Factor for Alzheimer’s Disease

2020 ◽  
Author(s):  
Andy P. Tsai ◽  
Chuanpeng Dong ◽  
Christoph Preuss ◽  
Miguel Moutinho ◽  
Peter Bor-Chian Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Immune Cell ◽  
Missense Variant ◽  
Brain Regions ◽  
Disease Pathogenesis ◽  
Surface Receptors ◽  
The Brain ◽  
Brain Amyloid Deposition

AbstractAlzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Indeed, genetic variants in microglial genes are linked to risk for AD. Phospholipase C γ 2 (PLCG2) participates in the transduction of signals emanating from immune cell-surface receptors that regulate the inflammatory response and is selectively expressed by microglia in the brain. A rare variant in PLCG2 (P522R) was previously found to be protective against AD, indicating that PLCG2 may play a role in AD pathophysiology. Here, we report that a rare missense variant in PLCG2 confers increased AD risk (p=0.047; OR=1.164 [95% CI=1.002-1.351]). Additionally, we observed that PLCG2 expression levels are increased in several brain regions of AD patients, correlating with brain amyloid deposition. This provides further evidence that PLCG2 may play an important role in AD pathophysiology. Together, our findings indicate that PLCG2 is a potential new therapeutic target for AD.

scholarly journals Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome

2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Jerzy Wegiel ◽  
Michael Flory ◽  
Izabela Kuchna ◽  
Krzysztof Nowicki ◽  
Jarek Wegiel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Functional Decline ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Strongly Correlated ◽  
Full Spectrum ◽  
Fourth Decade ◽  
Intellectual Deficits

AbstractThe increased life expectancy of individuals with Down syndrome (DS) is associated with increased prevalence of trisomy 21–linked early-onset Alzheimer’s disease (EOAD) and dementia. The aims of this study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26–72 years of age were to identify the magnitude of brain region–specific developmental neuronal deficits contributing to intellectual deficits, to apply this baseline to identification of the topography and magnitude of neurodegeneration and neuronal and volume losses caused by EOAD, and to establish age-based staging of the pattern of genetically driven neuropathology in DS. Both DS subject age and stage of dementia, themselves very strongly correlated, were strong predictors of an AD-associated decrease of the number of neurons, considered a major contributor to dementia. The DS cohort was subclassified by age as pre-AD stage, with 26–41-year-old subjects with a full spectrum of developmental deficit but with very limited incipient AD pathology, and 43–49, 51–59, and 61–72-year-old groups with predominant prevalence of mild, moderately severe, and severe dementia respectively. This multiregional study revealed a 28.1% developmental neuronal deficit in DS subjects 26–41 years of age and 11.9% AD-associated neuronal loss in DS subjects 43–49 years of age; a 28.0% maximum neuronal loss at 51–59 years of age; and a 11.0% minimum neuronal loss at 61–72 years of age. A total developmental neuronal deficit of 40.8 million neurons and AD-associated neuronal loss of 41.6 million neurons reflect a comparable magnitude of developmental neuronal deficit contributing to intellectual deficits, and AD-associated neuronal loss contributing to dementia. This highly predictable pattern of pathology indicates that successful treatment of DS subjects in the fourth decade of life may prevent AD pathology and functional decline.

scholarly journals A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Rongcan Luo ◽  
Yu Fan ◽  
Jing Yang ◽  
Maosen Ye ◽  
Deng-Feng Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Neurofibrillary Tangle ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Missense Variant ◽  
Lysosomal Function

AbstractAlzheimer’s disease (AD) is characterized by progressive synaptic dysfunction, neuronal death, and brain atrophy, with amyloid-β (Aβ) plaque deposits and hyperphosphorylated tau neurofibrillary tangle accumulation in the brain tissue, which all lead to loss of cognitive function. Pathogenic mutations in the well-known AD causal genes including APP, PSEN1, and PSEN2 impair a variety of pathways, including protein processing, axonal transport, and metabolic homeostasis. Here we identified a missense variant rs117916664 (c.896T>C, p.Asn299Ser [p.N299S]) of the acetyl-CoA acyltransferase 1 (ACAA1) gene in a Han Chinese AD family by whole-genome sequencing and validated its association with early-onset familial AD in an independent cohort. Further in vitro and in vivo evidence showed that ACAA1 p.N299S contributes to AD by disturbing its enzymatic activity, impairing lysosomal function, and aggravating the Aβ pathology and neuronal loss, which finally caused cognitive impairment in a murine model. Our findings reveal a fundamental role of peroxisome-mediated lysosomal dysfunction in AD pathogenesis.

scholarly journals Seizures in Alzheimer’s disease are highly recurrent and associated with a poor disease course

2020 ◽  
Vol 267 (10) ◽  
pp. 2941-2948
Author(s):  
Jonathan Vöglein ◽  
Ingrid Ricard ◽  
Soheyl Noachtar ◽  
Walter A. Kukull ◽  
Marianne Dieterich ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Duration ◽  
Functional Performance ◽  
Age Of Onset ◽  
Recurrence Risk ◽  
Cognitive Symptoms ◽  
Seizure Recurrence ◽  
Therapeutic Decisions ◽  
Increased Risk

Abstract Background Seizures are an important comorbidity in Alzheimer’s disease (AD). Conflicting results regarding clinical parameters associated with seizures in AD were previously reported. Data on seizure recurrence risk, a crucial parameter for treatment decisions, are lacking. Methods National Alzheimer’s Coordinating Center data were analyzed. Seizure prevalence in AD and an association with disease duration were investigated. Associations of seizures with age of AD onset and with cognitive and functional performance, and seizure recurrence risk were studied. Results 20,745 individuals were investigated. In AD dementia, seizure recurrence risk was 70.4% within 7.5 months. Seizure history was associated with an earlier age of onset of cognitive symptoms (seizures vs. no seizures: 64.7 vs. 70.4 years; p < 0.0001) and worse cognitive and functional performance (mean MMSE score: 16.6 vs. 19.6; mean CDR-sum of boxes score: 9.3 vs. 6.8; p < 0.0001; adjusted for disease duration and age). Seizure prevalence increased with duration of AD dementia (standardized OR = 1.55, 95% CI = 1.39–1.73, p < 0.0001), rising from 1.51% at 4.8 years to 5.43% at 11 years disease duration. Seizures were more frequent in AD dementia compared to normal controls (active seizures: 1.51% vs. 0.35%, p < 0.0001, OR = 4.34, 95% CI = 3.01–6.27; seizure history: 3.14% vs. 1.57%, p < 0.0001, OR = 2.03, 95% CI = 1.67–2.46). Conclusion Seizures in AD dementia feature an exceptionally high recurrence risk and are associated with a poor course of cognitive symptoms. AD patients are at an increased risk for seizures, particularly in later disease stages. Our findings emphasize a need for seizure history assessment in AD, inform individual therapeutic decisions and underline the necessity of systematic treatment studies of AD-associated epilepsy.

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