Alzheimer disease: modeling an Aβ-centered biological network

Campion, Dominique; Pottier, Cyril; Nicolas, Gaël; Guennec, Kilan Le; Rovelet‐Lecrux, Anne

doi:10.1038/mp.2016.38

Cited by 48 publications

(39 citation statements)

References 180 publications

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“…Since its formulation in the early 1990s, the amyloid hypothesis has been somewhat refined but remains the most influential conceptual framework for AD [58]. Centered on Aβ, Campion et al manually curated a biological network of 335 genes/proteins which have been shown to interfere with Aβ production, clearance, aggregation, or toxicity, including amyloid precursor protein APP , beta-secretase BACE1 , gamma-secretases PSEN1 / PSEN2 , and Aβ clearance proteins like APOE and CLU (reviewed in [59]). Of these 335 genes, 330 were profiled by the current microarray dataset.…”

Section: Resultsmentioning

confidence: 99%

Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease

Wang¹,

Roussos²,

McKenzie³

et al. 2016

Genome Med

242

279

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BackgroundAlzheimer’s disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. However, despite extensive clinical and genomic studies, the molecular basis of AD development and progression remains elusive.MethodsTo elucidate molecular systems associated with AD, we developed a large scale gene expression dataset from 1053 postmortem brain samples across 19 cortical regions of 125 individuals with a severity spectrum of dementia and neuropathology of AD. We excluded brain specimens that evidenced neuropathology other than that characteristic of AD. For the first time, we performed a pan-cortical brain region genomic analysis, characterizing the gene expression changes associated with a measure of dementia severity and multiple measures of the severity of neuropathological lesions associated with AD (neuritic plaques and neurofibrillary tangles) and constructing region-specific co-expression networks. We rank-ordered 44,692 gene probesets, 1558 co-expressed gene modules and 19 brain regions based upon their association with the disease traits.ResultsThe neurobiological pathways identified through these analyses included actin cytoskeleton, axon guidance, and nervous system development. Using public human brain single-cell RNA-sequencing data, we computed brain cell type-specific marker genes for human and determined that many of the abnormally expressed gene signatures and network modules were specific to oligodendrocytes, astrocytes, and neurons. Analysis based on disease severity suggested that: many of the gene expression changes, including those of oligodendrocytes, occurred early in the progression of disease, making them potential translational/treatment development targets and unlikely to be mere bystander result of degeneration; several modules were closely linked to cognitive compromise with lesser association with traditional measures of neuropathology. The brain regional analyses identified temporal lobe gyri as sites associated with the greatest and earliest gene expression abnormalities.ConclusionsThis transcriptomic network analysis of 19 brain regions provides a comprehensive assessment of the critical molecular pathways associated with AD pathology and offers new insights into molecular mechanisms underlying selective regional vulnerability to AD at different stages of the progression of cognitive compromise and development of the canonical neuropathological lesions of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0355-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease

Wang¹,

Roussos²,

McKenzie³

et al. 2016

Genome Med

242

279

View full text Add to dashboard Cite

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“…Its aggregation in cerebromeningeal vessels leads to cerebral amyloid angiopathy (CAA), a condition frequently associated with AD and responsible for recurrent haemorrhagic strokes and white matter lesions. PSEN1 and PSEN2 encode the presenilins, which constitute the catalytic subunit of the γ-secretase complex (for review, see [10,11]). AD-EOAD causative mutations are thought to be responsible for the increased aggregation of the Aβ peptide in the brain’s parenchyma through one of the two following mechanisms: increased overall production of all Aβ species (e.g., APP duplications or APP mutations located around the β cleavage site) or production of a more aggregation-prone form of the Aβ peptide.…”

Section: Introductionmentioning

confidence: 99%

APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases

et al. 2017

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BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012–2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers—total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42—in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

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“…a combination of factors whose effects are cumulative over a single susceptibility curve [27] . This assumption is in contradiction with current knowledge on AD susceptibility with diverse pathways reported to converge and probably interact towards Aβ toxicity [3] .…”

Section: Introductionmentioning

confidence: 62%

“…According to the amyloid cascade [1] , in AD the killer is Tau, Aβ being the trigger [2] . Note that according to this framework, protein-altering variants of virtually all genes encoding a protein involved in the regulation of APP processing, Aβ secretion, clearance, or toxicity may influence the AD pathophysiological process and therefore be part of the genetic determinism of AD [3] .…”

Section: Introductionmentioning

confidence: 99%

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

Nicolas

Charbonnier²,

Campion³

2016

Hum Hered

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Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants.

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Alzheimer disease: modeling an Aβ-centered biological network

Cited by 48 publications

References 180 publications

Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease

Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease

APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

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